Figure - available via license: CC BY
Content may be subject to copyright.
Guidelines for treatment of filarial parasite infections through preventive chemotherapy mass drug administration campaigns.
Source publication
The intracellular bacteria now known as Wolbachia were first described in filarial worms in the 1970s, but the idea of Wolbachia being used as a macrofilaricidal target did not gain wide attention until the early 2000s, with research in filariae suggesting the requirement of worms for the endosymbiont. This new-found interest prompted the eventual...
Contexts in source publication
Context 1
... treatments against filarial worms (ivermectin, diethylcarbamazine (DEC), albendazole) (Table 2), alone or in combination (Table 3), are only partially effective against the long-lived macrofilariae. While the combination of DEC and albendazole has been reported to exhibit significant macrofilaricidal activity against worms that cause lymphatic filariasis [28,29] the main effect of the treatments is to temporarily sterilize the adults. ...Context 2
... neurological severe adverse events (SAEs) can cause loss of consciousness, can be fatal and are associated with high titers of L. loa microfilariae in the blood (>30,000 microfilariae/mL). Therefore, treatments for onchocerciasis in L. loa co-endemic areas are not recommended and in the case of LF, albendazole monotherapy may be applied (Table 3); however, the overall antifilarial effectiveness (microfilariae prevalence measured over 2 weeks to 12 months after treatment) of albendazole has been questioned [35], and other approaches are being investigated. For example, the Test and Not Treat (TnT) method, enabled by development of a mobile phone microscope, advocates for identification of patients who should not receive microfilaricidal treatment due to high burdens of circulating L. loa microfilariae and the associated risk of developing SAEs. ...Context 3
... neurological severe adverse events (SAEs) can cause loss of consciousness, can be fatal and are associated with high titers of L. loa microfilariae in the blood (>30,000 microfilariae/mL). Therefore, treatments for onchocerciasis in L. loa co-endemic areas are not recommended and in the case of LF, albendazole monotherapy may be applied (Table 3); however, the overall antifilarial effectiveness (microfilariae prevalence measured over 2 weeks to 12 months after treatment) of albendazole has been questioned [35], and other approaches are being investigated. For example, the Test and Not Treat (TnT) method, enabled by development of a mobile phone microscope, advocates for identification of patients who should not receive microfilaricidal treatment due to high burdens of circulating L. loa microfilariae and the associated risk of developing SAEs. ...Context 4
... neurological severe adverse events (SAEs) can cause loss of consciousness, can be fatal and are associated with high titers of L. loa microfilariae in the blood (>30,000 microfilariae/mL). Therefore, treatments for onchocerciasis in L. loa co-endemic areas are not recommended and in the case of LF, albendazole monotherapy may be applied (Table 3); however, the overall antifilarial effectiveness (microfilariae prevalence measured over 2 weeks to 12 months after treatment) of albendazole has been questioned [35], and other approaches are being investigated. For example, the Test and Not Treat (TnT) method, enabled by development of a mobile phone microscope, advocates for identification of patients who should not receive microfilaricidal treatment due to high burdens of circulating L. loa microfilariae and the associated risk of developing SAEs. ...Context 5
... neurological severe adverse events (SAEs) can cause loss of consciousness, can be fatal and are associated with high titers of L. loa microfilariae in the blood (>30,000 microfilariae/mL). Therefore, treatments for onchocerciasis in L. loa co-endemic areas are not recommended and in the case of LF, albendazole monotherapy may be applied (Table 3); however, the overall antifilarial effectiveness (microfilariae prevalence measured over 2 weeks to 12 months after treatment) of albendazole has been questioned [35], and other approaches are being investigated. For example, the Test and Not Treat (TnT) method, enabled by development of a mobile phone microscope, advocates for identification of patients who should not receive microfilaricidal treatment due to high burdens of circulating L. loa microfilariae and the associated risk of developing SAEs. ...Citations
... The key disadvantage is that treatments require the drug to be administered daily for four to six weeks, which makes control programmes using these drugs logistically complex and financially challenging to implement (Ta-Tang et al., 2021;Ferreira et al., 2023). Because this long treatment time affects the viability of antibiotic-based filarial control programmes, a great amount of effort and financial resources have been invested in identifying alternative Wolbachia-targeting drugs with shorter treatment times (Bakowski and McNamara, 2019;Johnston et al., 2021). Thus, a number of curative short-course anti-Wolbachia drugs for onchocerciasis and lymphatic filariasis are now available at various stages of clinical trials (Johnston et al., 2021;Ehrens et al., 2022b). ...
... Two anti-Wolbachia drugs (CC6166 and Corallopyronin A) are presently in phase I clinical trials and could help to bring down treatment times significantly, possibly to seven days or less. It thus seems likely that elimination by MDA of both onchocerciasis and mansonellosis in the Brazilian Amazon and beyond is now closer than ever before (Bakowski and McNamara, 2019;Ta-Tang et al., 2021;Ferreira et al., 2023). Anti-Wolbachia drugs could also potentially be used synergistically to control other neglected tropical diseases of the Amazon region and potentially in combination with classical antihelminthic drugs like ivermectin too. ...
Following the successful eradication of Wuchereria bancrofti, there are now just three species of conventional microfilaremic human filarial parasites endemic to the Brazilian Amazon region: Mansonella ozzardi, Mansonella perstans and Onchocerca volvulus. The zoonotic filarial parasite Dirofilaria immitis is also found in the Amazon region as are several sylvatic filarial parasites, some of which have been recorded causing zoonoses and some of which have never been recorded outside the region. Onchocerca volvulus is only found in the Amazonia onchocerciasis focus in the Brazilian state of Roraima where it affects the people of the Yanomami tribe living around the densely forested Venezuela border region. Mansonella ozzardi is by far the most common filarial parasite in Brazil and has a broad but patchy distribution throughout the western Amazon region. Recorded in the Brazilian states of Acre, Roraima, Matto Grosso, and within almost every municipality of Amazonas state, it is believed that pollution of the urban stream and river systems prevents the development of the simuliid vectors of M. ozzardi and explains the parasiteʼs reduced distribution within urban areas and an absence of recent reports from the state capital Manaus. Decades of WHO-led periodic ivermectin treatment of Yanomami tribeʼs people have resulted in the partial suppression of O. volvulus transmission in this focus and has also probably affected the transmission of M. ozzardi in the region. Mansonella perstans, O. volvulus and very probably M. ozzardi infections can all be treated and most likely cured with a 4–6-week treatment course of doxycycline. The Brazilian Ministry of Health does not, however, presently recommend any treatment for mansonellosis infections and thus parasitic infections outside the Amazonia focus are typically left untreated. While the long treatment courses required for doxycycline-based mansonellosis therapies preclude their use in control programmes, new fast-acting filarial drug treatments are likely to soon become available for the treatment of both onchocerciasis and mansonellosis in the Amazon region. Filarial disease management in the Brazilian Amazon is thus likely to become dramatically more viable at a time when the public health importance of these diseases is increasingly being recognized.
... Although we have not been able to establish the exact size of the wDgra genome in our study, we established that it is larger than its closets relative (wDcau), which is the smallest reported Wolbachia genome to date (Lefoulon et al. 2020). With Wolbachia genomics having an increasingly important role in the development of filarial parasite therapeutics and small genomes being especially valuable for comparative genomics studies, it is also possible that the Wolbachia contigs reported here could be of use to studies beyond those focused on filarial parasite identification and systematics, and be of value for comparative genomics studies assessing what genes and metabolic pathways are essential for Wolbachia functionality (Slatko et al. 2010;Bennuru et al. 2017;Bakowski et al. 2019). ...
The primates that inhabit the rainforest surrounding the city of Manaus (Amazonas, Brazil) have long been recognised as potentially important reservoirs of emerging and re-emerging infectious diseases (ERIDs). PCR amplification of filarial sequences from wild-caught Simulium oyapockense has been used to incriminate potentially important Amazon-region ERID bridge vectors by showing they had previously fed on non-human primates. The broader use of filarial parasite sequences for the incrimination of biting insects as potentially important zoonotic disease vectors is limited by a paucity of primate-derived filarial parasite reference sequences which can be matched to the PCR amplified sequences obtained from insect-vector vectors. Here we have used shotgun sequencing to obtain reference data from an adult Dipetalonema gracile parasite which was found infecting a wild pied tamarin (Saguinus bicolor) in a peripheral region of Manaus. We report the parasite´s complete mitochondrial genome (which is 13,647 base pairs in length), 894,846 base pairs of its Wolbachia genome and 6,426 base pairs of its ribosomal DNA locus (spanning from the start of its 18S subunit to the end of its 28S subunit). Despite being critically endangered, S. bicolor is commonly encountered around the periphery of Manaus and in urban forest fragments. The reported sequences may be a useful reference tool for identifying ERID bridge vectors and potentially provide some insights into the amount and the nature of contact between primate pathogen reservoirs and the residents of Manaus.
KEYWORDS:
zoonotic filariasis; non-human primates; Amazonia; emerging infectious disease
... In the search for new anti-filarial drugs, some researchers have chosen Wolbachia as an anti-filarial drug target. Previous research has shown that eliminating Wolbachia from the host filarial nematodes leads to anti-filarial effects by reducing adult worm's lifespan 8,9 . Although the anti-bacteria drug doxycycline has been used clinically for the treatment of filarial diseases over the years, the treatment method is not efficient enough for use through MDA owing to its requirement for extended treatment periods (4-6 weeks) as well as contraindications in pregnancy and children 9 . ...
... Previous research has shown that eliminating Wolbachia from the host filarial nematodes leads to anti-filarial effects by reducing adult worm's lifespan 8,9 . Although the anti-bacteria drug doxycycline has been used clinically for the treatment of filarial diseases over the years, the treatment method is not efficient enough for use through MDA owing to its requirement for extended treatment periods (4-6 weeks) as well as contraindications in pregnancy and children 9 . Therefore, advances in developing new anti-Wolbachia agents with short treatment periods and reduced complications are necessary. ...
Filariasis (Lymphatic filariasis and Onchocerciasis) is a common neglected tropical disease caused by parasitic nematodes called filarial worms, which often host the Wolbachia bacteria. A good treatment approach seeks Wolbachia as a drug target. Here, a computer-aided design of some boron-pleuromutilin analogs was conducted using the ligand-based drug design approach while performing molecular docking investigation and pharmacokinetics analyses to evaluate their drug-likeness properties. The newly designed compounds (49a, 49b, and 49c) showed improved inhibitory activities (pEC50) over those of the template and the clinically relevant pleuromutilins (retapamulin and lefamulin) in the order; 49b (pEC50 = 9.0409) > 49c (8.8175) > 49a (8.5930) > template (49) (8.4222) > retapamulin (6.7403) > lefamulin (6.1369). Standard docking performed with OTU deubiquitinase (6W9O) revealed the order of binding energies; 49c (-88.07 kcal/mol) > 49b (-84.26 kcal/mol) > doxycycline (-83.70 kcal/mol) > template (-82.57 kcal/mol) > 49a (-78.43 kcal/mol) > lefamulin (-76.83 kcal/mol) > retapamulin (-76.78 kcal/mol), with the new compounds all showing good pharmacological interactions with the receptor’s amino acids. The new analogs were also predicted to be orally bioavailable with better pharmacokinetic profiles than the template, retapamulin, lefamulin, and doxycycline having no more than one violation of Lipinski’s ROF. Therefore, the newly designed compounds could be considered potential anti-filarial drug candidates.
... A heightened awareness of the disease´s presence within Manaus should also be encouraged; there are effective treatments and prophylactics available for D. immitis infections and thus if Manaus veterinary practitioners and companion animal owners who live in the city are made aware of them the parasites transmission could be reduced (Simón et al., 2012, Turner et al., 2020. At present it is recommended that D. immitis infections are treated with a 28-day program of doxycycline in combination with ivermectin and melarsomine (Turner et al., 2020;Ta-Tang et al., 2021;Simón et al., 2012), however, it is very likely that faster-acting curative treatments for Dirofilariosis infections will soon be made available (Bakowski & McNamara, 2019;Turner et al., 2020). There is therefore also a need for Manaus´s veterinarians and companion animal owners to stay abreast of the latest developments in D. immitis treatment options. ...
Short Communication Braz J Vet Parasitol 2023; 32(2): e000223 | https://doi. This is an Open Access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Dirofilaria immitis is endemic in rural areas of the Brazilian Amazonas state capital, Manaus Dirofilaria immitis é endêmica em áreas rurais da capital do estado do Amazonas, Manaus How to cite: Barbosa UC, Nava AFD, Ferreira Neto JV, Dias CA, Silva VC, Mesquita HG, et al. Dirofilaria immitis is endemic in rural areas of the Brazilian Amazonas state capital, Manaus. Braz J Vet Parasitol 2023; 32(2): e000223. https://doi. Abstract The canine filarial parasite Dirofilaria immitis has not been reported in Brazil´s Amazonas state capital, Manaus, for over a century. Here, we report one imported and 27 autochthonous D. immitis infections from a microfilarial survey of 766 domestic dog blood samples collected between 2017 and 2021 in Manaus. An Overall prevalence estimate of 15.44% (23/149) was calculated from our two rural collection sites; a prevalence of 1.22% (4/328) was estimated at our periurban collection site, and an overall prevalence of 0.35% (1/289) was calculated from our two urban clinic collections. Our data suggest that in the urban areas of Manaus, where the parasites are very likely vectored by the same species of mosquito that historically vectored Wuchereria bancrofti (Culex quinquefasciatus), prevalence levels are very low and possibly maintained by an influx from rural areas where sylvatic reservoirs and/or more favorable vector transmission dynamics maintain high prevalences. Resumo O parasita filarial canino Dirofilaria immitis causa doença zoonótica mas não tem sido registrado na capital do estado do Amazonas, há mais de um século. Neste trabalho relatamos uma infecção por D. immitis alóctone e 27 autóctones de um levantamento de microfilárias em 766 amostras de sangue em cães domésticos, coletados entre 2017 e 2021 em Manaus. A prevalência de 15,44% (23/149) foi estabelecida em áreas rurais, 1,22% (4/328) para áreas periurbanas e de 0,35% (1/289) para duas clínicas veterinárias localizadas na zona urbana da cidade. Nossos dados sugerem, portanto, que nas áreas urbanas de Manaus, onde o parasita é muito provavelmente vetorizado pela mesma espécie de mosquito que historicamente transmitiu Wuchereria bancrofti (Culex quinquefasciatus), os níveis de prevalência são baixos e possivelmente mantidos por um influxo de áreas rurais onde reservatórios silvestres e/ou dinâmicas de transmissão vetorial mais favoráveis mantêm uma prevalência mais elevada.
... Targeting the endosymbiont Wolbachia to sterilize and slowly kill adult worms is an alternative strategy, and doxycycline has been successfully used in a test-and-treat approach for onchocerciasis 41 . High-throughput screening has recently identified a number of anti-Wolbachia leads that exhibit desirable preclinical traits, some of which are now in clinical trials [42][43][44][45] . However, compounds that act directly on parasites are still highly desirable, even if leveraging high-throughput technologies to identify them are hindered. ...
Development of direct acting macrofilaricides for the treatment of human filariases is hampered by limitations in screening throughput imposed by the parasite life cycle. In vitro adult screens typically assess single phenotypes without prior enrichment for chemicals with antifilarial potential. We developed a multivariate screen that identified dozens of compounds with submicromolar macrofilaricidal activity, achieving a hit rate of >50% by leveraging abundantly accessible microfilariae. Adult assays were multiplexed to thoroughly characterize compound activity across relevant parasite fitness traits, including neuromuscular control, fecundity, metabolism, and viability. Seventeen compounds from a diverse chemogenomic library elicited strong effects on at least one adult trait, with differential potency against microfilariae and adults. Our screen identified five compounds with high potency against adults but low potency or slow-acting microfilaricidal effects, at least one of which acts through a novel mechanism. We show that the use of microfilariae in a primary screen outperforms model nematode developmental assays and virtual screening of protein structures inferred with deep learning. These data provide new leads for drug development, and the high-content and multiplex assays set a new foundation for antifilarial discovery.
... Wolbachia, endosymbiotic bacteria that lives within D. immitis, is involved in both the damage caused by HWD and the worm's survival [35][36][37]. Thus, eliminating Wolbachia is important in both microfilaricide and adulticide therapy. ...
Canine dirofilariasis is a global parasitic disease caused by Dirofilaria immitis with a pooled prevalence of 10.91%. Given the zoonotic potential and clinical importance of canine dirofilariasis, investigating its diagnosis and treatment is deemed important, which may also help to control its prevalence. Current diagnostic methods include microfilarial tests, immunodiagnostic antigen tests, polymerase chain reaction technique, and imaging. In which the combination of microfilarial tests and antigen tests is recommended to use in annual screening due to the established specificity, sensitivity, and accuracy. Despite the high accuracy of polymerase chain reaction technique, it has not been broadly used in commercial settings. Imaging, on the other hand, helps to determine the severity of infection. In terms of treatment, 3 injections of melarsomine dihydrochloride with adjunct use of macrocyclic lactones and tetracyclines are recommended to all dogs, except those with caval syndrome. However, due to inevitable severe complications, prevention is deemed vital. The use of macrocyclic lactones for prevention is preferred and highly recommended to all owners.
... Rifampicin, an inhibitor of bacterial DNA-dependent RNA polymerase, exerts macrofilaricidal activity more rapidly than doxycycline in vitro and in animal models [111]. However, two-and four-week standard dosing regimens were not fully macrofilaricidal in onchocerciasis patients [112]. ...
... Interest in this area has led to the identification of several new antibiotics that hold some promise for achieving high macrofilaricidal efficacy in acceptably short courses [111,115,116]. A derivative of tylosin ( Figure 10.9), an antibiotic macrolide used in veterinary medicine, has advanced into development [117,118]. ...
... Although mechanism of action studies have not been published, it is reasonable to assume that this derivative, TylaMac, acts like the prototype of the series as a bacteriostatic inhibitor of protein synthesis in Wolbachia through interactions with the 50S ribosomal subunit. Additional antibiotics with macrofilaricidal activity have been discovered in phenotypic screens; included are a number with unknown mechanisms of action as well as inhibitors of protein synthesis and of bacterial DNA-dependent RNA polymerase [111,115,116]. ...
Filarial parasites of humans and animals represent a heterogeneous group of pathogenic nematodes, interacting throughout their life cycles with two hosts and, for most species, a bacterial endosymbiont. Various control strategies have been implemented since the mid‐twentieth century, including vector control in endemic zones, mass drug administration campaigns, and preventive chemotherapy in companion animals. The challenges posed by the incompletely understood biology of these long‐lived pathogens, their restricted accessibility, discrepant life stage‐dependent sensitivities to drugs, as well as the potential for severe adverse events, have greatly complicated progress toward elimination of human filariases. This chapter chronicles the history of antifilarial medicines and reviews current understanding of their mechanisms of action, highlighting persisting knowledge gaps some 70 years after the first efforts were undertaken to control filarial infections.
... Onchocerciasis, caused by Onchocerca volvulus is a major cause of blindness and skin lesions in the tropics, notably in sub-Saharan African countries, Yemen, and in specific areas in the Americas; Brazil, Mexico, Guatemala, Colombia, Venezuela and Ecuador [1][2][3]. The World Health Organization (WHO) estimates that about 37 million people are infected [4,5] with about 600,000 blind, and 500,000 Africans visually impaired [6]. ...
Onchocerciasis is the leading cause of blindness and severe skin lesions which remain a major public health problem, especially in tropical areas. The widespread use of antibiotics and the long duration required for effective treatment continues to add to the increasing global menace of multi-resistant pathogens. Onchocerca volvulus harbors the endosymbiont bacteria Wolbachia, essential for the normal development of embryos, larvae and long-term survival of the adult worm, O. volvulus. We report here results of using structure-based drug design (SBDD) approach aimed at identifying potential novel Wolbachia inhibitors from natural products against the Wolbachia surface protein (WSP). The protein sequence of the WSP with UniProtKB identifier Q0RAI4 was used to model the three-dimensional (3D) structure via homology modelling techniques using three different structure-building algorithms implemented in Modeller, I-TASSER and Robetta. Out of the 15 generated models of WSP, one was selected as the most reasonable quality model which had 82, 15.5, 1.9 and 0.5% of the amino acid residues in the most favored regions, additionally allowed regions, generously allowed regions and disallowed regions, respectively, based on the Ramachandran plot. High throughput virtual screening was performed via Autodock Vina with a library comprising 42,883 natural products from African and Chinese databases, including 23 identified anti-Onchocerca inhibitors. The top six compounds comprising ZINC000095913861, ZINC000095486235, ZINC000035941652, NANPDB4566, acetylaleuritolic acid and rhemannic acid had binding energies of −12.7, −11.1, −11.0, −11, −10.3 and −9.5 kcal/mol, respectively. Molecular dynamics simulations including molecular mechanics Poisson-Boltzmann (MMPBSA) calculations reinforced the stability of the ligand-WSP complexes and plausible binding mechanisms. The residues Arg45, Tyr135, Tyr148 and Phe195 were predicted as potential novel critical residues required for ligand binding in pocket 1. Acetylaleuritolic acid and rhemannic acid (lantedene A) have previously been shown to possess anti-onchocercal activity. This warrants the need to evaluate the anti-WSP activity of the identified molecules. The study suggests the exploitation of compounds which target both pockets 1 and 2, by investigating their potential for effective depletion of Wolbachia. These compounds were predicted to possess reasonably good pharmacological profiles with insignificant toxicity and as drug-like. The compounds were computed to possess biological activity including antibacterial, antiparasitic, anthelmintic and anti-rickettsials. The six natural products are potential novel antiwolbachial agents with insignificant toxicities which can be explored further as filaricides for onchocerciasis.
... 9,10,24,66 New Wolbachia-targeting drugs with short-course treatment regimens could however change this scenario by making curative (anti-Wolbachia) treatment regimens cheaper and more practical to deliver than doxycycline-based MDA regimes. 9,[75][76][77] In recognition of the potential of Wolbachia targeting drugs for accelerating the elimination of filarial diseases a team at the Liverpool School of Tropical Medicine, set up the anti-Wolbachia (A-WOL) consortium with the objective to develop Wolbachia-targeting therapeutics with good efficacy and safety profiles and with the potential to replace the present anti-helminthic treatment drugs being used in MDA, which break parasite transmission but do not offer clear clinical benefits to those that are treated with them. 9,75-78 ...
... Using insect cell lines and robotics, the A-WOL consortium and its partners have tested more than 2 million pharmaceutically active compounds from pharmaceutical companies' chemical compound libraries for their activity against Wolbachia endosymbionts and their toxicity to their eukaryotic cellular hosts. 9,35,75,79 From these initial screens around 22,500 chemical compounds with an ability to kill Wolbachia, but not their host cells, were identified. 35 These compounds were then subjected to a cheminformatic screen to identify potential compounds that should be prioritised for animal testing. ...
... 35 One particularly interesting compound that was identified by A-WOL compound screening was Tylosin A, which was already licenced for medical use on animals. 9,75,77,79 In experiments using this drug against filarial parasites in animal model systems, however, it was noted that injections were far more effective than oral treatments and it was proposed that the drug's high solubility hampered its absorption from the gut lumen making it unsuitable for oral delivery. 35,75,77 To improve this drug ´s oral bioavailability around 150 Tylosin A analogous, with carbamates or bulky esters, were designed, synthesised and tested on animal models. ...
Thuy-Huong Ta-Tang,1 Sergio LB Luz,2 James L Crainey,2 José M Rubio3 1Malaria and NTDs Laboratory, National Centre of Tropical Medicine, Instituto de Salud Carlos III, Madrid, Spain; 2Laboratório de Ecologia de Doenças Transmissíveis na Amazônia, Instituto Leônidas e Maria Deane, Fundação Oswaldo Cruz, Manaus, Amazonas State, Brazil; 3Malaria & Emerging Parasitic Diseases Laboratory, National Microbiology Center, Instituto de Salud Carlos III, Madrid, SpainCorrespondence: José M RubioMalaria & Emerging Parasitic Diseases Laboratory, National Microbiology Center, Instituto de Salud Carlos III, Cra. Majadahonda-Pozuelo Km 2,5, Majadahonda, Madrid, 28220, SpainTel +34918223420Fax +34915097034Email jmrubio@isciii.esJames L CraineyLaboratório de Ecologia de Doenças Transmissíveis na Amazônia, Instituto Leônidas e Maria Deane, Fundação Oswaldo Cruz, 476 Rua Terezina, Adrianópolis, Manaus, Amazonas State, CEP 69057-070, BrazilEmail james.lee@fiocruz.brAbstract: Mansonellosis is caused by three filarial parasite species from the genus Mansonella that commonly produce chronic human microfilaraemias: M. ozzardi, M. perstans and M. streptocerca. The disease is widespread in Africa, the Caribbean and South and Central America, and although it is typically asymptomatic it has been associated with mild pathologies including leg-chills, joint-pains, headaches, fevers, and corneal lesions. No robust mansonellosis disease burden estimates have yet been made and the impact the disease has on blood bank stocks and the monitoring of other filarial diseases is not thought to be of sufficient public health importance to justify dedicated disease management interventions. Mansonellosis´s Ceratopogonidae and Simuliidae vectors are not targeted by other control programmes and because of their small size and out-door biting habits are unlikely to be affected by interventions targeting other disease vectors like mosquitoes. The ivermectin and mebendazole-based mass drug administration (iMDA and mMDA) treatment regimens deployed by the WHO´s Elimination of Neglected Tropical Diseases (ESPEN) programme and its forerunners have, however, likely impacted significantly on the mansonellosis disease burden, principally by reducing the transmission of M. streptocerca in Africa. The increasingly popular plan of using iMDA to control malaria could also affect M. ozzardi parasite prevalence and transmission in Latin America in the future. However, a potentially far greater mansonellosis disease burden impact is likely to come from short-course curative anti-Wolbachia therapeutics, which are presently being developed for onchocerciasis and lymphatic filariasis treatment. Even if the WHO´s ESPEN programme does not choose to deploy these drugs in MDA interventions, they have the potential to dramatically increase the financial and logistical feasibility of effective mansonellosis management. There is, thus, now a fresh and urgent need to better characterise the disease burden and eco-epidemiology of mansonellosis so that effective management programmes can be designed, advocated for and implemented.Keywords: Mansonellosis, Mansonella perstans, Mansonella ozzardi, Mansonella streptocerca, Wolbachia, doxycycline
... The Wolbachia endosymbiont of filarial worms is now the main therapeutic target for the elimination of filarial diseases [33][34][35] . The heme biosynthetic pathway represents one of the most important metabolic pathways in the symbiotic relationship between the worm and the Wolbachia. ...
Filarial infections affect millions of individuals and are responsible for some notorious disabilities. Current treatment options involve repeated mass drug administrations, which have been met with several challenges despite some successes. Administration of doxycycline, an anti-Wolbachia agent, has shown clinical effectiveness but has several limitations, including long treatment durations and contraindications. We describe the use of an in silico drug repurposing approach to screening a library of over 3200 FDA-approved medications against the filarial endosymbiont, Wolbachia. We target the enzyme which catalyzes the first step of heme biosynthesis in the Wolbachia. This presents an opportunity to inhibit heme synthesis, which leads to depriving the filarial worm of heme, resulting in a subsequent macrofilaricidal effect. High throughput virtual screening, molecular docking and molecular simulations with binding energy calculations led to the identification of paritaprevir and nilotinib as potential anti-Wolbachia agents. Having higher binding affinities to the catalytic pocket than the natural substrate, these drugs have the structural potential to bind and engage active site residues of the wolbachia 5′-Aminolevulinic Acid Synthase. We hereby propose paritaprevir and nilotinib for experimental validations as anti-Wolbachia agents.
