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Parasitic filarial nematodes infect more than 200 million individuals worldwide, causing debilitating inflammatory diseases such as river blindness and lymphatic filariasis. Using a murine model for river blindness in which soluble extracts of filarial nematodes were injected into the corneal stroma, we demonstrated that the predominant inflammatory response in the cornea was due to species of endosymbiotic Wolbachia bacteria. In addition, the inflammatory response induced by these bacteria was dependent on expression of functional Toll-like receptor 4 (TLR4) on host cells.

We compared the impact of IL-4 and IL-5 deficiency during the fully permissive infection of BALB/c mice with the rodent filaria Litomosoides sigmodontis. IL-5, in contrast to IL-4, is crucial for the containment of adult worms during short-and longterm infections. IL-5 KO mice allowed development of more larvae into adult worms and showed up to 200 times more adult worms persisting during chronic infection (day 60 until 200 post-infection). This increased persistence was accompanied by a reduction in inflammatory nodules around adult filariae. In contrast, adult worm survival and nodule formation did not differ between BALB/c wild-type mice and BALB/c IL-4 KO or BALB/c IL-4 receptor (IL-4R) a-chain KO mice. In both IL-4 and IL-5 KO mice microfilaraemia was greatly enhanced (160-fold) and prolonged compared to wild-type mice. This extent of susceptibility to microfilariae required the presence of adult worms in a full infection cycle since upon intraperitoneal injection of microfilariae alone they were removed from BALB/c, BALB/c IL-4 KO and BALB/c IL-4R a-chain KO mice with equivalent kinetics, and since microfilarial survival was only slightly increased in IL-5 KO mice (factor of 5 vs. factor of 160 in full infection). In conclusion, IL-4 and IL-5 dependent effector pathways operate against different stages of filarial worms, and IL-5 has a greater impact on parasite containment than IL-4.

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Litomosoides sigmodontis is the only filaria which develops from infective larvae into microfilaria-producing adults in immunocompetent laboratory mice. In this study we report that interleukin-4 knockout (IL-4 KO) mice have an up to 100-fold-higher and a significantly prolonged microfilaremia compared to wild-type BALB/c mice, as well as 20 times more microfilariae in the thoracic cavity, the site of infection. While worm development and adult worm persistence were equivalent in IL-4 KO and wild-type mice, the fertility and length of adult female worms in IL-4 KO mice was clearly enhanced. The high susceptibility to microfilariae in IL-4 KO mice required the presence of adult worms in a full infection cycle since microfilariae loads did not differ much between IL-4 KO and wild-type mice when purified microfilariae were injected into mice. In addition, we found that eosinophilia was diminished and immunoglobulin E (IgE) was absent in IL-4 KO mice. IgE, however, does not seem to be the essential factor for microfilarial containment since microfilaremia was not elevated in B-cell KO mice. In conclusion, IL-4 is shown for the first time to be essential for the control of microfilarial loads but not of adult worm loads in a fully permissive murine filarial infection. IL-4 dependent effector pathways seem to operate on adult worms rather than directly on microfilariae.Filariasis is an arthropode-borne parasitism which affects more than 120 million people in the tropics and confronts them with debilitating outcomes such as blindness, e.g., in onchocerciasis or elefantiasis. Infective third-stage larvae (L3 larvae) are injected into the host during a blood meal of the arthropod vector and develop into adult worms which release microfilariae into either skin (e.g., onchocerciasis) or blood (e.g., lymphatic filarioses).Experimental studies with Brugia species in mice (20) have shown that intraperitoneally (i.p.) injected microfilariae elicit a T H 1-type response. In contrast, infective third-stage larvae, as well as adult worms, induced a T H 2-type response. In addition, the strong T H 2-type response to adult, especially female, worms was able to override the T H 1-type response to emerging microfilariae. However, interleukin-4 knockout (IL-4 KO) mice showed no alteration of parasitic loads in this model (18). In contrast, in another study where the infection of BALB/c and C57BL/6 mice with Brugia malayi was partially permissive, IL-4 deficiency resulted in prolonged worm survival (5). Thus, there remains some uncertainty as to whether T H 2 responses are indeed host protective.L. sigmodontis in BALB/c mice is the only model of filariasis which allows the observation of the complete development in an immunocompetent mouse (32). All developmental stages of the worm can be examined during one course of infection, in contrast to non-or semipermissive models. In addition, in nonpermissive models immune reactions can arise that differ from those in a permissive system because the parasite cannot reach its proper sanctuary ...

SummaryEndobacteria of the genus Wolbachia in filarial nematodes are related to Rickettsiaceae and can be depleted by tetracycline antibiotics. This depletion blocks female worm development as well as early embryogenesis, in contrast to the currently used microfilaricidal ivermectin which blocks only the last stage of embryogenesis. Since targeting Wolbachia is becoming an area of research for the treatment of human filariases, it was investigated if antibiotics other than tetracyclines are able to deplete Wolbachia from filariae. BALB/c mice infected with the rodent filaria Litomosoides sigmodontis were treated with erythromycin, chloramphenicol or ciprofloxacin. All drugs were well resorbed and resulted in serum levels clearly above breakpoint levels for bacteria susceptible to the respective antibiotic. However, contrary to tetracycline, none of these antibiotics depleted Wolbachia or altered worm development and fertility, as evidenced by immunohistology, immunoelectron microscopy and semiquantitative PCR.

There has been a prevailing perception that Th1 and Th2 immune responses induce antagonistic immune effector mechanisms during an infection. We investigated the role of the Th1 cytokine gamma interferon (IFN-␥) and the Th2 cytokine interleukin-5 (IL-5) in murine filariasis infections with the rodent filarial nematode Litomosoides sigmodontis with regard to immune responses to the parasite. Earlier data showed an important role for IL-5 and IFN-␥ in effective immune responses to filarial infection. Therefore, in this study it was asked whether IL-5 and IFN-␥ act synergistically or antagonistically. Indeed, IL-5 as well as IFN-␥ knockout (KO) mice show a higher worm load than the wild-type controls. IFN-␥/IL-5 double-KO mice had a significantly higher worm load than any of the single-KO mice, suggesting a synergism between IFN-␥ and IL-5 in controlling worm infection. Neutrophils are known to play an important role for the containment and encapsulation process of the worms. In infected IFN-␥ KO, IL-5 KO, and IFN-␥/IL-5 double-KO mice, neutrophils were significantly reduced in chemotactic activity levels compared to controls. In addition, the level of phagocytosis activity of neutrophils from IFN-␥/IL-5 double-KO mice was further decreased in comparison to that of the single-KO mice. Levels of tumor necrosis factor alpha, which is an important factor for neutrophil activation, were found to be reduced in macrophages from KO mice. In conclusion, these results argue for immune effector mechanisms in murine filarial infection that are dependent on both IFN-␥ and IL-5. Synergistic effects of the two cytokines may be mediated, at least in part, by neutrophils for the control of adult worms.There has been a common view that Th1 and Th2 immune responses act antagonistically toward each other. For example, a strong Th1 immune response is necessary for an effective immune reaction to Mycobacterium leprae. A Th2 response led to high level of susceptibility during this infection, and animals as well as humans were unable to control the infection (23,29,44). In C57BL/6 mice Leishmania major induces an effective Th1 immune response, while in BALB/c mice a nonprotective Th2 immune response is induced (1,14,38). Moreover, in this model it was shown that gamma interferon (IFN-␥) as a typical Th1 cytokine and interleukin-5 (IL-5) as a typical Th2 cytokine have antagonistic effects (38). In contrast, a strong Th2 immune response was reported to be important for survival of an infection with Schistosoma mansoni. Survival was attributed to the ability of Th2 cells to secrete cytokines that were antiinflammatory. A failure to produce anti-inflammatory cytokines (because of IL-4 deficiency) led to elevated production of inflammatory cytokines such as IFN-␥ and the death of the animals (8, 9, 15).Human filariasis puts at risk more than a 1 billion people and affects over 180 million people. Analysis of the role of the Th1 cytokine IFN-␥ and the Th2 cytokine IL-4 in a non-fullypermissive filarial model using Brugia malayi demonstrated tha...