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Different Genospecies of Borrelia burgdorferi Are Associated with Distinct Clinical Manifestations of Lyme Borreliosis
Abstract
Borrelia burgdorferi sensu lato has been subdivided into three genospecies: B. burgdorferi sensu stricto, B. garinii, and B. burgdorferi group VS461. Sixty-eight isolates cultured from patients and 26 strains from ticks were characterized with use of SDS-PAGE,
western blotting, and rRNA gene restriction analysis. Fifty-seven of 58 strains obtained from the skin of 70 patients who
had erythema migrans or acrodermatitis chronica atrophicans were of group VS461, whereas the genotype of the remaining strain
was unidentifiable. Of 10 strains cultured from CSF (n = 3) and skin (n = 7) of 20 patients with extracutaneous symptoms of Lyme borreliosis, nine were B. garinii and one was B. burgdorferi sensu stricto. Of these 20 patients, 17 had neuroborreliosis, one had arthritis and carditis, one had myalgia, and one had
erythema and arthralgia. All 26 isolates from ticks were of group VS461. In conclusion, infections due to group VS461 and
B. garinii are associated with cutaneous and extracutaneous symptoms, respectively. Our findings suggest that B. burgdorferi genotypes have different pathogenic potentials.
... For example, all Borreliella spirochetes cause LD, but the clinical manifestations of LD vary based on the infecting genotype. B. burgdorferi is strongly associated with LA [9] ; B. garinii and B. bavariensis are strongly associated with LNB [10][11][12] , and B. afzelii is associated with ACA [10][11][12] and Borrelial lymphocytoma [13,14] . At the genotype level, which is best studied for B. burgdorferi sensu stricto, OspC type A / RST 1 genotypes of B. burgdorferi disseminate in humans at higher rates [15][16][17][18] , cause higher rates of symptoms [19] , greater inflammation [19,20] , and more severe LA [19] . ...
... For example, all Borreliella spirochetes cause LD, but the clinical manifestations of LD vary based on the infecting genotype. B. burgdorferi is strongly associated with LA [9] ; B. garinii and B. bavariensis are strongly associated with LNB [10][11][12] , and B. afzelii is associated with ACA [10][11][12] and Borrelial lymphocytoma [13,14] . At the genotype level, which is best studied for B. burgdorferi sensu stricto, OspC type A / RST 1 genotypes of B. burgdorferi disseminate in humans at higher rates [15][16][17][18] , cause higher rates of symptoms [19] , greater inflammation [19,20] , and more severe LA [19] . ...
The Family Borreliaceae contains arthropod-borne spirochetes that cause two widespread human diseases, Lyme disease (LD) and relapsing fever (RF). LD is a subacute, progressive illness with variable stage and tissue manifestations. RF is an acute febrile illness with prominent bacteremia that may recur and disseminate, particularly to the nervous system. Clinical heterogeneity is a hallmark of both diseases. While human clinical manifestations are influenced by a wide variety of factors, including immune status and host genetic susceptibility, there is evidence that Borreliaceae microbial factors influence the clinical manifestations of human disease caused by this Family of spirochetes. Despite these associations, the spirochete genes that influence the severity and manifestations of human disease are, for the most part, unknown. Recent work has identified lineage-specific expansions of lipoproteome-rich accessory genome elements in virulent clones of B. burgdorferi. Using publicly available genome assemblies, I show here that all Borreliaceae lineages for which sufficient sequence data is available harbor a similar pattern of strongly structured, lineage-specific expansions in their accessory genome, particularly among lipoproteins, and that this pattern holds across phylogenetic scales including genera, species, and genotypes. The relationships among pangenome elements suggest that infrequent episodes of marked genomic change followed by clonal expansion in geographically and enzootically structured populations may account for the unique lineage structure of Borreliaceae. This analysis informs future genotype-phenotype studies among Borreliaceae and lays a foundation for studies of individual gene function guided by phylogenetic patterns of conservation, diversification, gain, and/or loss.
... VS116 group and B. afzelii) [240]. In the Greek island of Thassos, B. valaisiana was identified in the cerebrospinal fluid of a patient with a slow progressive spastic paraparesis, indicating a possible association of this genospecies with disease in humans and suggesting that it might be the causative agent of neuroborreliosis [241]. Indirect evidence suggests that B. valaisiana is involved in some chronic clinical manifestations [242] ...
... Clinical features of LB are wide and variable, with clinical manifestations linked to distinct tissue tropisms of specific Borrelia burgdorferi s.l. genospecies [241]. The early infection is localized and, in the absence of treatment, the spirochete can spread. ...
Borreliae are divided into three groups, namely the Lyme group (LG), the Echidna-Reptile group (REPG) and the Relapsing Fever group (RFG). Currently, only Borrelia of the Lyme and RF groups (not all) cause infection in humans. Borreliae of the Echidna-Reptile group represent a new monophyletic group of spirochaetes, which infect amphibians and reptiles. In addition to a general description of the phylum Spirochaetales, including a brief historical digression on spirochaetosis, in the present review Borreliae of Lyme and Echidna-Reptile groups are described, discussing the ecology with vectors and hosts as well as microbiological features and molecular characterization. Furthermore, differences between LG and RFG are discussed with respect to the clinical manifestations. In humans, LG Borreliae are organotropic and cause erythema migrans in the early phase of the disease, while RFG Borreliae give high spirochaetemia with fever, without the development of erythema migrans. With respect of LG Borreliae, recently Borrelia mayonii, with intermediate characteristics between LG and RFG, has been identified. As part of the LG, it gives erythema migrans but also high spirochaetemia with fever. Hard ticks are vectors for both LG and REPG groups, but in LG they are mostly Ixodes sp. ticks, while in REPG vectors do not belong to that genus.
... It is well accepted that genetic variability within the B. burgdorferi s.l. complex is associated with different clinical outcome in patients (Van Dam et al. 1993) as well as with different reservoir hosts (Humair and Gern 2000;Kurtenbach et al. 2002). The association to the reservoir hosts is given by the response of the specific host complement system to different Borrelia genospecies (Kurtenbach et al. 2002). ...
... To summarise, LB in Slovakia is a common multifactorial disease presenting mostly in early manifestation with EM, or if diagnosed later, mostly as neuroborreliosis Bazovská et al. 2011). Borrelial infection prevalence in the vector I. ricinus tick is among the highest in Europe (Van Dam et al. 1993;Lenčáková et al. 2006), however, it varies between habitats and years, and depends on the presence of reservoir hosts. Even though urban habitats have lower prevalence of borrelia in ticks they still pose a significant risk for acquiring infection in humans. ...
In Slovakia, 22 tick species have been found to occur to date. Among them, Ixodes ricinus, Dermacentor reticulatus, D. marginatus and marginally Haemaphysalis concinna, H. inermis and H. punctata have been identified as the species of public health relevance. Ticks in Slovakia were found to harbour and transmit zoonotic and/or potentially zoonotic agents such as tick-borne encephalitis virus (TBEV), spirochaetes of the Borrelia burgdorferi sensu lato (s.l.) complex, the relapsing fever sprirochaete Borrelia miyamotoi, bacteria belonging to the orders Rickettsiales (Rickettsia spp., Anaplasma phagocytophilum, Neoehrlichia mikurensis), Legionellales (Coxiella burnetii), and Thiotrichales (Francisella tularensis), and Babesia spp. parasites (order Piroplasmida). Ixodes ricinus is the principal vector of the largest variety of microorganisms including viruses, bacteria and piroplasms. TBEV, B. burgdorferi s.l., rickettsiae of the spotted fever group, C. burnetii and F. tularensis have been found to cause serious diseases in humans, whereas B. miyamotoi, A. phagocytophilum, N. mikurensis, Babesia microti, and B. venatorum pose lower or potential risk to humans. Distribution of TBEV has a focal character. During the last few decades, new tick-borne encephalitis (TBE) foci and their spread to new areas have been registered and TBE incidence rates have increased. Moreover, Slovakia reports the highest rates of alimentary TBE infections among the European countries. Lyme borreliosis (LB) spirochaetes are spread throughout the distribution range of I. ricinus. Incidence rates of LB have shown a slightly increasing trend since 2010. Only a few sporadic cases of human rickettsiosis, anaplasmosis and babesiosis have been confirmed thus far in Slovakia. The latest large outbreaks of Q fever and tularaemia were recorded in 1993 and 1967, respectively. Since then, a few human cases of Q fever have been reported almost each year. Changes in the epidemiological characteristics and clinical forms of tularaemia have been observed during the last few decades. Global changes and development of modern molecular tools led to the discovery and identification of emerging or new tick-borne microorganisms and symbionts with unknown zoonotic potential. In this review, we provide a historical overview of research on ticks and tick-borne pathogens in Slovakia with the most important milestones and recent findings, and outline future directions in the investigation of ticks as ectoparasites and vectors of zoonotic agents and in the study of tick-borne diseases.
... surrounding the brain and spinal cord) or myelitis (a chronic inflammation in the spinal cord) 138 . The Bannwarth´s syndrome is often associated with a bite from a B. garinii infected tick 72,99 . B. afzelii can also cause neurological involvement. ...
... However, PCR-analysis of SF has high diagnostic sensitivity since the method is able to detect non-viable spirochetes. The diagnostic sensitivity in cultures of spirochetes from skin biopsies is higher (>50 % and up to 88 % in EM)72,206 and skin biopsies from EM are the most useful material for culture in early LB. However, visual recognition of the characteristic lesion is usually sufficient for an accurate diagnosis, ...
... Different species of B. burgdorferi s. l. have been associated with different symptoms. Arthritis often occurs in the presence of B. burgdorferi s. s. infection, neurological symptoms are associated with B. garinii species, and skin lesions are associated with B. afzelii (Balmelli, Piffaretti, 1995;van Dam et al., 1993). Primary erythema migrans is the most common clinical symptom of B. burgdorferi infection and can be diagnosed in up to 89% of Lyme disease patients (Dandache, Nadelman, 2008;Es-posito et al., 2013). ...
The aim of this study was to determine the prevalence of IgG antibodies against Borrelia burgdorferi in adults who were bitten by a tick at least once and did not have classical signs and symptoms of Lyme disease. A total of 88 people from different cities in Lithuania were tested for the presence of Lyme disease IgG. The results showed that the prevalence of infection among participants was 11.4%. Unit values ranged from 12.26 U to 44.78 U. A higher number of Lyme disease cases was observed in older people and those who actively spend their time outdoors. This study shows the importance of the use of serological tests in the diagnosis of Lyme disease for patients with non-specific symptoms.
... garinii and B. bavariensis are often associated with neurological symptoms, and B. burgdorferi s.s. mainly causes Lyme arthritis (LA) [22][23][24]. ...
Lyme disease is a tick-borne disease caused by spirochetes belonging to the Borrelia burgdorferi sensu lato complex. The disease is characterized by a varied course; therefore, the basis for diagnosis is laboratory methods. Currently, a two-tiered serological test is recommended, using an ELISA as a screening test and a Western blot as a confirmatory test. This approach was introduced due to the relatively high number of false-positive results obtained when using an ELISA alone. However, even this approach has not entirely solved the problem of false-positive results caused by cross-reactive antibodies. Many highly immunogenic B. burgdorferi s.l. proteins are recognized nonspecifically by antibodies directed against other pathogens. This also applies to antigens, such as OspC, BmpA, VlsE, and FlaB, i.e., those commonly used in serodiagnostic assays. Cross-reactions can be caused by both bacterial (relapsing fever Borrelia, Treponema pallidum) and viral (Epstein–Baar virus, Cytomegalovirus) infections. Additionally, a rheumatoid factor has also been shown to nonspecifically recognize B. burgdorferi s.l. proteins, resulting in false-positive results. Therefore, it is necessary to carefully interpret the results of serodiagnostic tests so as to avoid overdiagnosis of Lyme disease, which causes unnecessary implementations of strong antibiotic therapies and delays in the correct diagnosis.
... The clinical triad of lymphocytic meningitis, cranial neuritis and radiculoneuritis is a well-described entity in literature. Unifocal or [31,32]. Furthermore, the occurrence of LNB and the specific reactivity with VlsE B. garinii antigen in five LNB patients indicate that B. garinii may be involved in the clinical expression of LNB in North India. ...
Background:
To describe the clinical features and therapeutic outcomes of a prospective cohort of children with eosinophilic meningoencephalitis.
Methods:
Children admitted with clinical features suggestive of meningitis along with cerebrospinal fluid (CSF) eosinophilia during the period of 14 years (2008 to 2021) were included. Their baseline characteristics, epidemiologic associations, and treatment outcomes were analyzed and compared with the previous studies.
Results:
We identified 25 children (13 males) satisfying the inclusion criteria. The median age at presentation was 3.9 years (range 0.8 to 17 years); 68% were aged less than two years. Fourteen (56%) children had a history of exposure to snails. Most of them presented with fever, headache, irritability, lateral rectus palsy, and early papilledema. Symptoms started three to 42 days (median duration: 14 days) before admission to our center. All children had peripheral eosinophilia, which ranged from 9% to 41%. The mean CSF white blood cell count was 416/mm3 (range 50 to 1245 cells/mm3) with CSF eosinophilia ranging from 11% to 80%. Brain magnetic resonance imaging was done in 24 children and was normal in 15 (62.5%). Leptomeningeal enhancement was seen in two (8.3%) children, and other nonspecific changes were noted in seven (29.1%) children. All children recovered without any neurological deficits with a standard treatment regimen of albendazole and oral steroids. All were asymptomatic at the last follow-up. None of them had any recurrence during the follow-up period.
Conclusion:
We report one of the largest clinical series of children with eosinophilic meningoencephalitis from an endemic area of South India.
... The clinical manifestations and their relative frequencies differ between Europe and North America, probably depending on the geographical distribution and organotropism of the various human pathogenic B. burgdorferi sensu lato (s.l.) species (van Dam et al. 1993;Balmelli and Piffaretti 1995;Piesman and Gern 2004). The early, localized skin lesion called erythema migrans (EM) is the most common manifestation on both continents but tends to be associated with more systemic symptoms and earlier dissemination in North American patients, where B. burgdorferi sensu stricto (s.s.) generally is the causative species ). ...
Lyme borreliosis (LB) and relapsing fever (RF) are zoonotic diseases that are caused by spirochetal bacteria belonging to the genus Borrelia. The agents are generally maintained in natural transmission cycles by vector ticks (exception: body louse) and reservoir hosts. Lyme borreliosis (synonym in North America: Lyme disease, LD) is the most frequently reported tick-borne disease in Europe and North America. It mainly affects skin, large joints, nervous system or heart and is considered a multi-system disorder. Relapsing fever manifests as recurrent febrile attacks accompanied by headaches, muscle and joint aches, interrupted by afebrile intervals. It mainly occurs in tropical and subtropical regions including North and South America, Africa, Asia, and South European countries. In this chapter we describe the genus Borrelia, the huge diversity that has become apparent in recent years, the geographical distribution of its species, and the complex genome that is reflected in the complex ecology and disease symptoms. We also give information on diagnostics and its challenges, therapy, and prophylactic measures.
... B. burgdorferi zeigen einen Spezies-abhängigen Gewebetropismus [41]. B. afzelii wird meist mit Hautmanifestationen assoziiert, während B. garinii den ausgeprägtesten Tropismus für neuronale Gewebe aufweist und B. burgdorferi ss häufig Gelenkmanifestationen verursacht [3]. ...
Lyme Disease - Epidemiology and Pathophysiology Abstract. Lyme disease is a zoonosis caused by the spirochete Borrelia burgdorferi and its genospecies. Its distribution includes Europe and some parts of North America. The dominant vector in Europe is the tick Ixodes ricinus. Its three developmental stages (larvae, nymph, adult) take blood meals from small rodents, birds, and deer, some of which may also host B. burgdorferi. This is how the majority of the ticks become infected. Transmission of the pathogen to a new host occurs via tick saliva at the next blood meal, which induces phenotypical modifications of the spirochete that facilitate migration from the tick intestine to the salivary gland and survival in the vertebrate host. Both, tick saliva and the remodeled surface proteins of the bacteria, provide protection from the host's immune system. Dissemination occurs predominantly via the hematogenous route, but motility of the spirochete facilitates tissue migration. The species-dependent tropism for skin, joints and neuronal structures appears to be mediated by specific interactions between host and pathogen proteins. While extrapolated total cases of Lyme disease in Switzerland have remained stable over the past years, areas where infected ticks can be found have expanded. Milder winters and higher temperatures may explain this observation. In addition to measures helping to avoid tick bites, vaccines may contribute to protect against Lyme disease in the future. A promising, multivalent, protein-based vaccine appears to provide protection from several subspecies of B. burgdorferi.
... Infection with B. burgdorferi s.s., the causative genospecies of LD in both the United States and Europe, often results in arthritis. In contrast, B. afzelii and B. garinii, which are other pathogenic genospecies found in Europe, predominantly cause dermatological and neurological symptoms, respectively (Van Dam et al., 1993;Steere, 2001;Steere et al., 2016). ...
Lyme disease (LD), the leading tick-borne disease in the Northern hemisphere, is caused by spirochetes of several genospecies of the Borreliella burgdorferi sensu lato complex. LD is a multi-systemic and highly debilitating illness that is notoriously challenging to diagnose. The main drawbacks of the two-tiered serology, the only approved diagnostic test in the United States, include poor sensitivity, background seropositivity, and cross-reactivity. Recently, Raman spectroscopy (RS) was examined for its LD diagnostic utility by our earlier proof-of-concept study. The previous investigation analyzed the blood from mice that were infected with 297 and B31 strains of Borreliella burgdorferi sensu stricto (s.s.). The selected strains represented two out of the three major clades of B. burgdorferi s.s. isolates found in the United States. The obtained results were encouraging and prompted us to further investigate the RS diagnostic capacity for LD in this study. The present investigation has analyzed blood of mice infected with European genospecies, Borreliella afzelii or Borreliella garinii, or B. burgdorferi N40, a strain of the third major class of B. burgdorferi s.s. in the United States. Moreover, 90 human serum samples that originated from LD-confirmed, LD-negative, and LD-probable human patients were also analyzed by RS. The overall results demonstrated that blood samples from Borreliella-infected mice were identified with 96% accuracy, 94% sensitivity, and 100% specificity. Furthermore, human blood samples were analyzed with 88% accuracy, 85% sensitivity, and 90% specificity. Together, the current data indicate that RS should be further explored as a potential diagnostic test for LD patients.
... Differences in the number of human cases of B miyamotoi disease between continents might be explained by variable transmission potential of the four endemic vector species, differing pathogenic potential of the distinct B miyamotoi genetic variants they carry (as has been shown for B burgdorferi sensu lato), or both. [62][63][64] The higher number of cases of B miyamotoi disease in Russia also could be attributed to the higher prevalence of B miyamotoi in I persulcatus and the finding that human I persulcatus bites are mainly caused by adult females (infection rate 2·9% [range 2·6-3·3]), 65 whereas the majority of I scapularis (infection rate 1·7% [1·5-1·8]) and I ricinus (infection rate 1·4% [1·3-1·5]) bites are caused by nymphs or larvae. 66 Additionally, high public awareness of tick-borne encephalitis virus in Russia might drive more patients with fever after a tick bite to present at the hospital, increasing the reported prevalence relative to settings with lower awareness. ...
Background
Various studies have evaluated the infection of Ixodes ticks and humans with the relapsing fever spirochaete Borrelia miyamotoi. However, to our knowledge, the prevalence of infection and disease has not been assessed systematically. We aimed to examine the prevalence of B miyamotoi in Ixodes ticks and humans, and the disease it can cause, in the northern hemisphere.
Methods
For this systematic review and meta-analysis, we searched PubMed and Web of Science up to March 1, 2021. Studies assessing Ixodes tick infection published since Jan 1, 2011 were eligible, whereas no time limitation was placed on reports of human infection and disease. We extracted B miyamotoi test positivity ratios and used a random-effects model to calculate estimated proportions of infected ticks, infected humans, and human disease with 95% CI. This study was registered with PROSPERO, CRD42021268996.
Findings
We identified 730 studies through database searches and 316 additional studies that referenced two seminal articles on B miyamotoi. Of these 1046 studies, 157 were included in the review, reporting on 165 637 questing ticks, 45 608 unique individuals, and 504 well described cases of B miyamotoi disease in humans. In ticks, the highest prevalence of B miyamotoi was observed in Ixodes persulcatus (2·8%, 95% CI 2·4–3·1) and the lowest in Ixodes pacificus (0·7%, 0·6–0·8). The overall seroprevalence in humans was 4·4% (2·8–6·3), with significantly (p<0·0001) higher seroprevalences in the high-risk group (4·6%, 2·6–7·1), participants with confirmed or suspected Lyme borreliosis (4·8%, 1·8–8·8), and individuals suspected of having a different tick-borne disease (11·9%, 5·6–19·9) than in healthy controls (1·3%, 0·4–2·8). Participants suspected of having a different tick-borne disease tested positive for B miyamotoi by PCR significantly more often than did the high-risk group (p=0·025), with individuals in Asia more likely to test positive than those in the USA (odds ratio 14·63 [95% CI 2·80–76·41]).
Interpretation
B miyamotoi disease should be considered an emerging infectious disease, especially in North America and Asia. Prospective studies and increased awareness are required to obtain further insights into the burden of disease.
Funding
ZonMW and the European Regional Development Fund (Interreg).
... Five different species of spirochaetes that can cause Lyme disease are known in Europe. The pathogenic potential of the different Bb species varies [28]. It is the most frequent tick-borne infectious disease. ...
Background
Lyme disease is the most frequent tick-borne infectious disease in Europe. It often presents with a wide variety of symptoms. For this reason, affection of the temporomandibular joint (TMJ) caused by Lyme disease (LD) can be misdiagnosed as a common temporomandibular disorder (TMD).
Case presentation
The purpose of this case report of a 25-year-old woman presenting to the Departments of Orthodontics and Oral and Maxillofacial Surgery with extensive symptoms of temporomandibular disorder is to illustrate the delayed diagnosis of Lyme disease which was only made after extensive therapy of the temporomandibular joint. The specialist literature only reports a few cases of patients suffering from Lyme disease with TMJ manifestations.
Conclusion
This case report and the relevant literature review aim to emphasize the importance of accurate request of medical history and differential diagnosis of acute TMJ arthritis and arthralgia. Early interdisciplinary diagnosis of Lyme disease and early antibiotic therapy are essential to avoid misdiagnosis and unnecessary, sometimes invasive, therapies.
... The majority of LNB research data comes from the European region due to infections with B. garinii or B. bavariensis neurotropic species of Bbsl complex. B. burgdorferi sensu stricto and recently B. mayonii are the only infecting species found in the US [31,32]. Furthermore, the occurrence of LNB and the specific reactivity with VlsE B. garinii antigen in five LNB patients indicate that B. garinii may be involved in the clinical expression of LNB in North India. ...
Background:
Lyme disease is endemic to parts of the Americas, Europe and Asia. However, only a handful of sporadic cases have been reported from India. In this study, we systematically evaluated the clinical and epidemiological features of Lyme disease in North India.
Method:
All samples were tested by using the standard two-tiered testing algorithm (STTA). Paired serum and cerebrospinal fluid (CSF) were used for demonstrating Borrelia burgdorferi specific intrathecal IgG antibody synthesis (AI). In addition, a commercial tick-borne bacterial flow chip (TBFC) system and a real-time PCR were also used to detect Borrelia species and Anaplasma phagocytophilum in patients who were positive by STTA.
Results:
The diagnosis of Lyme disease was confirmed in 18 (7.14%) of the 252 clinically suspected cases by STTA. Neurological involvement was reported in 14 (77.78%) patients, whereas joint and heart involvement was reported in five (27.78%) and three (16.67%) patients, respectively. Lymphocytic pleocytosis (median 37.5 cells/mm3; range 12-175 cells/mm3) in the CSF was seen in 11 of 14 Lyme neuroborreliosis (LNB) patients. Intrathecal production of Borrelia specific IgG antibodies was demonstrated in 9 (64.28%, n = 14) patients, a highly specific finding for neuroborreliosis. Two patients (11.11%) were also found to be co-infected with human granulocytic anaplasmosis.
Conclusions:
The results of this study show clinical and laboratory evidence of endemic Lyme disease in North India and thus, highlight the importance for travel medicine practitioners and physicians to evaluate for Lyme disease in patients with compatible symptoms and a history of travel to tick risk areas.
... Nevertheless, B. burgdorferi s.s. and B. afzelii can also be associated with neurological manifestation; however, not at such a high incidence [46,47]. B. afzelii in humans seems to have a tropism for skin, since it preferentially causes EM, lymphadenosis benigna cutis [48] and acrodermatitis chronica atrophicans (ACA) [49]. B. afzelii is the predominant, but not the exclusive, etiologic agent of ACA; B. garinii has also been detected in patients with ACA [47,50]. ...
Transmission of the causative agents of numerous infectious diseases might be potentially conducted by various routes if this is supported by the genetics of the pathogen. Various transmission modes occur in related pathogens, reflecting a complex process that is specific for each particular host-pathogen system that relies on and is affected by pathogen and host genetics and ecology, ensuring the epidemiological spread of the pathogen. The recent dramatic rise in diagnosed cases of Lyme borreliosis might be due to several factors: the shifting of the distributional range of tick vectors caused by climate change; dispersal of infected ticks due to host animal migration; recent urbanization; an increasing overlap of humans' habitat with wildlife reservoirs and the environment of tick vectors of Borrelia; improvements in disease diagnosis; or establishment of adequate surveillance. The involvement of other bloodsucking arthropod vectors and/or other routes of transmission (human-to-human) of the causative agent of Lyme borreliosis, the spirochetes from the Borrelia burgdorferi sensu lato complex, has been speculated to be contributing to increased disease burden. It does not matter how controversial the idea of vector-free spirochete transmission might seem in the beginning. As long as evidence of sexual transmission of Borrelia burgdorferi both between vertebrate hosts and between tick vectors exists, this question must be addressed. In order to confirm or refute the existence of this phenomenon, which could have important implications for Lyme borreliosis epidemiology, the need of extensive research is obvious and required.
... Nevertheless, B. burgdorferi s.s. and B. afzelii can also be associated with neurological manifestation; however, not at such a high incidence [46,47]. B. afzelii in humans seems to have a tropism for skin, since it preferentially causes EM, lymphadenosis benigna cutis [48] and acrodermatitis chronica atrophicans (ACA) [49]. B. afzelii is the predominant, but not the exclusive, etiologic agent of ACA; B. garinii has also been detected in patients with ACA [47,50]. ...
Transmission of the causative agents of numerous infectious diseases might be potentially conducted by various routes if this is supported by the genetics of the pathogen. Various transmission modes occur in related pathogens, reflecting a complex process that is specific for each particular host–pathogen system that relies on and is affected by pathogen and host genetics and ecology, ensuring the epidemiological spread of the pathogen. The recent dramatic rise in diagnosed cases of Lyme borreliosis might be due to several factors: the shifting of the distributional range of tick vectors caused by climate change; dispersal of infected ticks due to host animal migration; recent urbanization; an increasing overlap of humans’ habitat with wildlife reservoirs and the environment of tick vectors of Borrelia; improvements in disease diagnosis; or establishment of adequate surveillance. The involvement of other bloodsucking arthropod vectors and/or other routes of transmission (human-to-human) of the causative agent of Lyme borreliosis, the spirochetes from the Borrelia burgdorferi sensu lato complex, has been speculated to be contributing to increased disease burden. It does not matter how controversial the idea of vector-free spirochete transmission might seem in the beginning. As long as evidence of sexual transmission of Borrelia burgdorferi both between vertebrate hosts and between tick vectors exists, this question must be addressed. In order to confirm or refute the existence of this phenomenon, which could have important implications for Lyme borreliosis epidemiology, the need of extensive research is obvious and required.
... Both studies lack data on the corticosteroid dosing regimen. It should also be noted that the studies were conducted in the United States where all cases of LNB are caused by the genotype B. burgdorferi sensu stricto, in contrast to Europe, where the majority of LNB cases are caused by Borrelia garinii [25][26][27]. LNB case definitions differ between Europe and the United States; CSF pleocytosis is not required for an LNB diagnosis in the United States. The clinical presentation also differs; painful meningoradiculitis is a more common symptom of LNB in Europe. ...
Background:
Lyme neuroborreliosis peripheral facial palsy (LNB PFP) and idiopathic peripheral facial palsy, Bell's palsy (BP), are the most common causes of facial palsy in borrelia-endemic areas and are clinically similar. Early treatment with corticosteroids has been shown to be effective in Bell's palsy and antibiotics improve outcome in LNB, but there is a lack of knowledge on how the addition of corticosteroids to standard antibiotic treatment affects outcome in LNB PFP.
Methods:
This prospective open trial with historical controls was conducted at two large hospitals in western Sweden between 2011 and 2018. Adults presenting with LNB PFP were included in the study group and were treated with oral doxycycline 200 mg b.i.d. for 10 days and prednisolone 60 mg o.d. for 5 days, then tapered over 5 days. The historical controls were adult patients with LNB PFP included in previous studies and treated with oral doxycycline. Both groups underwent a follow-up lumbar puncture and were followed until complete recovery or for 12 months.
Results:
Fifty-seven patients were included, 27 in the study group and 30 in the control group. Two patients (6%) in the study group and 6 patients (20%) in the control group suffered from sequelae at end follow up. There was no statistically significant difference between the groups, neither in the proportion of patients with sequelae, nor in the decline in CSF mononuclear cell count.
Conclusions:
Adjunctive corticosteroids neither improve nor impair the outcome for patients with Lyme neuroborreliosis peripheral facial palsy treated with doxycycline.
... Clinical data were collected by retrospective assessment of patient records (Table 1). LB diagnoses were classified as proven when PCR-or culture-confirmed or as well-defined when based on a composite of clinical features and laboratory work-up as determined by the treating physician (13,14). In this context, clinical features denote that there were objective unambiguous clinical findings of early or disseminated LB (e.g., expanding erythematous skin lesion of .5 cm, classical Bannwarth syndrome, monoor oligo-arthritis involving large joints such as the knee); laboratory work-up means specific LB-related work-up (e.g., electrocardiogram [EKG] for Lyme carditis or cerebral spinal fluid [CSF] analysis for Lyme neuroborreliosis) and importantly also encompassed exclusion of other potential causes. ...
Objectives
Serodiagnosis of Lyme borreliosis (LB) comes with several drawbacks, among which limited sensitivity in early disease. This study assesses the sensitivity and specificity of the novel BioPlex 2200 Lyme IgG & Lyme IgM assays. It also assesses potential improvements to the assays through ROC-analysis.
Methods
The BioPlex assays were performed on sera of 158 Dutch patients with physician-confirmed LB (both early localized and disseminated), 800 healthy blood donors from the Netherlands and 90 cross-reactive controls. The BioPlex assays were compared with two commercial enzyme immunoassays (Euroimmun/C6-ELISA) and one immunoblot (recomLine).
Results
The highest sensitivity in early LB was achieved with the BioPlex assays, which outperformed the Euroimmun and C6-ELISA (Biopl: 81/88, 92.1%; Eur: 64/88, 72.7%; C6: 72/88, 81.8%). Sensitivity of all assays was comparable in patients with disseminated LB. The BioPlex assays were outperformed in terms of specificity (all healthy blood donors, Biopl: 571/800, 71.4%; Eur: 711/800, 88.9%; C6: 727/800, 90.9%), but further analyses showed promising avenues following cut-off optimization. ROC-analysis showed 2/6 antigens of the combined BioPlex IgG & IgM assays had significantly higher AUCs than the others. Potential modified versions of the assays based on these antigens largely outperformed the Euroimmun & C6-EIA in EM patients (Biopl: 81/80, 92.1%), while maintaining a comparable or even higher specificity (Biopl: 714/800, 89.3%).
Conclusions
The BioPlex 2200 Lyme IgG & Lyme IgM assays are promising tools for the serodiagnosis of early LB, with the potential to be used as a standalone test. Further research is necessary to validate the findings of this discovery cohort.
... according to their antigenic structure or their ability to react with specific antibodies, other typing methods have been developed to harness B. burgdorferi s.l.'s genetic composition as ways of differentiation (Wang et al., 1999, Wang et al., 2014b. These so-called 'molecular methods' include DNA-DNA homology analysis, as well as ribotyping, which is rRNA gene restriction analysis (van Dam et al., 1993), and PCR methods targeting conserved regions such as 16S rRNA DNA sequences, flagellin (fla) and ospA. Other PCR-based methods such as pulsed-field gel electrophoresis (PFGE) (Belfaiza et al., 1993), random amplified polymorphic DNA (RAPD) ...
... www.nature.com/scientificreports/ cutaneous manifestations of Lyme borreliosis 4 . B. afzelii is acquired by the larval tick during its first blood meal, it can survive in the tick to later life stages and can be transmitted with each following blood meal. ...
Ixodes ricinus is the vector for Borrelia afzelii, the predominant cause of Lyme borreliosis in Europe, whereas Ixodes scapularis is the vector for Borrelia burgdorferi in the USA. Transcription of several I. scapularis genes changes in the presence of B. burgdorferi and contributes to successful infection. To what extend B. afzelii influences gene expression in I. ricinus salivary glands is largely unknown. Therefore, we measured expression of uninfected vs. infected tick salivary gland genes during tick feeding using Massive Analysis of cDNA Ends (MACE) and RNAseq, quantifying 26.179 unique transcripts. While tick feeding was the main differentiator, B. afzelii infection significantly affected expression of hundreds of transcripts, including 465 transcripts after 24 h of tick feeding. Validation of the top-20 B. afzelii-upregulated transcripts at 24 h of tick feeding in ten biological genetic distinct replicates showed that expression varied extensively. Three transcripts could be validated, a basic tail protein, a lipocalin and an ixodegrin, and might be involved in B. afzelii transmission. However, vaccination with recombinant forms of these proteins only marginally altered B. afzelii infection in I. ricinus-challenged mice for one of the proteins. Collectively, our data show that identification of tick salivary genes upregulated in the presence of pathogens could serve to identify potential pathogen-blocking vaccine candidates.
... If similar phenomenon of skin persistence exists for Borreliae in humans, it might constitute a new approach to identify active markers of infection in patients with disseminated infections 16 . Interestingly, persistence of cultivable Borrelia at the site of untreated, spontaneously cured erythema migrans has been repeatedly documented in patients with symptoms of disseminated disease, providing a strong rational to test this hypothesis [31][32][33] . As most patients with symptoms of late disseminated Lyme disease do not remember occurrence of a previous erythema migrans rash, a short course of topical corticosteroids on randomly chosen asymptomatic skin may be helpful to increase the sensitivity of the detection of either protein or DNA from Borrelia bystanders. ...
Lyme borreliosis is the most prevalent vector-borne disease in northern hemisphere. Borrelia burgdorferi sensu lato spirochetes are transmitted by Ixodes species ticks. During a blood meal, these spirochetes are inoculated into the skin where they multiply and often spread to various target organs: disseminated skin sites, the central nervous system, the heart and large joints. The usual diagnosis of this disease relies on serological tests. However, in patients presenting persistent clinical manifestations, this indirect diagnosis is not capable of detecting an active infection. If the serological tests are positive, it only proves that exposure of an individual to Lyme spirochetes had occurred. Although culture and quantitative PCR detect active infection, currently used tests are not sensitive enough for wide-ranging applications. Animal models have shown that B. burgdorferi persists in the skin. We present here our targeted proteomics results using infected mouse skin biopsies that facilitate detection of this pathogen. We have employed several novel approaches in this study. First, the effect of lidocaine, a local anesthetic used for human skin biopsy, on B. burgdorferi presence was measured. We further determined the impact of topical corticosteroids to reactivate Borrelia locally in the skin. This local immunosuppressive compound helps follow-up detection of spirochetes by proteomic analysis of Borrelia present in the skin. This approach could be developed as a novel diagnostic test for active Lyme borreliosis in patients presenting disseminated persistent infection. Although our results using topical corticosteroids in mice are highly promising for recovery of spirochetes, further optimization will be needed to translate this strategy for diagnosis of Lyme disease in patients.
... 99 100 Differences between clinical manifestations in North America and Europe The differences in Borrelia genospecies between the continents 101 result in differences in clinical presentation. 102 In North America, central clearing of erythema migrans is uncommon: up to 18% of erythema migrans cases are multiple, and Lyme borreliosis is more often associated with constitutional symptoms, such as fever and malaise. 80 103 B burgdorferi ss in North America is more arthritogenic, and Lyme arthritis is more frequently encountered in North America (28% of Lyme borreliosis cases) 104 than in Europe (3-7%). ...
Lyme borreliosis is the most common vectorborne disease in the northern hemisphere. It usually begins with erythema migrans; early disseminated infection particularly causes multiple erythema migrans or neurologic disease, and late manifestations predominantly include arthritis in North America, and acrodermatitis chronica atrophicans (ACA) in Europe. Diagnosis of Lyme borreliosis is based on characteristic clinical signs and symptoms, complemented by serological confirmation of infection once an antibody response has been mounted. Manifestations usually respond to appropriate antibiotic regimens, but the disease can be followed by sequelae, such as immune arthritis or residual damage to affected tissues. A subset of individuals reports persistent symptoms, including fatigue, pain, arthralgia, and neurocognitive symptoms, which in some people are severe enough to fulfil the criteria for post-treatment Lyme disease syndrome. The reported prevalence of such persistent symptoms following antimicrobial treatment varies considerably, and its pathophysiology is unclear. Persistent active infection in humans has not been identified as a cause of this syndrome, and randomized treatment trials have invariably failed to show any benefit of prolonged antibiotic treatment. For prevention of Lyme borreliosis, post-exposure prophylaxis may be indicated in specific cases, and novel vaccine strategies are under development.
... It is accepted that genetic variability within the B. burgdorferi s.l. genospecies complex is associated with different clinical outcomes in LD patients [24] as well as with different reservoir hosts [25,26]. While B. garinii is mainly associated with neuroborreliosis, B. afzelii most often induces erythema migrans and acrodermatitis chronica atrophicans [15]. ...
Lyme disease (LD) is the most common tick-borne human disease in Europe, and Borrelia garinii, which is associated with avian reservoirs, is one of the most genetically diverse and widespread human pathogenic genospecies from the B. burgdorferi sensu lato (s.l.) complex. The clinical manifestations of LD are known to vary between regions and depend on the genetic strain even within Borrelia genospecies. It is thus of importance to explore the genetic diversity of such pathogenic borreliae for the wide range of host and ecological contexts. In this study, multilocus sequence typing (MLST) was employed to investigate the local population structure of B. garinii in Ixodes ricinus ticks. The study took place in a natural wetland in Slovakia, temporally encompassing spring and autumn bird migration periods as well as the breeding period of resident birds. In total, we examined 369 and 255 ticks collected from 78 birds and local vegetation, respectively. B. burgdorferi s.l. was detected in 43.4% (160/369) of ticks recovered from birds and in 26.3% (67/255) of questing ticks, respectively. Considering the ticks from bird hosts, the highest prevalence was found for single infections with B. garinii (22.5%). Infection intensity of B. garinii in bird-feeding ticks was significantly higher than that in questing ticks. We identified ten B. garinii sequence types (STs) occurring exclusively in bird-feeding ticks, two STs occurring exclusively in questing ticks, and one ST (ST 244) occurring in both ticks from birds and questing ticks. Four B. garinii STs were detected for the first time herein. With the exception of ST 93, we detected different STs in spring and summer for bird-feeding ticks. Our results are consistent with previous studies of the low geographic structuring of B. garinii genotypes. However, our study reveals some consistency in local ST occurrence and a geographic signal for one of the clonal complexes.
... In the U.S., Lyme borreliosis is caused primarily by B. burgdorferi and commonly features arthritis [3]. In contrast, in Europe and Asia, Lyme disease can also be caused by B. afzelii and B. garinii, which commonly give rise to late stage infections featuring dermatologic or neurologic manifestations, respectively [4][5][6][7]. ...
Lyme disease, caused by Borrelia burgdorferi, B. afzelii and B. garinii, is a chronic, multi-systemic infection and the spectrum of tissues affected can vary with the Lyme disease strain. For example, whereas B. garinii infection is associated with neurologic manifestations, B. burgdorferi infection is associated with arthritis. The basis for tissue tropism is poorly understood, but has been long hypothesized to involve strain-specific interactions with host components in the target tissue. OspC (outer surface protein C) is a highly variable outer surface protein required for infectivity, and sequence differences in OspC are associated with variation in tissue invasiveness, but whether OspC directly influences tropism is unknown. We found that OspC binds to the extracellular matrix (ECM) components fibronectin and/or dermatan sulfate in an OspC variant-dependent manner. Murine infection by isogenic B. burgdorferi strains differing only in their ospC coding region revealed that two OspC variants capable of binding dermatan sulfate promoted colonization of all tissues tested, including joints. However, an isogenic strain producing OspC from B. garinii strain PBr, which binds fibronectin but not dermatan sulfate, colonized the skin, heart and bladder, but not joints. Moreover, a strain producing an OspC altered to recognize neither fibronectin nor dermatan sulfate displayed dramatically reduced levels of tissue colonization that were indistinguishable from a strain entirely deficient in OspC. Finally, intravital microscopy revealed that this OspC mutant, in contrast to a strain producing wild type OspC, was defective in promoting joint invasion by B. burgdorferi in living mice. We conclude that OspC functions as an ECM-binding adhesin that is required for joint invasion, and that variation in OspC sequence contributes to strain-specific differences in tissue tropism displayed among Lyme disease spirochetes.
... In the 4 larger US studies, mild to no cognitive abnormalities were identi ed [1,2,12,13]. As both the Borrelia species and the clinical presentation of Lyme disease in Europe and the US differ [14], cognitive function in European Lyme patients requires separate assessment. Furthermore, most previous studies have not taken performance validity into account. ...
Background: Persistent symptoms attributed to Lyme borreliosis often include self-reported cognitive impairment. However, it remains unclear whether these symptoms can be substantiated by objective cognitive testing. Methods: For this observational study, cognitive performance was assessed in 280 adults with persistent symptoms attributed to Lyme borreliosis (as part of baseline data collected for the Dutch PLEASE study). Cognitive testing covered the five major domains: episodic memory, attention, verbal fluency, information-processing speed and executive function. Patients’ profiles of test scores were compared to a large age-, education- and sex-adjusted normative sample using multivariate normative comparison. Performance validity was assessed to detect suboptimal effort, and questionnaires were administered to measure self-reported cognitive complaints, fatigue, anxiety, depressive symptoms and several other psychological factors. Results: Of 280 patients, one was excluded as the test battery could not be completed. Of the remaining 279 patients, 239 (85.4%) displayed sufficient performance validity. Patients with insufficient performance validity felt significantly more helpless and physically fatigued, and less orientated. Furthermore, they had a lower education level and less often paid work. Of the total study cohort 5.7% (n=16) performed in the impaired range. Among patients who displayed sufficient performance validity, 2.9% (n=7) were classified as cognitively impaired. No association between subjective cognitive symptoms and objective impairment was found. Conclusions: Only a small percentage of patients with borreliosis-attributed persistent symptoms have objective cognitive impairment. Performance validity should be taken into account in neuropsychological examinations of these patients. Self-report questionnaires are insufficiently valid to diagnose cognitive impairment.
... In the 4 larger US studies, mild to no cognitive abnormalities were identi ed [1,2,12,13]. As both the Borrelia species and the clinical presentation of Lyme disease in Europe and the US differ [14], cognitive function in European Lyme patients requires separate assessment. Furthermore, most previous studies have not taken performance validity into account. ...
Background: Persistent symptoms attributed to Lyme borreliosis often include self-reported cognitive impairment. However, it remains unclear whether these symptoms can be substantiated by objective cognitive testing. Methods: For this observational study, cognitive performance was assessed in 280 adults with persistent symptoms attributed to Lyme borreliosis (as part of baseline data collected for the Dutch PLEASE study). Cognitive testing covered the five major domains: episodic memory, working memory/attention, verbal fluency, information-processing speed and executive function. Patients’ profiles of test scores were compared to a large age-, education- and sex-adjusted normative sample using multivariate normative comparison. Performance validity was assessed to detect suboptimal effort, and questionnaires were administered to measure self-reported cognitive complaints, fatigue, anxiety, depressive symptoms and several other psychological factors. Results: Of 280 patients, one was excluded as the test battery could not be completed. Of the remaining 279 patients, 239 (85.4%) displayed sufficient performance validity. Patients with insufficient performance validity felt significantly more helpless and physically fatigued, and less orientated. Furthermore, they had a lower education level and less often paid work. Of the total study cohort 5.7% (n=16) performed in the impaired range. Among the 239 patients who displayed sufficient performance validity, 2.9% (n=7) were classified as cognitively impaired. No association between subjective cognitive symptoms and objective impairment was found. Conclusions: Only a small percentage of patients with borreliosis-attributed persistent symptoms have objective cognitive impairment. Performance validity should be taken into account in neuropsychological examinations of these patients. Self-report questionnaires are insufficiently valid to diagnose cognitive impairment.
... It was detected in 4 of 160 skin isolates (all from erythema migrans) but has yet to be linked to Lyme neuroborreliosis (72 CSF isolates) in Germany [6]. The pathogenic potential of the various Borrelia burgdorferi species varies [7]. After B. garinii OspA-type 4 was reclassified as the new species Borrelia bavariensis [8], a reevaluation of 242 human isolates from Germany [6] found that the 72 countries. ...
Lyme borreliosis is the most common tick-borne infectious disease in Europe. A neurological manifestation occurs in 3-15% of infections and can manifest as polyradiculitis, meningitis and (rarely) encephalomyelitis. This S3 guideline is directed at physicians in private practices and clinics who treat Lyme neuroborreliosis in children and adults. Twenty AWMF member societies, the Robert Koch Institute, the German Borreliosis Society and three patient organisations participated in its development. A systematic review and assessment of the literature was conducted by the German Cochrane Centre, Freiburg (Cochrane Germany). The main objectives of this guideline are to define the disease and to give recommendations for the confirmation of a clinically suspected diagnosis by laboratory testing, antibiotic therapy, differential diagnostic testing and prevention.
Copyright © 2020 Rauer et al.
... wywołuje głównie boreliozowe zapalenie stawów (LA, Lyme arthritis). B. spielmanii do tej pory wyizolowano jedynie ze zmian skórnych [12,17,69]. ...
Lyme borreliosis, an infectious disease caused by tick-borne spirochetes of the Borrelia burgdorferi sensu lato complex, is regarded as the most commonly reported vector-borne infection in the Northern Hemisphere. Currently, the basis for laboratory diagnosis of Lyme disease is a two-step serological examination. The first is an enzyme-linked immunosorbent assay (ELISA). If the test result is positive or questionable, a Western blot is used as the second phase test. In both methods, the total cell lysates of B. burgdorferi s.l. are used as the main source of antigens. However, the huge diversity of genospecies within B. burgdorferi s.l. and the low degree of preservation of the sequence of their proteins means that using the cell lysates of one of the species is not sufficient to correctly diagnose Lyme disease. Numerous literature reports show that the use of B. burgdorferi s.l. recombinant or chimeric antigens may be a potential solution to problems occurring in Lyme disease immunodiagnosis. However, for diagnostic tests based on recombinant proteins to be as effective as possible, carefully selected antigens or fragments should be used. With this approach, a test can be developed with a sensitivity that remains independent of the B. burgdorferi s.l. species which caused the disease. In addition, the exclusive use of protein fragments may definitely reduce the frequency of cross-reactions.
1. Introduction. 2. Characterization of selected B. burgdorferi s.l. antigens. 3. Diagnosis of Lyme disease. 4. Problems in Lyme disease serodiagnosis. 5. Use of recombinant antigens and synthetic peptides in the diagnosis of Lyme disease. 6. Summary
Working together, two major pharmaceutical companies have developed a Lyme disease vaccine consisting of recombinant-derived outer surface protein A (OspA) of the etiologic agent Borrelia burgdorferi. Multiple clinical trials have shown the vaccine to have good safety and efficacy results, and it is hoped that it would become available for human use at least by the year 2025 after receiving approval from the U.S. Food and Drug Administration. There are still challenges left to ensure that the vaccine has, at most, minimal side effects. Also, because the previously developed Lyme disease vaccine was discontinued in 2002 after four years of distribution, due in part, for frivolous reasons having little or no scientific basis, that even led to legal entanglements involving the vaccine manufacturer and some of the medical personnel overseeing the clinical trials, there will be concerns that this newly developed one could be subject again to some of the same unnecessary scrutiny rendering its implementation suboptimal. Initially this review will focus on the key epidemiological, microbiologic, immunologic and clinical aspects of Lyme disease that provide the foundation for developing this type of vaccine that could have a serious impact on the prevalence of this and even certain other tick-transmitted infections.
We describe a rare case of early Lyme borreliosis in France caused by Borrelia spielmanii, which manifested as a large erythema chronicum migrans rash. The patient completely recovered after a 15-day course of amoxicillin. Absence of pathognomonic signs prevented distinguishing B. spielmanii from other etiologies as cause in this case-patient.
Human Lyme borreliosis (LB) represents a multisystem disorder that can progress in stages. The causative agents are transmitted by hard ticks of the Ixodes ricinus complex that have been infected with the spirochete Borrelia burgdorferi sensu lato. Today, LB is considered the most important human tick-borne illness in the Northern Hemisphere. The causative agent was identified and successfully isolated in 1982 and, shortly thereafter, antibiotic treatment was found to be safe and efficacious. Since then, various in vitro studies have been conducted in order to improve our knowledge of the activity of antimicrobial agents against B. burgdorferi s. l. The full spectrum of in vitro antibiotic susceptibility has still not been defined for some of the more recently developed compounds. Moreover, our current understanding of the in vitro interactions between B. burgdorferi s. l. and antimicrobial agents, and their possible mechanisms of resistance remains very limited and is largely based on in vitro susceptibility experiments on only a few isolates of Borrelia. Even less is known about the possible mechanisms of the in vitro persistence of spirochetes exposed to antimicrobial agents in the presence of human and animal cell lines. Only a relatively small number of laboratory studies and cell culture experiments have been conducted. This review summarizes what is and what is not known about the in vitro susceptibility of B. burgdorferi s. l. It aims to shed light on the known unknowns that continue to fuel current debates on possible treatment resistance and mechanisms of persistence of Lyme disease spirochetes in the presence of antimicrobial agents.
A total of 33 emerging tick-borne agents have been reported in the Chinese mainland from 1980 to 2015, including eight species of spotted fever group rickettsiae, seven species in the family Anaplasmataceae, six genospecies in the complex Borrelia burgdorferi sensu lato, 11 species of Babesia, and the severe fever with thrombocytopenia syndrome virus. Among them 15 emerging tick-borne agents have been identified to cause human disease, and their clinical characteristics were described and their geographic distributions mapped. The pathogenicity in humans of the other 18 tick-borne agents detected in ticks or animals is yet to be determined. Various factors have contributed to the emergence of emerging tick-borne diseases in China; for example, advances in and application of modern molecular techniques might facilitate the identification of emerging tick-borne agents and improve lab diagnosis of human cases. We anticipate that more emerging tick-borne agents will continue to be identified in ticks and animals and additional emerging tick-borne diseases will be discovered in humans.
Ixodes ricinus and Ixodes scapularis are the main vectors for the causative agents of Lyme borreliosis and a wide range of other pathogens. Repeated tick-bites are known to lead to tick rejection; a phenomenon designated as tick immunity. Tick immunity is mainly directed against tick salivary gland proteins (TSGPs) and has been shown to partially protect against experimental Lyme borreliosis. TSGPs recognized by antibodies from tick immune animals could therefore be interesting candidates for an anti-tick vaccine, which might also block pathogen transmission. To identify conserved Ixodes TSGPs that could serve as a universal anti-tick vaccine in both Europe and the US, a Yeast Surface Display containing salivary gland genes of nymphal I. ricinus expressed at 24, 48 and 72 h into tick feeding was probed with either sera from rabbits repeatedly exposed for 24 h to I. ricinus nymphal ticks and/or sera from rabbits immune to I. scapularis. Thus, we identified thirteen TSGP vaccine candidates, of which ten were secreted. For vaccination studies in rabbits, we selected six secreted TSGPs, five full length and one conserved peptide. None of these proteins hampered tick feeding. In contrast, vaccination of guinea pigs with four non-secreted TSGPs – two from the current and two from a previous human immunoscreening - did significantly reduce tick attachment and feeding. Therefore, non-secreted TSGPs appear to be involved in the development of tick immunity and are interesting candidates for an anti-tick vaccine.
Over the last decades, new knowledge has been accumulated on the worldwide spread of mixed tick-borne infections of different nature (viral, bacterial, protozoal), new pathogen species have been discovered, and it has been shown that individual ticks are infected with several pathogens simultaneously. This information has changed the ideas about the etiological landscape of diseases, which can develop by ixodid tick bites that led to the understanding that this practical problem requires comprehensive studies on the prevention, diagnosis, and treatment of these diseases. At present, there is an urgent need to develop unified approaches to the treatment of the mixed tick-borne infections of viral and bacterial nature. Simultaneous administration of specific drugs against both viral (tick-borne encephalitis virus) and bacterial pathogens (Borrelia spp., Rickettsia spp., Ehrlichia spp., Anaplasma phagocytophilum, and others) is required. This, however, is hampered by the scarcity of antivirals and the side effects of certain antibiotics, which can suppress the patient's immunity and possess a neurotoxic effect, aggravating the viral disease (in particular, tick-borne encephalitis). Thus, since the therapeutic approaches to tick-borne infections of viral and bacterial nature are fundamentally different, these coinfections present a major practical challenge for modern health care in affected regions. This chapter provides information on the spread of tick-borne encephalitis virus and the most significant bacterial pathogens in the world. It highlights Russian, European, and American recommendations for the treatment of tick-borne infections of viral and bacterial nature, as well as experimental studies on the effect of antibiotics on the acute and chronic course of tick-borne encephalitis.
Since the discovery of the etiological agents of Lyme disease, Borrelia burgdorferi sensu lato (s.l.), many efforts have been undertaken to understand the nature of the pathobiology these pathogens cause in humans. Here we describe the current knowledge of the most important borrelial determinants and factors and how they interact in different ways with soluble host proteins, tissues, and organs at different time points within the multistep infection process. We also describe the specific responses and signaling pathways that are induced by the human host to combat the intruding pathogen. While not a complete list, factors involved in host adaptation, tissue colonization, dissemination, and persistence of Borrelia are addressed, as well as factors playing a key role in immune evasion. Further aspects such as the induction of inflammatory mediators and the role of B and T cells in host responses, as well as the recognition and persistence of spirochetes are also discussed. Despite the huge collection and collation of data within the last two decades, our picture of the pathogenesis of Lyme diseases is still a big puzzle, in which the shape and certain characteristics are visible, but the whole picture is covered with a blurry veil.KeywordsImmune evasionadaptive immunityinnate immunitycomplementvirulence factorshost response
Lyme borreliosis is the most common vector-borne disease in the United States, where most infections are caused by Borrelia burgdorferi sensu stricto (s.s.) and transmitted by Ixodes scapularis. Both the geographic locations and the number of infections have steadily increased. Variations within Lyme borrelia, together with differences in the host response and time to antibiotic treatment, play a role in the diversity of disease manifestations and/or in their severity. Compared with Europe, early Lyme borreliosis presenting with erythema migrans in the United States is associated with more symptomatic disease and untreated infection is particularly linked with arthritis. Progress has been made toward new approaches for Lyme borreliosis laboratory diagnosis, including simplification of the current algorithm, opening the door for the development of point-of-care tests. Recommendations for the treatment of Lyme borreliosis are similar between the United States and European guidelines, with small differences regarding the use of phenoxymethylpenicillin, antibiotic treatment of pregnant women, and postexposure chemoprophylaxis. The majority of recognized coinfections in the United States involve two of the three most common pathogens, B. burgdorferi, Anaplasma phagocytophilum, and Babesia microti, but I. scapularis can also transmit B. mayonii, B. miyamotoi, Ehrlichia muris eauclairensis, and the deer tick virus subtype of Powassan virus. The controversial issue of chronic Lyme disease is a growing problem in both the United States and Europe, which will need well-designed approaches to investigate this heterogeneous group of patients and set up the groundwork for more effective treatment strategies for patients.KeywordsLyme diseaseLyme borreliosis
Borrelia burgdorferi
Borreliella burgdorferi
United StatesEurope
Lyme borreliosis is the most common tick-borne disease in the temperate northern hemisphere. The bacterium responsible for the disease, Borrelia burgdorferi sensu lato (s.l.), occurs predominantly in small mammals and is transmitted by certain species of Ixodes. Long-lasting blood meals for several days are characteristic for this tick species. Deer are one of the preferred hosts of Ixodes adults and therefore contribute substantially to the maintenance of tick populations. Although humans are accidental hosts, Lyme borreliosis represents an important challenge to Public Health. Personal protective measures against tick bite include adequate clothing and the use of repellents. Rapid detachment of the tick after a bite is essential and the bite site must be observed for the possible appearance of clinical symptoms.An integrative approach is required for the control of this zoonotic disease. Rodent reservoirs can be targeted by topical acaricides, oral vaccines against B. burgdorferi, or antibiotic baits. Reduction of deer abundance can be used to suppress tick populations. Effective modifications to make the environment less attractive for ticks include leaf removal, controlled vegetation burning, and lawn mowing. However, the ultimate gold standard to control this disease in humans would be an efficient vaccine, which is still not available.KeywordsLymeZoonosisDeerBorrelia burgdorferi sensu lato
Ixodes
RepellentsAnthropizationRodentPreventionVaccine
In Europe, Ixodes ricinus is the main vector for tick-borne pathogens (TBPs), the most common tick species in Italy, particularly represented in pre-alpine and hilly northern areas. From 2011 to 2017, ticks were collected by dragging in Belluno province (northeast Italy) and analyzed by molecular techniques for TBP detection. Several species of Rickettsia spp. and Borrelia spp. Anaplaspa phagocitophilum, Neoerlichia mikurensis and Babesia venatorum, were found to be circulating in the study area carried by I. ricinus (n = 2668, all stages). Overall, 39.1% of screened pools were positive for at least one TBP, with a prevalence of 12.25% and 29.2% in immature stages and adults, respectively. Pathogens were detected in 85% of the monitored municipalities, moreover the presence of TBPs varied from one to seven different pathogens in the same year. The annual TBPs prevalence fluctuations observed in each municipality highlights the necessity of performing continuous tick surveillance. In conclusion, the observation of TBPs in ticks remains an efficient strategy for monitoring the circulation of tick-borne diseases (TBDs) in a specific area.
In Europe, Ixodes ricinus is the most important vector of human infectious diseases, most notably Lyme borreliosis and tick-borne encephalitis virus. Multiple non-natural hosts of I. ricinus have shown to develop immunity after repeated tick bites. Tick immunity has also been shown to impair B. burgdorferi transmission. Most interestingly, multiple tick bites reduced the likelihood of contracting Lyme borreliosis in humans. A vaccine that mimics tick immunity could therefore potentially prevent Lyme borreliosis in humans. A yeast surface display library (YSD) of nymphal I. ricinus salivary gland genes expressed at 24, 48 and 72 h into tick feeding was constructed and probed with antibodies from humans repeatedly bitten by ticks, identifying twelve immunoreactive tick salivary gland proteins (TSGPs). From these, three proteins were selected for vaccination studies. An exploratory vaccination study in cattle showed an anti-tick effect when all three antigens were combined. However, immunization of rabbits did not provide equivalent levels of protection. Our results show that YSD is a powerful tool to identify immunodominant antigens in humans exposed to tick bites, yet vaccination with the three selected TSGPs did not provide protection in the present form. Future efforts will focus on exploring the biological functions of these proteins, consider alternative systems for recombinant protein generation and vaccination platforms and assess the potential of the other identified immunogenic TSGPs.
Lyme borreliosis is the most prevalent tick-borne disease in the United States, infecting ~476,000 people annually. Borrelia spp. spirochetal bacteria are the causative agents of Lyme disease in humans and are transmitted by Ixodes spp ticks. Clinical manifestations vary depending on which Borrelia genospecies infects the patient and may be a consequence of distinct organotropism between species. In the US, B. burgdorferi sensu stricto is the most commonly reported genospecies and infection can manifest as mild to severe symptoms. Different genotypes of B. burgdorferi sensu stricto may be responsible for causing varying degrees of clinical manifestations. While the majority of Lyme borreliae-infected patients fully recover with antibiotic treatment, approximately 15% of infected individuals experience long-term neurological and psychological symptoms that are unresponsive to antibiotics. Currently, long-term antibiotic treatment remains the only FDA-approved option for those suffering from these chronic effects. Here, we discuss the current knowledge pertaining to B. burgdorferi sensu stricto infection in the central nervous system (CNS), termed Lyme neuroborreliosis (LNB), within North America and specifically the United States. We explore the molecular mechanisms of spirochete entry into the brain and the role B. burgdorferi sensu stricto genotypes play in CNS infectivity. Understanding infectivity can provide therapeutic targets for LNB treatment and offer public health understanding of the B. burgdorferi sensu stricto genotypes that cause long-lasting symptoms.
Lyme disease is the most frequent tick-borne infectious disease in Europe. It often presents with a wide variety of symptoms. For this reason, affection of the temporomandibular joint (TMJ) caused by Lyme disease (LD) can be misdiagnosed as a common temporomandibular disorder (TMD). The purpose of this case report of a 25-year old woman presenting to the Departments of Orthodontics and Maxillofacial Surgery with extensive symptoms of Temporomandibular Disorder is to illustrate the delayed diagnosis of Lyme disease, which was only made after extensive therapy of the temporomandibular joint. The specialist literature only reports a few cases of patients suffering from Lyme disease with TMJ manifestations. This case report and the relevant literature review aim to emphasize the importance of accurate request of medical history and differential diagnosis of acute TMJ arthritis and arthralgia. Early interdisciplinary diagnosis of Lyme disease and early antibiotic therapy are essential to avoid misdiagnosis and unnecessary, sometimes invasive, therapies.
Lyme disease (Lyme borreliosis) is a tick-borne, zoonosis of adults and children caused by genospecies of the Borrelia burgdorferi sensu lato complex. The ailment, widespread throughout the Northern Hemisphere, continues to increase globally due to multiple environmental factors, coupled with increased incursion of humans into habitats that harbor the spirochete. B. burgdorferi sensu lato is transmitted by ticks from the Ixodes ricinus complex. In North America, B. burgdorferi causes nearly all infections; in Europe, B. afzelii and B. garinii are most associated with human disease. The spirochete's unusual fragmented genome encodes a plethora of differentially expressed outer surface lipoproteins that play a seminal role in the bacterium's ability to sustain itself within its enzootic cycle and cause disease when transmitted to its incidental human host. Tissue damage and symptomatology (i.e., clinical manifestations) result from the inflammatory response elicited by the bacterium and its constituents. The deposition of spirochetes into human dermal tissue generates a local inflammatory response that manifests as erythema migrans (EM), the hallmark skin lesion. If treated appropriately and early, the prognosis is excellent. However, in untreated patients, the disease may present with a wide range of clinical manifestations, most commonly involving the central nervous system, joints, or heart. A small percentage (~10%) of patients may go on to develop a poorly defined fibromyalgia-like illness, post-treatment Lyme disease (PTLD) unresponsive to prolonged antimicrobial therapy. Below we integrate current knowledge regarding the ecologic, epidemiologic, microbiologic, and immunologic facets of Lyme disease into a conceptual framework that sheds light on the disorder that healthcare providers encounter.
Antigen presentation is a crucial innate immune cell function that instructs adaptive immune cells. Loss of this pathway severely impairs the development of adaptive immune responses. To investigate whether B. burgdorferi s.l. spirochetes modulate the induction of an effective immune response, primary human PBMCs were isolated from healthy volunteers and stimulated with B. burgdorferi s.l.. Through cell entry, TNF receptor I, and RIP1 signaling cascades, B. burgdorferi s.l. strongly downregulated genes and proteins involved in antigen presentation, specifically HLA-DM, MHC class II and CD74. Antigen presentation proteins were distinctively inhibited in monocyte subsets, monocyte-derived macrophages, and dendritic cells. When compared to a range of other pathogens, B. burgdorferi s.l.-induced suppression of antigen presentation appears to be specific. Inhibition of antigen presentation interfered with T-cell recognition of B. burgdorferi s.l., and memory T-cell responses against C. albicans. Re-stimulation of PBMCs with the commensal microbe Candida albicans following B. burgdorferi s.l. exposure resulted in significantly reduced IFN-γ, IL-17 and IL-22 production. These findings may explain why patients with Lyme borreliosis develop delayed adaptive immune responses. Unravelling the mechanism of B. burgdorferi s.l.-induced inhibition of antigen presentation via cell entry, TNF receptor I, and RIP1 signaling cascades, explains the difficulty to diagnose the disease based on serology and to obtain an effective vaccine against Lyme borreliosis.
The rapid, ultrasensitive silver stains that have been developed recently for detecting proteins in polyacrylamide gels show variation in staining from gel to gel and do not stain certain proteins at all. It was found that treatment of gels with dithiothreitol prior to impregnation with silver nitrate results in more reproducible staining patterns that are also qualitatively similar to those obtained with Coomassie blue. In addition, it obviates the need for treatment with intense light, and results in sensitivities at least as high as those obtained with previously published methods.
We have determined and compared partial 16S rRNA sequences from 23 Lyme disease spirochete isolates and aligned these with 8 sequences previously presented. The 16S rRNA signature nucleotide compositions were defined for each isolate and compared with the genomic species signature nucleotide sets previously established. To identify positions truly indicative of species classification which could serve as targets for polymerase chain reaction species-specific identification primers, 16S rRNA-based phylogenetic analyses were conducted. On the basis of the identified signature nucleotides, we designed polymerase chain reaction primer sets which (i) amplify all spirochete species associated with Lyme disease and (ii) differentiate between these species. The primer sets were tested on 38 Borrelia isolates associated with Lyme disease and were found to be sensitive and specific. All Lyme disease isolates tested were amplification positive. These primers allow for the rapid species identification of Lyme disease isolates.
In order to assess the genetic variation of immunologically relevant structures among isolates of the Lyme disease spirochete, Borrelia burgdorferi, three chromosomal genes encoding flagellin (fla) and the heat shock proteins HSP60 and HSP70, as well as the plasmid gene encoding outer surface protein A (OspA), from 55 different European and North American strains obtained from ticks and mammal hosts have been investigated by restriction fragment length polymorphisms (RFLPs). RFLPs of fla and the HSP60 and HSP70 genes revealed two distinct banding patterns (A and B) for each of the three genes and allowed the definition of four genomic groups [AAA, BBB, BBA, and B(A/B)A] for the three chromosomal genes. On the other hand, RFLPs of the OspA gene revealed six distinct banding patterns (types I to VI) making up six independent genomic groups for the plasmid-encoded gene. Furthermore, we have sequenced the chromosomal HSP60 gene from B. burgdorferi ZS7 and the plasmid-encoded OspA gene from two strains, ZQ1 and 19857. Alignment of the deduced HSP60 amino acid sequence from B. burgdorferi ZS7 (genomic group AAA) to a previously published HSP60 sequence derived from strain ACA-1, which according to the proposed classification is in a different genomic group (BBA), revealed a sequence identity of > 99%. Similar alignments of the OspA sequence of strain ZQ1 to those of other isolates that were published previously revealed sequence identities of between 70 and 94% among strains of distinct OspA genomic groups. These data indicate the existence of a restricted number of species-specific subgroups and clearly show that genotypic variation is much more pronounced for the OspA gene than for fla and the HSP60 and HSP70 genes. A phylogenetic tree constructed on the basis of distance matrix analyses of 12 OspA sequences supports the proposed classification of genomic groups of B. burgdorferi.
We studied 48 Borrelia isolates that were associated with Lyme borreliosis or were isolated from ticks and identified three DNA relatedness groups by using the S1 nuclease method. The three DNA groups (genospecies) were associated with specific rRNA gene restriction patterns, protein electrophoresis patterns, and patterns of reactivity with murine monoclonal antibodies. Genospecies I corresponded to Borrelia burgdorferi sensu stricto since it contained the type strain of this species (strain ATCC 35210); this genospecies included 28 isolates from Europe and the United States. Genospecies II was named Borrelia garinii sp. nov. and included 13 isolates from Europe and Japan. Genospecies III (group VS461) included seven isolates from Europe and Japan.
The causative agent of Lyme disease, Borrelia burgdorferi, was first identified by Burgdorfer et al. in 1982 (W. Burgdorfer, A. G. Barbour, S. F. Hayes, J. L. Benach, E. Grunwaldt, and J. P. Davis, Science 216:1317-1319, 1982) and was isolated by Barbour et al. in 1983 (A. G. Barbour, W. Burgdorfer, S. E. Hayes, O. Peter, and A. Aeschlimann, Curr. Microbiol. 8:123-126, 1983). Since then, a large number of isolates have been collected, and there have been questions regarding the relationships among the various strains. Using genomic fingerprinting by an arbitrarily primed polymerase chain reaction, we resolved into three groups a collection of Eurasian and North American isolates of spirochetes that are generally categorized as B. burgdorferi. Group I strains have been identified in both North America and Eurasia, while strains belonging to Borrelia groups II and III have been found only in Eurasia. These same three groups have also been delineated by Baranton et al. (G. Baranton, D. Postic, I. Saint Girons, P. Boerlin, J.-C. Piffaretti, M. Assous, and P. A. D. Grimont, Int. J. Syst. Bacteriol. 42:370-375, 1992) by independent methods. Two isolates are distinct from all of the other strains in our collection but are clearly members of the genus Borrelia.
Fifty Borellia burgdorferi strains isolated from humans and ticks in Europe and the United States were analyzed by multilocus enzyme electrophoresis. Eleven genetic loci were characterized on the basis of the electrophoretic mobilities of their products. Ten loci were polymorphic. The average number of alleles per locus was 5.9, with a mean genetic diversity of 0.673 among electrophoretic types (ETs). The strains were grouped into 35 ETs constituting three main divisions (I, II, and III) separated at a genetic distance greater than 0.75. Divisions I, II, and III contained 13, 6, and 16 ETs, respectively. These findings, together with previous data from DNA hybridization and restriction enzyme analysis of rRNA genes, suggest that divisions I, II, and III may represent three distinct genomic species. All three divisions contained human clinical ETs. However, in division I, which includes the ET of the type strain of B. burgdorferi, the human pathogenic ETs constituted a single clone. The ETs of division I were from west-central Europe and the United States, whereas divisions II and III contained ETs from west-central and northern Europe but not from the United States. Finally, our data show that the genetic structure of B. burgdorferi populations is clonal.
A total of 23 isolates of Borrelia burgdorferi were characterized by SDS-PAGE and immunoblot analysis. One isolate came from the CSF of a Lyme neuro-borreliosis patient in Valais (Switzerland) and 22 were tick isolates (2 from I. dammini of Shelter Island, USA and 20 from I. ricinus of Valais, Switzerland). Based on the electrophoretic mobility of outer surface proteins (OspA and OspB), four groups of B. burgdorferi could be defined. Group I isolates possess an OspA of 31 KD and an OspB of 34 KD. The group II isolate showed an OspA of 32 KD and OspB of 35 KD. Group III isolates have a 33 KD OspA and group IV a 33.5 KD OspA. This classification was confirmed by the reactivity of a monoclonal antibody (D6) to a 12 KD antigen that was recognized in group III only. A Lyme patient's serum showed a 2-band pattern (10 and 13 KD) for group I and a one-band pattern (12 KD) for the other 3 groups. Therefore OspA, OspB and other proteins of low molecular weight (10, 12, and 13 KD) seem to be important keys for the classification of B. burgdorferi isolates. This typing system correlates with genetic analysis.
Skin biopsy specimens from the peripheral aspect of erythema migrans lesions (site 1) and from clinically normal perilesional areas (site 2) were compared as sources of Borrelia burgdorferi. This spirochete was isolated from the skin of 18 of 21 (86%) patients with untreated early Lyme disease at one or both biopsy sites. Site 1 specimens were superior to site 2 specimens for the isolation of B. burgdorferi. Site 1 specimens from 18 (86%) patients were culture positive, and site 2 specimens from 12 (57%) patients were culture positive. For patients whose site 2 specimens were culture positive, site 1 specimens were also found to be culture positive. B. burgdorferi was isolated from two patients with atypical lesions and from two patients with erythema migrans lesions that were less than 5 cm in diameter. This study demonstrates that the cultivation of B. burgdorferi from skin biopsy specimens from cutaneous lesions thought to be erythema migrans can be an efficacious procedure for confirming the diagnosis of Lyme disease and that the spirochete is present in clinically normal appearing perilesional skin.
By cloning and sequencing the flagellin gene of Borrelia hermsii and comparing this sequence with that of the corresponding gene from B. burgdorferi, I identified a central region within the two genes which showed a reduced level of sequence similarity. Oligonucleotide sequences selected from this region produced species-specific amplimers when used in polymerase chain reaction experiments. Thus, primers derived from the B. burgdorferi sequence amplified a 276-bp fragment from 22 strains of B. burgdorferi of diverse geographic origin but not from 5 strains of B. hermsii, 5 other Borrelia species, 16 Treponema, Leptospira, and Spirochaeta species, or representatives of 10 other bacterial genera. However, when the amplified fragments were tested for hybridization with an oligonucleotide probe derived from the nonhomologous region, seven strains from either Germany or Switzerland did not hybridize. Cloning and sequencing of the amplified fragments from these strains revealed that the 22 strains of B. burgdorferi tested could be divided into three groups based on the nucleic acid sequence of the central region of the flagellin gene. With this information, oligonucleotide probes that hybridized to the amplified fragments and were able to differentiate the three groups of B. burgdorferi were designed. The corresponding primers, derived from the B. hermsii gene sequence, were tested for their ability to amplify DNA from this collection of strains. Although no amplification was obtained with representatives of the three groups of B. burgdorferi or various Treponema, Leptospira, and Spirochaeta species, amplification was obtained with the five other Borrelia species (B. parkeri, B. turicatae, B. crocidurae, B. anserina, and B. coriaceae) in addition to the five strains of B. hermsii. Sequencing of the amplified fragments from one strain of B. hermsii as well as B. parkeri and B. turicatae allowed the design of oligonucleotide probes that were able to differentiate the three species of North American relapsing fever spirochetes into two separate groups. These studies suggest that there is sufficient diversity within the flagellin gene sequences of closely related Borrelia species to differentiate them into groups and to pursue taxonomic studies both within and between species.
The dermatological symptoms of Lyme borreliosis present with a typical clinical pattern and characteristic time of appearance. In contrast to other manifestations of Lyme borreliosis they are easily recognizable in most of the cases. In the first stage, erythema migrans arises at the tick bite site. With this symptom the diagnosis of Lyme borreliosis can be established. During all manifestations of Lyme borreliosis the history of erythema migrans is an important parameter to verify the diagnosis. In the early stage of disease a lymphocytic proliferation can appear at the tick bite site, at the ear lobe, or at the mamilla. Borrelia lymphocytoma can be diagnosed when antibodies against Borrelia burgdorferi are positive. Years after infection, acrodermatitis chronica atrophicans arises at distal body sites causing livid swelling and gradually skin atrophy. Skin lesions can be accompanied by neuropathies, mostly of the lower legs, which in contrast to the skin lesions, do not respond well to antibiotic therapy. There is evidence that some cases of Shulman syndrome, morphea and lichen sclerosus et atrophicus might be related to a borrelia infection as indicated by cultivation of B. burgdorferi from skin biopsies of morphea and response to antibiotic treatment in some cases. The classical dermatological symptoms of Lyme borreliosis, erythema migrans, borrelia lymphocytoma and acrodermatitis chronica atrophicans respond to oral antibiotic treatment. In acrodermatitis chronica atrophicans parenteral antibiotic therapy is sometimes necessary.
In this paper, we present a series of murine mAb recognizing B. burgdorferi antigens. The antibodies were characterized by immuno-blotting and immuno-fluorescence studies using isolates of B. burgdorferi from North America and Europe, respectively. Moreover, reactivity of the antibodies with recombinant B. burgdorferi flagellin and OspA was studied. The results suggest these anti-B. burgdorferi mAb as valuable tools for the serological analysis of B. burgdorferi isolates and for affinity-purification of the respective proteins. Moreover, these mAb appear suitable to classify antigenic variants of B. burgdorferi and to study the protective capacity of antibodies in a murine model for B. burgdorferi infection.
Attempts were made to culture spirochetes from cerebrospinal fluid samples of 105 patients suspected of having Lyme borreliosis with neurological complications. At the final evaluation, only 38 patients fulfilled the criteria of neuroborreliosis. Spirochetes were cultured from cerebrospinal fluid samples of four of these patients. All four patients had pleocytosis in their cerebrospinal fluid and a history of neurological symptoms of only 4 to 10 days in duration. Two of them had no detectable antibodies against any of the isolated spirochetes in their cerebrospinal fluid, both when tested with an enzyme-linked immunosorbent assay and when tested by immunoblotting. An antibody reaction against the homologous isolate that was distinctly stronger than that against the heterologous isolates was found in the serum and cerebrospinal fluid samples from one patient. The cells of the isolates were morphologically similar and showed a very similar protein pattern when analyzed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Cells of all isolates reacted with the monoclonal antibodies H5332 and H9724, which also react with Borrelia burgdorferi B31, the type strain. One isolate lost a major protein of 23 kilodaltons after subcultivation for 4 months. We conclude that isolation of spirochetes from cerebrospinal fluid might prove successful in clinically selected cases of Lyme borreliosis.
We examined 46 isolates of Borrelia burgdorferi, the etiologic agent of Lyme disease and related disorders, with polyacrylamide gel electrophoresis and monoclonal antibodies.
Our attention was on the OspA proteins, which are major proteins of the spirochete. There were at least four discernible phenotypes
of the OspA protein. While 25 North American isolates were, with one exception, homogeneous in the type of OspA protein that
they produced, 21 European isolates were heterogeneous in the types of OspA proteins represented. Only three European strains
resembled North American strains in their OspA phenotype. Application of a deoxyribonucleic acid probe for an ospA gene demonstrated that the arrangement of ospA-associated sequences in the DNA differed between isolates.
Deoxyribonucleic acid from 41 different bacterial species (including Gram-negative and Gram-positive species) were cleaved by different restriction endonucleases, electrophoresed in agarose and transferred to nylon filters. The DNA fragments carrying rRNA genes (rDNA) were localized by hybridization with a 32P-labelled Escherichia coli 16 + 23S rRNA probe. A pattern of hybridized fragments was obtained for each DNA tested. Within a bacterial species (defined as a DNA hybridization group), one or several rDNA restriction patterns were observed. When DNA hybridization data were available, strains showing identical patterns were highly related with insignificant divergence. In a species, different patterns corresponded to significant divergence, as evaluated by thermal stability studies of DNA/DNA hybrids. Sets of rDNA restriction fragment sizes might constitute useful data for inclusion in species and type strain descriptions. Such data might later prove useful in identification of bacteria when biochemical characteristics are poor or atypical.
Clinical symptoms were studied in 161 consecutive patients with erythema chronicum migrans Afzelius and in a follow-up study signs of late manifestations were investigated. General symptoms such as headache, fever, myalgia and/or arthralgia were found in about half of the patients with a disease duration of less than or equal to 3 weeks. Three patients had coexisting lymphadenosis benigna cutis. Two untreated patients developed meningitis/meningoradiculitis and one untreated patient arthritis. The importance of a sufficient antibiotic therapy to prevent late manifestations is stressed. Although there are many similarities between erythema chronicum migrans Afzelius and Lyme disease, the results of the present study also point to differences. Multiple skin lesions, pronounced general symptoms, laboratory abnormalities and major symptoms from the joints were less common in patients with erythema chronicum migrans Afzelius than reported in patients with Lyme disease, but a prolonged course of the skin eruption was more common.
Borrelia burgdorferi, the etiologic agent of Lyme borreliosis, was isolated from the CSF of a patient with elevated serum IgG antibody titers against B burgdorferi and a history of multiple tick bites. The absence of concurrent inflammatory signs of CSF as well as intrathecal antibody production indicates a phase of latent Lyme neuroborreliosis in which no tissue infection or reaction has yet occurred. Bilateral tinnitus was the only clinical symptom in this patient. The persistence of the bilateral tinnitus after antibiotic therapy did not support a causal relationship between this symptom and the borrelial infection.
Growth of Borrelia burgdorferi in a modified Kelly-medium is described. Borrelia strains were isolated from patients (n = 11) and ticks I. ricinus (n = 19). The modified medium which contained Co-trimoxazole is a very effective medium for isolating and culturing of Borrelia sp. The susceptibility of 7 strains of B. burgdorferi to antibiotics was studied by the macrodilution and microdilution test. After preliminary testing for optimal conditions, we determined MICs in modified Kelly medium. The MIC concentration of each antibiotic was determined as the lowest concentration which completely inhibited growth of the tested organism. The B. burgdorferi was most susceptible to Erythromycin with MIC of less than or equal to 0.15 microgram/ml. Of the Penicillins tested, Ampicillin and Mezlocillin were more active than Penicillin G. The use of Tetracycline-HCl is recommended because of its low MIC in vitro its extra- and intracellular efficiency.
The recent discovery that spirochetes transmitted by the tick Ixodes ricinus are involved in the etiology of erythema chronicum migrans Afzelius (ECMA), Bannwarth's syndrome, and acrodermatitis chronica atrophicans (ACA) has thrown new light upon these disorders. Thirty-two patients showing clinical and serological evidence of ACA were investigated. Histologically, constant findings in active ACA lesions were telangiectases and a lymphocytic infiltrate with a moderate to rich admixture of plasma cells. Clinically, besides ACA lesions, lichen sclerosus et atrophicus (LSA)-like lesions were found in five patients. Four of these patients displayed a histopathological picture compatible with LSA. These findings suggest a relationship between ACA and LSA. In six patients spontaneous healing of ECMA was followed by ACA lesions after a latency period of 1-8 years. Six patients reported histories of cranial nerve involvement. Radiography revealed subluxation of joints in hands or feet in six patients, and periosteal thickening in another three patients. The results indicate that ACA may be a late manifestation of infection with the same spirochete that causes ECMA and Bannwarth's syndrome. If untreated, the infection may continue for many years and result in irreversible degenerative lesions.
Using an improved method of gel electrophoresis, many hitherto unknown
proteins have been found in bacteriophage T4 and some of these have been
identified with specific gene products. Four major components of the
head are cleaved during the process of assembly, apparently after the
precursor proteins have assembled into some large intermediate
structure.
Late cutaneous Lyme disease: acrodermatitis chronica atrophicans
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Kaufman LD, Gruber BL, Phillips ME, Benach JL. Late cutaneous Lyme disease: acrodermatitis chronica atrophicans. Am J Med 1989;86:828-30. at University of Manchester on October 16, 2014 http://cid.oxfordjournals.org/ Downloaded from