The endosymbiont Wolbachia rebounds following antibiotic treatment.

Antibiotic treatment has emerged as a promising strategy to sterilize and kill filarial nematodes due to their dependence on their endosymbiotic bacteria, Wolbachia. Several studies have shown that novel and FDA-approved antibiotics are efficacious at depleting the filarial nematodes of their endosymbiont, thus reducing female fecundity. However, it remains unclear if antibiotics can permanently deplete Wolbachia and cause sterility for the lifespan of the adult worms. Concerns about resistance arising from mass drug administration necessitate a careful exploration of potential Wolbachia recrudescence. In the present study, we investigated the long-term effects of the FDA-approved antibiotic, rifampicin, in the Brugia pahangi jird model of infection. Initially, rifampicin treatment depleted Wolbachia in adult worms and simultaneously impaired female worm fecundity. However, during an 8-month washout period, Wolbachia titers rebounded and embryogenesis returned to normal. Genome sequence analyses of Wolbachia revealed that despite the population bottleneck and recovery, no genetic changes occurred that could account for the rebound. Clusters of densely packed Wolbachia within the worm's ovarian tissues were observed by confocal microscopy and remained in worms treated with rifampicin, suggesting that they may serve as privileged sites that allow Wolbachia to persist in worms while treated with antibiotic. To our knowledge, these clusters have not been previously described and may be the source of the Wolbachia rebound.

In vivo efficacy of the boron-pleuromutilin AN11251 against Wolbachia of the rodent filarial nematode Litomosoides sigmodontis.

The elimination of filarial diseases such as onchocerciasis and lymphatic filariasis is hampered by the lack of a macrofilaricidal-adult worm killing-drug. In the present study, we tested the in vivo efficacy of AN11251, a boron-pleuromutilin that targets endosymbiotic Wolbachia bacteria from filarial nematodes and compared its efficacy to doxycycline and rifampicin. Doxycycline and rifampicin were previously shown to deplete Wolbachia endosymbionts leading to a permanent sterilization of the female adult filariae and adult worm death in human clinical studies. Twice-daily oral treatment of Litomosoides sigmodontis-infected mice with 200 mg/kg AN11251 for 10 days achieved a Wolbachia depletion > 99.9% in the adult worms, exceeding the Wolbachia reduction by 10-day treatments with bioequivalent human doses of doxycycline and a similar reduction as high-dose rifampicin (35 mg/kg). Wolbachia reductions of > 99% were also accomplished by 14 days of oral AN11251 at a lower twice-daily dose (50 mg/kg) or once-per-day 200 mg/kg AN11251 treatments. The combinations tested of AN11251 with doxycycline had no clear beneficial impact on Wolbachia depletion, achieving a > 97% Wolbachia reduction with 7 days of treatment. These results indicate that AN11251 is superior to doxycycline and comparable to high-dose rifampicin in the L. sigmodontis mouse model, allowing treatment regimens as short as 10-14 days. Therefore, AN11251 represents a promising pre-clinical candidate that was identified in the L. sigmodontis model, and could be further evaluated and developed as potential clinical candidate for human lymphatic filariasis and onchocerciasis.

Short-course quinazoline drug treatments are effective in the Litomosoides sigmodontis and Brugia pahangi jird models.

The quinazolines CBR417 and CBR490 were previously shown to be potent anti-wolbachials that deplete Wolbachia endosymbionts of filarial nematodes and present promising pre-clinical candidates for human filarial diseases such as onchocerciasis. In the present study we tested both candidates in two models of chronic filarial infection, namely the Litomosoides sigmodontis and Brugia pahangi jird model and assessed their long-term effect on Wolbachia depletion, microfilariae counts and filarial embryogenesis 16-18 weeks after treatment initiation (wpt). Once per day (QD) oral treatment with CBR417 (50 mg/kg) for 4 days or twice per day (BID) with CBR490 (25 mg/kg) for 7 days during patent L. sigmodontis infection reduced the Wolbachia load by >99% and completely cleared peripheral microfilaremia from 10-14 wpt. Similarly, 7 days of QD treatments (40 mg/kg) with CBR417 or CBR490 cleared >99% of Wolbachia from B. pahangi and reduced peritoneal microfilariae counts by 93% in the case of CBR417 treatment. Transmission electron microscopy analysis indicated intensive damage to the B. pahangi ovaries following CBR417 treatment and in accordance filarial embryogenesis was inhibited in both models after CBR417 or CBR490 treatment. Suboptimal treatment regimens of CBR417 or CBR490 did not lead to a maintained reduction of the microfilariae and Wolbachia load. In conclusion, CBR417 or CBR490 are pre-clinical candidates for filarial diseases, which achieve long-term clearance of Wolbachia endosymbionts of filarial nematodes, inhibit filarial embryogenesis and clear microfilaremia with treatments as short as 7 days.

Pyruvate produced by Brugia spp. via glycolysis is essential for maintaining the mutualistic association between the parasite and its endosymbiont, Wolbachia.

Human parasitic nematodes are the causative agents of lymphatic filariasis (elephantiasis) and onchocerciasis (river blindness), diseases that are endemic to more than 80 countries and that consistently rank in the top ten for the highest number of years lived with disability. These filarial nematodes have evolved an obligate mutualistic association with an intracellular bacterium, Wolbachia, a symbiont that is essential for the successful development, reproduction, and survival of adult filarial worms. Elimination of the bacteria causes adult worms to die, making Wolbachia a primary target for developing new interventional tools to combat filariases. To further explore Wolbachia as a promising indirect macrofilaricidal drug target, the essential cellular processes that define the symbiotic Wolbachia-host interactions need to be identified. Genomic analyses revealed that while filarial nematodes encode all the enzymes necessary for glycolysis, Wolbachia does not encode the genes for three glycolytic enzymes: hexokinase, 6-phosphofructokinase, and pyruvate kinase. These enzymes are necessary for converting glucose into pyruvate. Wolbachia, however, has the full complement of genes required for gluconeogenesis starting with pyruvate, and for energy metabolism via the tricarboxylic acid cycle. Therefore, we hypothesized that Wolbachia might depend on host glycolysis to maintain a mutualistic association with their parasitic host. We did conditional experiments in vitro that confirmed that glycolysis and its end-product, pyruvate, sustain this symbiotic relationship. Analysis of alternative sources of pyruvate within the worm indicated that the filarial lactate dehydrogenase could also regulate the local intracellular concentration of pyruvate in proximity to Wolbachia and thus help control bacterial growth via molecular interactions with the bacteria. Lastly, we have shown that the parasite's pyruvate kinase, the enzyme that performs the last step in glycolysis, could be a potential novel anti-filarial drug target. Establishing that glycolysis is an essential component of symbiosis in filarial worms could have a broader impact on research focused on other intracellular bacteria-host interactions where the role of glycolysis in supporting intracellular survival of bacteria has been reported.

The Complexity of Zoonotic Filariasis Episystem and Its Consequences: A Multidisciplinary View.

Vector-borne transmitted helminthic zoonosis affects the health and economy of both developing and developed countries. The concept of episystem includes the set of biological, environmental, and epidemiological elements of these diseases in defined geographic and temporal scales. Dirofilariasis caused by different species of the genus Dirofilaria is a disease affecting domestic and wild canines and felines and man, transmitted by different species of culicid mosquitoes. This complexity is increased because Dirofilaria species harbor intracellular symbiont Wolbachia bacteriae, which play a key role in the embryogenesis and development of dirofilariae and in the inflammatory pathology of the disease. In addition, the vector transmission makes the dirofilariasis susceptible to the influence of the climate and its variations. The present review addresses the analysis of dirofilariasis from the point of view of the episystem, analyzing the complex network of interactions established between biological components, climate, and factors related to human activity, as well as the different problems they pose. The progress of knowledge on human and animal dirofilariasis is largely due to the multidisciplinary approach. Nevertheless, different aspects of the disease need to continue being investigated and cooperation between countries and specialists involved should be intensified.

Nódulo subcutáneo paraciliar de origen infrecuente / Subcutaneous paraciliar nodule of rare origin

No disponible

Wolbachia endosymbiont of Brugia malayi elicits a T helper type 17-mediated pro-inflammatory immune response through Wolbachia surface protein.

Wolbachia is an endosymbiotic bacterium of the filarial nematode Brugia malayi. The symbiotic relationship between Wolbachia and its filarial host is dependent on interactions between the proteins of both organisms. However, little is known about Wolbachia proteins that are involved in the inflammatory pathology of the host during lymphatic filariasis. In the present study, we cloned, expressed and purified Wolbachia surface protein (r-wsp) from Wolbachia and administered it to mice, either alone or in combination with infective larvae of B. malayi (Bm-L3) and monitored the developing immune response in infected animals. Our results show that spleens and mesenteric lymph nodes of mice immunized with either r-wsp or infected with Bm-L3 show increased percentages of CD4(+) T helper type 17 (Th17) cells and Th1 cytokines like interferon-γ and interleukin-2 (IL-2) along with decreased percentages of regulatory T cells, Th2 cytokines like IL-4 and IL-10 and transforming growth factor ß (TGF-ß) levels in culture supernatants of splenocytes. These observations were stronger in mice immunized with r-wsp alone. Interestingly, when mice were first immunized with r-wsp and subsequently infected with Bm-L3, percentages of CD4(+) Th17 cells and Th1 cytokines increased even further while that of regulatory T cells, Th2 cytokines and TGF-ß levels decreased. These results for the first time show that r-wsp acts synergistically with Bm-L3 in promoting a pro-inflammatory response by increasing Th17 cells and at the same time diminishes host immunological tolerance by decreasing regulatory T cells and TGF-ß secretion.

[How to fight parasitic infectious diseases with bacteria. The case of Wolbachia pipientis]. / Cómo combatir con bacterias a las enfermedades infecciosas parasitarias. El caso de Wolbachia pipientis.

In Nature, no individual can live in isolation; hence, living organisms are forced to interact with each other. This necessity has led many organisms to establish heterogeneous relations to enhance their ability to adapt to the environment, thus acquiring evolutionary advantages. These relationships are sometimes so intense, that on the long term the organisms may lose their individual identity. An example of these associations is the endosymbiotic ones, where eukaryote organisms generally harbor different prokaryote organisms. The endosymbiotic bacterium Wolbachia pipientis is a species described by Hertig and Wolbach in 1924. This microorganism can be isolated in a large variety of eukaryote organisms, with which it maintains different links. Until now, this species has only been described with 11 serogroups numbered from A to K within the Wolbachia genus. This work is intended to illustrate the relationship of Wolbachia pipientis with human pathogenic filaria and with arthropods, as well as to describe the implications of this bacterium in the treatment of filariasis. Finally, this work tries to describe recent studies that have targeted the use of artificially-created Wolbachia pipientis virulent strains that, once inoculated in infectious diseases-transmitting vectors, develop negative effects within them in order to, in this way, erradicate mosquito-transmitted infectious diseases for which no treatment is available at the moment or the prevention of its transmissibility has not been achieved.

En la naturaleza ningún individuo puede vivir de forma aislada, de tal forma que los organismos vivos se ven obligados a interactuar unos con otros. Esta necesidad ha llevado a que diferentes organismos establezcan relaciones heterogéneas para mejorar su capacidad de adaptación al medio, obteniendo así ventajas evolutivas. Estas relaciones a veces son tan intensas que a la larga los organismos pueden perder su identidad individual. Un ejemplo de estas asociaciones son las endosimbióticas, en las cuales generalmente organismos eucariotas albergan a diferentes organismos procariotas. La bacteria endosimbiótica Wolbachia pipientis es una especie descrita en 1924 por Hertig y Wolbach. Este microorganismo se puede aislar en gran variedad de organismos eucariotas, con los que mantiene diferentes vínculos. Hasta el momento solo se ha descrito esta especie con 11 serogrupos enumerados de la A a la K dentro del género Wolbachia. En este trabajo se pretende ilustrar la relación de Wolbachia pipientis con las filarias patógenas humanas y con los artrópodos, así como describir las implicaciones de esta bacteria en el tratamiento de las filariasis. Finalmente, se pretende exponer los estudios recientes que han apuntado el uso de cepas virulentas de Wolbachia pipientis creadas artificialmente que una vez inoculadas en los vectores transmisores de enfermedades desarrollan efectos negativos en estos, para de esa forma lograr la erradicación de enfermedades infecciosas transmitidas por mosquitos para las cuales de momento no existe tratamiento o no se ha logrado impedir su transmisibilidad.

Preliminary analysis to target pyruvate phosphate dikinase from wolbachia endosymbiont of Brugia malayi for designing anti-filarial agents.

Filariasis causing nematode Brugia malayi is shown to harbor wolbachia bacteria as symbionts. The sequenced genome of the wolbachia endosymbiont from B.malayi (wBm) offers an unprecedented opportunity to identify new wolbachia drug targets. Genome analysis of the glycolytic/gluconeogenic pathway has revealed that wBm lacks pyruvate kinase (PK) and may instead utilize the enzyme pyruvate phosphate dikinase (PPDK; ATP: pyruvate, orthophosphate phosphotransferase, EC 2.7.9.1). PPDK catalyses the reversible conversion of AMP, PPi and phosphoenolpyruvate into ATP, Pi and pyruvate. Most organisms including mammals exclusively possess PK. Therefore the absence of PPDK in mammals makes this enzyme as attractive wolbachia drug target. In the present study we have modeled the three dimensional structure of wBm PPDK. The template with 50% identity and 67% similarity in amino acid sequence was employed for homology-modeling approach. The putative active site consists of His476, Arg360, Glu358, Asp344, Arg112, Lys43 and Glu346 was selected as site of interest for designing suitable inhibitor molecules. Docking studies were carried out using induced fit algorithms with OPLS force field of Schrödinger's Glide. The lead molecules which inhibit the PPDK activity are taken from the small molecule library (Pubchem database) and the interaction analysis showed that these compounds may inhibit the function of PPDK in wBm.

Wolbachia heat shock protein 60 induces pro-inflammatory cytokines and apoptosis in monocytes in vitro.

Recombinant Wolbachia heat shock protein 60 (rWmhsp60) induces gene expression of pro-inflammatory cytokines IL-1ß, IL-6 and TNF-α in human monocytic cell line THP-1. In addition, it inhibits the phagocytic activity and does not alter the nitric oxide production by differentiated THP-1 macrophages, which corroborates with no significant change in inducible nitric oxide synthase gene expression in rWmhsp60 treated THP-1 monocytes. Further, 24 h stimulation of peripheral blood mononuclear cells from normal individuals by rWmhsp60 reveals that monocytes enter the late apoptotic stage, while lymphocytes do not show apoptosis. Thus these findings suggest that rWmhsp60 may contribute to inflammation mediated monocyte dysfunction in filarial pathogenesis.

Wolbachia and its implications for the immunopathology of filariasis.

Filarial infections are characterized by immunopathological phenomena, that are responsible for the onset of often dramatic pathological outcomes, such as blindness (Onchocerca volvulus) and elephantiasis (W. bancrofti). In addition, the long-term survival (as long as 10 years) of these parasites in otherwise immunocompetent hosts indicates that these nematodes are capable of manipulating the host immune response. The ground-breaking discovery of the bacterial endosymbiont Wolbachia, which resides in most filarial nematodes causing disease, has led to increasing interest in the role it may play in immuno-modulation, pro-inflammatory pathology and other aspects of filarial infection. Indeed, Wolbachia has been shown to be responsible for exacerbating inflammation (as in river blindness), while at the same time blocking efficient elimination of parasites through the host immune response (Onchocerca ochengi). While studies aimed at identifying Wolbachia as a potential target for anti-filarial therapy are at the forefront of current research, understanding its role in the immunology of filarial infection is a fascinating field that has yet to uncover many secrets.

Las filariasis en la práctica clínica / Filariasis in clinical practice

Las filariasis son un conjunto de enfermedades infecciosas que afectan fundamentalmente al tejido linfático y la piel. Están causadas por distintas especies de nematodos y son transmitidas mediante la picadura de insectos. Están catalogadas como enfermedad desatendida, afectan a millones de personas, y producen gran invalidez y problemas sociosanitarios. Para su desarrollo suelen precisar de la permanencia en zona endémica durante largos períodos, por lo que son infrecuentemente diagnosticadas en viajeros de corta estancia. Aunque habitualmente cursan de manera asintomática, la aparición de sintomatología viene determinada, fundamentalmente, por el grado de respuesta inmune del huésped a la infección y por la carga parasitaria. El diagnóstico se basa en la demostración de las microfilarias correspondientes en muestras de sangre o de piel, aunque otros métodos pueden apoyar el diagnóstico. El tratamiento individual es efectivo, pero las medidas a nivel comunitario, sobre todo la administración de tratamiento en masa, son las más efectivas para disminuir la incidencia de las filariasis (AU)

Filariases are infections caused by distinct species of nematodes. These infections are transmitted through insect bites and primarily affect lymph nodes and skin. Filariases are classified as neglected diseases and affect millions, producing severe disability and social stigma. This type of infection is rarely diagnosed in travellers, as prolonged stays in endemic areas are usually required acquire infection. Infections may be asymptomatic, and clinical manifestations depend on the host immune response to the infection and the parasite burden. Diagnosis is based on the demonstration of microfilariae in blood or skin, but there are other methods that support the diagnosis. Individual treatment is effective, but community interventions, mostly mass drug administration, have helped to diminish the incidence of filariases (AU)

Diagnóstico diferencial de filariasis importada mediante técnicas moleculares (2006-2009) / Differential diagnosis of imported filariasis by molecular techniques (2006-2009)

Introducción: Durante los últimos años se ha registrado un aumento creciente de la población inmigrante y de viajeros procedentes de áreas endémicas de filariasis producidas por Loa loa (L. loa), Mansonella perstans(M. perstans) y Wuchereria bancrofti (W. bancrofti). Esta situación epidemiológica ha hecho necesario el desarrollo de técnicas específicas de diagnóstico molecular, alternativas al método parasitológico clásico.Por lo tanto, el objetivo planteado en este trabajo ha sido la utilización de las técnicas moleculares optimizadas en nuestro laboratorio, nested-PCR e ITS1-RFLP, en el diagnóstico de filariasis importadas, y la comparación de los resultados obtenidos con los derivados del diagnóstico parasitológico. Material y métodos: Se ha estudiado mediante la técnica de concentración de Knott, nested-PCR e ITS1-RFLP un total de 523 muestras (517 sangres, 5 helmintos adultos y un humor vítreo) que fueron remitidas al Servicio de Parasitología del Centro Nacional de Microbiología-Instituto de Salud Carlos III, entre los años 2006 y 2009, por 47 centros sanitarios de las comunidades autónomas. Resultados: Las técnicas moleculares utilizadas demostraron ser más sensibles que el método de concentración de Knott, tanto en el diagnóstico de L. loa (n = 12 frente a n = 4) como en el de M. perstans (n=57frente a n = 25) en el total de muestras de sangre estudiadas. Conclusión: Los métodos de PCR utilizados permiten un diagnóstico específico y más sensible de L. loay M. perstans en muestras clínicas de población inmigrante y viajeros procedentes de áreas endémicas, donde estas especies de filarias son coendémicas. El método de concentración de Knott debe emplearse como técnica complementaria siempre que sea posible (AU)

Introduction: The last few years has seen an increase in the number of immigrants and travellers from endemic areas where filariasis are mainly caused by Loa loa (L. loa), Mansonella perstans (M. perstans) and Wuchereria bancrofti (W. bancrofti) species. These demographic changes has led to the need for better filariae species-specific molecular diagnostic tests to solve problems, as alternatives to the more time consuming classic parasitology methods. Thus, the objective of the present work was the implementation of optimised molecular protocols (nested-PCR and ITS1-RFLP) developed in our laboratory, for the differential diagnosis of filarial parasites. The results obtained were compared with those obtained using the conventional parasitological methods. Material and methods: A total of 523 samples (517 peripheral blood, 5 adult worms and one vitreous body)were sent to Parasitology Department of the National Microbiology Centre, Carlos II Research Institute(ISCIII), from 47 Health Centres in the Autonomous Regions of Spain, from 2006 to 2009. The samples were studied by the Knott technique, nested-PCR and ITS1-RFLP.Results: The molecular techniques applied on blood samples showed to be more sensitive that Knott’s concentration technique in the diagnosis of both L. loa (n=12 versus n=4) and M. perstans (n=57 versusn = 25) infections (AU)

Confección por dos filarias (Loa loa y Mansonella perstans) en una paciente proveniente de Guinea / Loa Loa and Mansonella perstans coinfection in a patient from Guinea

Presentamos un caso de una infección mixta por 2filarias (Loa loa y Mansonella perstans). La infección sesospechó, al aparecer, una marcada eosinofilia en unaanalítica de rutina. En la extensión de sangre periféricase observaban microfilarias envainadas y sin envainar,con lo que se estableció un diagnóstico de infecciónmixta por filarias. El diagnóstico definitivo de especiese realizó en el Centro Nacional de Microbiología deMajadahonda. Se instauró un tratamiento con dietilcarbamicinay mebendazol que conllevó la curación de lossíntomas de la paciente y la eliminación de las microfilariasen sangre.La filariasis es todavía endémica en muchos países.Debido al aumento de viajeros a dichas zonas y alos movimientos migratorios desde dichas áreas, no esinfrecuente enfrentarnos a su diagnóstico. La implantaciónde tratamientos masivos contra las filarias en zonasendémicas por parte de la Organización Mundial dela Salud está disminuyendo su transmisión, consiguiendola eliminación de la enfermedad en algunas áreas(AU)

We present a case of mixed infection by two filariae(Loa loa and Mansonella perstans). It seems that theinfection was suspected due to a pronounced eosinophiliain a routine analysis. Sheathed and unsheathedmicrofilariae were observed in the spread of peripheralblood, which enabled a diagnosis to be established ofmixed infection by filariae. The definitive diagnosis ofthe species was carried out at the National Centre ofMicrobiolgy of Majadahonda. A treatment was initiatedwith dietilcarbamazina and mebendazole which resultedin the patient’s being cured and in the elimination ofthe microfilariae in the patient’s blood.Filariasis is still endemic in many countries. Due tothe increase of travellers to such zones and the migratorymovements from such areas it is not unusual forus to come across such a diagnosis. The implantationof massive treatments against filariae in endemic zonesby the World Health Organisation is reducing theirtransmission and is managing to eliminate the diseasein some areas(AU)

The bacteria Wolbachia in filariae, a biological Russian dolls' system: new trends in antifilarial treatments.

Filarial nematode species can host Wolbachia bacterial endosymbionts. To understand the symbiosis, a higher level of complexity should be considered, taking in account the tripartite association between Wolbachia, filariae and mammals. This overview article discusses the biology of Wolbachia in filariae, including their distribution and phylogeny, mechanisms of action, inflammatory consequences on mammal host and biological control implications for filariases. Potential directions for future research are also discussed.

Biochemical changes in cerebrospinal fluid of Chlorocebus aethiops naturally infected with zoonotic Meningonema peruzzii.

BACKGROUND: Thirty-four wild Chlorocebus aethiops monkeys were trapped for research purposes. METHODS: During routine quarantine check-up, cerebrospinal fluid (CSF) and blood were microscopically examined for parasites. Estimations of CSF protein levels were made by the biuret method and the white cell counts by the hemocytometer. RESULTS: Seven monkeys demonstrated microfilariae in blood and CSF. This was accompanied by a two- and ninefold increase in CSF total protein and white cell counts, respectively. Necropsy of one of the blood and CSF microfilariae-positive animals revealed the presence of adult worms in the brain meninges. The parasites were identified as the zoonotic filaroid nematode Meningonema peruzii. CONCLUSIONS: Wild C. aethiops monkeys developed CSF changes resulting, most probably, from infection with M. peruzii. Moreover, the monkeys could be acting as an important reservoir. The study highlights the need for epidemiological and pathogenological studies of this parasite, which is of public health significance. Moreover, C. aethiops proved to be a useful primate model for the study of this zoonotic infection.

Clinico-laboratory profile of 45 filarial arthritis cases.

This prospective observational study was done during the period from January 2000 to December 2004 including 45 cases of lymphatic filariasis manifested with acute arthritis. Different investigations were carried out to exclude allergy, parasitic and infectious diseases, autoimmune disorder and malignancy. They were given standard treatment with oral non-steroidal anti-inflammatory drugs (NSAIDs). Articular symptoms were not relived satisfactorily. Later they were given oral corticosteroids. During treatment slight relief of symptoms were noted, but all sign-symptoms reappear after withdrawal of corticosteroid drugs. Treatment with oral diethylcarbamazine citrate (DEC) (150 mg/day) for 3 weeks showed complete resolution of arthritis. No side effects or relapse were encountered. The basic mechanism of relief of pain remains unknown. It was assumed that during benign course of lymphatic filariasis, development of arthritis result most likely due to reaction against some occult agents in the joints.

New strategies to combat filariasis.

Two of the major filarial infections, lymphatic filariasis (LF) and onchocerciasis, affect 150 million people, while 1 billion living in endemic areas are at risk of infection. Public health programs to control these infections have successfully existed for years and have evolved from activities driven by the WHO into global programs with public-private partnerships. Currently, these programs use yearly mass application of drugs that mainly kill the larval stages (the microfilariae), with the aim of preventing uptake by the transmitting insect vectors and thus, to block transmission and reduce the infections to such levels that in 15-30 years from now, they will no longer pose a public health problem. While the programs have been very successful in general, there are drawbacks such as coverage being too low within the population, reappearance of infection by migration of infected people into controlled areas, targeting of a stage (the microfilaria) that does not induce pathology in LF and thus lowers compliance, and the potential development of drug resistance, first indications of which have been clearly observed in onchocerciasis. In addition, even without drawbacks, program scopes are not the eradication of filarial infections, which is, however, an ultimate goal of control activities. There is therefore an unequivocal call for the development of higher efficient, complementary chemotherapeutical approaches that lead to a long-lasting reduction of the pathology-inducing worm stages; that is, microfilariae in onchocerciasis and adult worms in LF, or to a macrofilaricidal effect. The recent discovery that depletion of Wolbachia endosymbionts by tetracycline antibiotics leads to long-lasting sterility of adult female worms in onchocerciasis and a macrofilaricidal effect in LF fulfils these requirements. Successful regimens have already been published and agreed upon for use by expert panels. While these regimens are still too long for mass application, the antiwolbachial chemotherapy can currently be applied in the form of a suitable doxycycline regimen for 6 weeks for the treatment of individuals, and exploited in the future for the development of new drugs suitable for mass application. In addition, first data suggest that Wolbachia may also be major mediators of lymphangiogenesis and that their depletion is associated with reduction of lymph vessel-specific vascular endothelial growth factors and reduced lymph vessel size.