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(A) Salivarian trypanosomes use antigenic variation of their surface coat as a first line of defense against host antibody attack. During early infection, quorum sensing ensures that peak parasitemia does not reach lethal levels (1). After clearance of the first variant, parasitemia is characterized by the presence of parasites expressing a novel VSG coat, usually giving rise to several lowpeak infections (2). Improved peak control results from a combination of antibody activity, innate inflammatory responses and intrinsic quorum sensing. Subsequent parasitemia waves start to be comprised of multiple VSG variants that occur at the same time, indicating a loss of proper antibody-mediated parasite population control. In experimental models, infection will most often result in late-stage uncontrolled parasitemia and death ( †). (B) As early parasitemia progresses in mice, infection-associated splenomegaly results in an initial increase in organ size and cellularity (7 dpi). By 14 dpi, spleen cell numbers usually drop and important populations such as Marginal Zone B cells start to disappear. Organ structure is also completely destroyed. As infection progresses, most adaptive immune cell populations collapse, while the spleen is being filled with non-immune cells such as pre-erythrocytes. This stage of spleen dysfunction coincides with the loss of parasitemia control. The diameter of the pie-charts is representative of the total spleen numbers during infection. Percentages of all major immune cell populations are indicated in the color-coded pie charts.
Source publication
Salivarian trypanosomes are extracellular parasites affecting humans, livestock and game animals. Trypanosoma brucei rhodesiense and Trypanosoma brucei gambiense are human infective sub-species of T. brucei causing human African trypanosomiasis (HAT—sleeping sickness). The related T. b. brucei parasite lacks the resistance to survive in human serum...
Context in source publication
Context 1
... latter could be considered as collateral damage, but the loss of anti-VSG memory by the host means that 'old' or 'previously used' VSG molecules can be reused later on in infection. In addition, newly arising mosaic VSG variants that can carry cross-reactive epitopes can also be expressed on the surface as fully functional VSG coats [94] (Figure 3). Deregulation of the B cell compartment by the trypanosome also requires a parasite intervention at the T cell level, as these cells play a crucial role in the resistance to trypanosomiasis [95]. ...
Similar publications
While both human and animal trypanosomiasis continue to present as major human and animal public health constraints globally, detailed analyses of trypanosome wildlife reservoir hosts remain sparse. African animal trypanosomiasis (AAT) affects both livestock and wildlife carrying a significant risk of spillover and cross-transmission of species and...
Citations
... Protozoan parasites of the genus Trypanosoma, most prominently including T. brucei spp, T. congolense, T. simiae, T. vivax, T. evansi and T. equiperdum, cause a wide range of diseases affecting humans and animals. With the exception of T. equiperdum, which is transmitted by copulation, pathogenic trypanosomes are mostly transmitted by insect vectors (Magez et al., 2021) and in parts of South America also by vampire bats (Herrera et al., 2004). In Africa south of the Sahara, trypanosomiasis is mostly transmitted by the tsetse fly and known as African animal trypanosomiasis (AAT) or nagana, whereas beyond the tsetse belt, T. vivax and T. evansi are transmitted by other haematophagous flies such as tabanids and Stomoxys spp. ...
Animal trypanosomiasis (AT) is a complex of veterinary diseases known under various names such as nagana, surra, dourine and mal de caderas, depending on the country, the infecting trypanosome species and the host. AT is caused by parasites of the genus Trypanosoma, and the main species infecting domesticated animals are T. brucei brucei, T. b. rhodesiense, T. congolense, T. simiae, T. vivax, T. evansi and T. equiperdum. AT transmission, again depending on species, is through tsetse flies or common Stomoxys and tabanid flies or through copulation. Therefore, the geographical spread of all forms of AT together is not restricted to the habitat of a single vector like the tsetse fly and currently includes almost all of Africa, and most of South America and Asia. The disease is a threat to millions of companion and farm animals in these regions, creating a financial burden in the billions of dollars to developing economies as well as serious impacts on livestock rearing and food production. Despite the scale of these impacts, control of AT is neglected and under-resourced, with diagnosis and treatments being woefully inadequate and not improving for decades. As a result, neither the incidence of the disease, nor the effectiveness of treatment is documented in most endemic countries, although it is clear that there are serious issues of resistance to the few old drugs that are available. In this review we particularly look at the drugs, their application to the various forms of AT, and their mechanisms of action and resistance. We also discuss the spread of veterinary trypanocide resistance and its drivers, and highlight current and future strategies to combat it.
... Human African trypanosomiasis (HAT), also referred to as sleeping sickness, is a neglected disease solely found in Africa, and it is caused by Trypanosoma brucei-a parasitic protozoan transmitted to mammals through the bite of an infected tsetse fly (Dunn et al., 2021). Two subspecies of T. brucei, T. b. gambiense and T. b. rhodesiense, cause HAT in humans (Magez et al., 2021). If untreated, the illness is almost always lethal (Beteck et al., 2019). ...
Trypanosomes and Leishmania are parasitic protozoans that affect millions of people globally. Herein we report the synthesis of 2-aroyl quinazolinones and their antiprotozoal efficacy against Trypanosoma brucei, Trypanosoma brucei rhodesiense, Trypanosoma cruzi, and Leishmania infantum. These compounds were counter-screened against a human cell line for cytotoxicity. Thirteen of the twenty target compounds in this study inhibited the growth of these parasites, with compounds KJ1, and KJ10 exhibiting IC50 values of 4.7 μM (T. b. brucei) and 1.1 μM (T. b. rhodesiense), respectively.
... The invertebrate vectors of trypanosomes include dipterans (e.g. mosquitoes, biting midges and hippoboscid louse flies), triatomine bugs and leeches (Ramos and Urdaneta-Morales, 1977), in which the trypomastigotes typically undergo complex development, transforming into several different stages before infecting a new host (Magez et al., 2021;Vanhove et al., 2022). Generally, trypanosomes alternate between infecting a vertebrate and invertebrate host during their lifecycles (Hamilton et al., 2007). ...
The aquatic and terrestrial clades of species of Trypanosoma could provide insight into the evolutionary history of the genus, as well as complementary information for biomedical studies of medically and economically important species of Trypanosoma . The ecological interactions and phylogeny of aquatic trypanosomes are currently not well-understood, mostly due to their complex life cycles and a deficiency of data. The species of Trypanosoma from African anuran hosts are of the least understood taxa in the genus. Trypanosomes were collected from South African frogs and subjected to morphological and phylogenetic analyses. This study redescribes Trypanosoma ( Trypanosoma ) nelspruitense Laveran, 1904 and Trypanosoma ( Haematomonas ) grandicolor Pienaar, 1962, with morphological and molecular data. The present study aims to create a platform for further future research on African anuran trypanosomes.
... Therefore, T. evansi parasites rely on mechanical transmission by several species of hematophagous flies (4). This has allowed the parasite to spread from the African tsetse belt to other parts of the world (5). In contrast, tsetse transmitted animal infections caused by T. brucei and T. congolense, as well as human trypanosomiasis caused by T. b. gambiense and T. b. rhodesiense, are restricted to sub-Saharan Africa (6). ...
Introduction
Trypanosoma evansi parasite infections cause a chronic animal wasting disease called Surra, and cases of atypical Human Trypanosomosis (aHT). In experimental models, T. evansi infections are hallmarked by the early onset of excessive inflammation. Therefore, balancing the production of inflammatory cytokines by anti-inflammatory IL-10 is crucial for prolonged survival.
Methods
To improve the understanding of trypanosomosis induced immunopathology, we used scRNA-seq data from an experimental chronic T. evansi infection mouse model, resembling natural infection in terms of disease characteristics.
Results and discussion
For the first time, obtained results allowed to assess the transcriptomic profile and heterogeneity of splenic CD4 ⁺ T cell subsets, during a trypanosome infection. Here, the predominant subpopulation of T cells was represented by Tbx21 (T-bet) ⁺ Ccr5 ⁺ Id2 ⁺ type 1 helper T cells (Th1), followed by Icos ⁺ Cxcr5 ⁺ Follicular T helper cells (Tfh) and very minor fraction of Il2ra (CD25) ⁺ Foxp3 ⁺ regulatory T cells (Tregs). Interestingly, the profile of Th1 cells shows that besides Ifng , these cells express high levels of Il10 and Il21 , coding for anti-inflammatory and immunoregulatory cytokines. This coincides with the elevated expression of key genes involved in IL-10 and IL-21 secretion pathway such as Stat1 and Stat3 , as well as the transcriptional factors Prdm1 (Blimp 1), and Maf (c-Maf). In contrast, there is virtually no IL-10 transcription detected in the Treg population. Finally, differential gene expression and gene ontology analysis of infection-induced Ifng ⁺ Il10 ⁺ Il21 ⁺ Th1 cells highlights their suppressive function on T cell activation, differentiation and INF-γ production itself. This indicates that during trypanosome infections, the Ifng ⁺ Il10 ⁺ Il21 ⁺ Th1 cells, rather than Tregs, assume an immune regulatory role that is needed for dampening inflammation.
... Subsequently, other pathogenic insect-transmitted animal trypanosomes were described, including T. congolense and T. vivax, and a sexually transmitted parasite, i.e., T. equiperdum, was found to specifically affect equines. Interestingly, salivarian trypanosomes are unique parasites in the sense that despite their unicellular small size, they live freely in the blood and lymphatics of their host, without using any intracellular "hiding" mechanisms that would protect them from being attacked by the host's immune system (6). They are able to do so, as they have developed an intricate system of antigenic variation of their surface coat that allows trypanosomes to evade elimination by antibodies and other adaptive immune system components. ...
... Finally, the CATT sensitivity and specificity values range between 87 and 98% (15) ( Table 1), but can be affected by (i) a low parasitemia, or (ii) the setting, as patients from different places can be infected with different strains of T. b gambiense, some lacking or not expressing the LiTat 1.3 gene (15,24,25). Considering the current situation of HAT prevalence (less than 0.1%), the occurrence of a relatively large number of false negative cases will not impact the overall negative predictive value (NPV) of the test, reaching 99% (6,26). However, the opposite situation arises for the positive predictive value (PPV) of the test, when large number of false positive cases occur (26). ...
Human African Trypanosomiasis (HAT) is caused by unicellular flagellated protozoan parasites of the genus Trypanosoma brucei. The subspecies T. b. gambiense is mainly responsible for mostly chronic anthroponotic infections in West- and Central Africa, accounting for roughly 95% of all HAT cases. Trypanosoma b. rhodesiense results in more acute zoonotic infections in East-Africa. Because HAT has a two-stage pathogenesis, treatment depends on clinical assessment of patients and the determination whether or not parasites have crossed the blood brain barrier. Today, ultimate confirmation of parasitemia is still done by microscopy analysis. However, the introduction of diagnostic lateral flow devices has been a major contributor to the recent dramatic drop in T. b. gambiense HAT. Other techniques such as loop mediated isothermal amplification (LAMP) and recombinant polymerase amplification (RPA)-based tests have been published but are still not widely used in the field. Most recently, CRISPR-Cas technology has been proposed to improve the intrinsic diagnostic characteristics of molecular approaches. This will become crucial in the near future, as preventing the resurgence of HAT will be a priority and will require tools with extreme high positive and negative predicted values, as well as excellent sensitivity and specificity. As for treatment, pentamidine and suramin have historically been the drugs of choice for the treatment of blood-stage gambiense-HAT and rhodesiense-HAT, respectively. For treatment of second-stage infections, drugs that pass the blood brain barrier are needed, and melarsoprol has been effectively used for both forms of HAT in the past. However, due to the high occurrence of post-treatment encephalopathy, the drug is not recommended for use in T. b. gambiense HAT. Here, a combination therapy of eflornithine and nifurtimox (NECT) has been the choice of treatment since 2009. As this treatment requires IV perfusion of eflornithine, efforts were launched in 2003 by the drugs for neglected disease initiative (DNDi) to find an oral-only therapy solution, suitable for rural sub-Saharan Africa treatment conditions. In 2019 this resulted in the introduction of fexinidazole, with a treatment regimen suitable for both the blood-stage and non-severe second-stage T. b. gambiense infections. Experimental treatment of T. b. rhodesiense HAT has now been initiated as well.
... The AAT data of Cameroon in 2020 shows that the disease occurs beyond the tsetse belt (Abah, 2020). A near-worldwide Trypanosoma species distribution map by Magez et al. (2021) revealed the presence of only T. congolense, T. vivax, T. brucei brucei, and T. brucei gambiense in Cameroon, but previous molecular studies reveals the circulation of T. evansi, T. grayi, T. theileri, T. simiae in animals and tsetse (Nimpaye et al., 2011;Ngomtcho et al., 2017). AAT-causing T. vivax have been reported in cattle in the tsetse free (tabanid infested) area of the Far North region and it was suggested to be transmitted by tabanids that were observed around domestic animals (Mamoudou et al., 2016;Fongho et al., 2017;Fongho et al., 2019). ...
The role of tabanids as potential transmitters of animal trypanosomiasis (AAT) has not yet been established in Cameroon. The objectives of this study were: (i) to trap and determine the species richness and abundance of tabanids, (ii) to identify circulating trypansomes in cattle and tabanids in a tsetse free area. A three year (2015 to 2017) tabanid survey in six regions of Cameroon was conducted. In Galim village, which is in a tsetse free area, both tabanids and cattle blood samples were screened by PCR for the presence of trypanosome DNA. Tabanids were diverse in Littoral (13 species) and in Adamawa (13 species), but were abundant in the Far North region (36.37 to 145.58 tabanids per trap per day (t/t/d)). In Galim, the tabanid trypanosomal DNA presence was 24.4% (95% CI: 11.25-37.53), while the bovine trypanosomal DNA presence was 4.8% (95% CI: 1.68-11.20). In this village, the Trypanosoma spp. identified in tabanids were T. theileri, T. vivax and T. evansi, while those in cattle were T. theileri and T. vivax. The control of tabanids is required to stop the mechanical spread of AAT in tsetse free areas.
... The AAT data of Cameroon in 2020 shows that the disease occurs beyond the tsetse belt (Abah, 2020). A near-worldwide Trypanosoma species distribution map by Magez et al. (2021) revealed the presence of only T. congolense, T. vivax, T. brucei brucei, and T. brucei gambiense in Cameroon, but previous molecular studies reveals the circulation of T. evansi, T. grayi, T. theileri, T. simiae in animals and tsetse (Nimpaye et al., 2011;Ngomtcho et al., 2017). AAT-causing T. vivax have been reported in cattle in the tsetse free (tabanid infested) area of the Far North region and it was suggested to be transmitted by tabanids that were observed around domestic animals (Mamoudou et al., 2016;Fongho et al., 2017;Fongho et al., 2019). ...
The role of tabanids as potential transmitters of animal trypanosomiasis (AAT) has not yet been established in Cameroon. The objectives of this study were: (i) to trap and determine the species richness and abundance of tabanids, (ii) to identify circulating trypansomes in cattle and tabanids in a tsetse free area. A three year (2015 to 2017) tabanid survey in six regions of Cameroon was conducted. In Galim village, which is in a tsetse free area, both tabanids and cattle blood samples were screened by PCR for the presence of trypanosome DNA. Tabanids were diverse in Littoral (13 species) and in Adamawa (13 species), but were abundant in the Far North region (36.37 to 145.58 tabanids per trap per day (t/t/d)). In Galim, the tabanid trypanosomal DNA presence was 24.4% (95% CI: 11.25–37.53), while the bovine trypanosomal DNA presence was 4.8% (95% CI: 1.68–11.20). In this village, the Trypanosoma spp. identified in tabanids were T. theileri, Tabanus vivax and T. evansi, while those in cattle were T. theileri and T. vivax. The control of tabanids is required to stop the mechanical spread of AAT in tsetse free areas.
... There have been several recent developments in the diagnosis of AT towards understanding the disease transmission and distribution which is necessary for any successful treatment [17]. These advances have enabled accurate detection and identification of previously unidentified zoonotic Trypanosoma species [18]. ...
Background
Trypanosomiasis is a fatal disease that threatens the economy of at least 37 countries in sub-Saharan Africa, particularly with regard to livestock farming. In this study, we investigated the prevalence of trypanosome infection in cattle, and molecularly identified the species of trypanosomes in infected cattle and the spatial distribution of trypanosome-infected herds along the Jebba axis of the River Niger.
Methods
A randomized cross-sectional study was conducted along the Jebba axis of the River Niger by screening cattle from 36 herd clusters by nested PCR using ITS-1 generic primers. Data generated were analysed using the Chi-square test at a 95% confidence interval.
Results
Microscopic examination revealed three infected cattle out of 398 examined, representing 0.8% prevalence. Twelve animals (3.0%) were positive by PCR. Our results showed a decline in the packed cell volume of infected animals (24.7%). The infection rates were categorized as single infection in 11/12 (91.7%) and mixed infection in 1/12 (8.3%). Animals were most frequently infected by Trypanosoma congolense (50.0%), with T. congolense Savannah being the most prevalent subspecies (71.4%). Aside from the infection rate by age (10.0%) and relative distance of animals from the River Niger (56.2%), statistical differences in every other parameter tested were based on mere probabilistic chance. Spatial data showed that the disease was prevalent among herds located less than 3 km from the River Niger.
Conclusions
Six species of trypanosomes were identified in cattle herds along the Jebba axis of the River Niger, with T. congolense being the most prevalent. Age and relative distance of herds from the River Niger may be risk factors for trypanosome infection in cattle herds in this area.
Graphical abstract
... Within the group of mammalian parasites, salivarian trypanosomes must be considered as rather unique, as they have adopted all necessary means to survive in plain sight of the host immune system [24]. They are extracellular single-cell organisms that should in principle be easily targeted by the phagocytic as well as the antibody-mediated immune system, yet they thrive in the blood and lymphatics of their host, and cause infections that can perpetuate for years. ...
Salivarian trypanosomes comprise a group of extracellular anthroponotic and zoonotic parasites. The only sustainable method for global control of these infection is through vaccination of livestock animals. Despite multiple reports describing promising laboratory results, no single field-applicable solution has been successful so far. Conventionally, vaccine research focusses mostly on exposed immunogenic antigens, or the structural molecular knowledge of surface exposed invariant immunogens. Unfortunately, extracellular parasites (or parasites with extracellular life stages) have devised efficient defense systems against host antibody attacks, so they can deal with the mammalian humoral immune response. In the case of trypanosomes, it appears that these mechanisms have been perfected, leading to vaccine failure in natural hosts. Here, we provide two examples of potential vaccine candidates that, despite being immunogenic and accessible to the immune system, failed to induce a functionally protective memory response. First, trypanosomal enolase was tested as a vaccine candidate, as it was recently characterized as a highly conserved enzyme that is readily recognized during infection by the host antibody response. Secondly, we re-addressed a vaccine approach towards the Invariant Surface Glycoprotein ISG75, and showed that despite being highly immunogenic, trypanosomes can avoid anti-ISG75 mediated parasitemia control.
