Immunopathogenesis of &lt;I&gt;Onchocerca volvulus&lt;/I&gt; keratitis (river blindness): a novel role for TLR4 and endosymbiotic &lt;I&gt;Wolbachia&lt;/I&gt; bacteria

Hise, Amy G.; Gillette‐Ferguson, Illona; Pearlman, Eric

doi:10.1179/096805103225002746

Cited by 6 publications

References 30 publications

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Patency of Litomosoides sigmodontis infection depends on Toll‐like receptor 4 whereas Toll‐like receptor 2 signalling influences filarial‐specific CD4⁺ T‐cell responses

et al. 2016

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Summary BALB/c mice develop a patent state [release of microfilariae (Mf), the transmission life‐stage, into the periphery] when exposed to the rodent filariae Litomosoides sigmodontis. Interestingly, only a portion of the infected mice become patent, which reflects the situation in human individuals infected with Wuchereria bancrofti. Since those individuals had differing filarial‐specific profiles, this study compared differences in immune responses between Mf+ and Mf– infected BALB/c mice. We demonstrate that cultures of total spleen or mediastinal lymph node cells from Mf+ mice produce significantly more interleukin‐5 (IL‐5) to filarial antigens but equal levels of IL‐10 when compared with Mf– mice. However, isolated CD4+ T cells from Mf+ mice produced significantly higher amounts of all measured cytokines, including IL‐10, when compared with CD4+ T‐cell responses from Mf– mice. Since adaptive immune responses are influenced by triggering the innate immune system we further studied the immune profiles and parasitology in infected Toll‐like receptor‐2‐deficient (TLR2−/−) and TLR4−/− BALB/c mice. Ninety‐three per cent of L. sigmodontis‐exposed TLR4−/− BALB/c mice became patent (Mf+) although worm numbers remained comparable to those in Mf+ wild‐type controls. Lack of TLR2 had no influence on patency outcome or worm burden but infected Mf+ mice had significantly lower numbers of Foxp3+ regulatory T cells and dampened peripheral immune responses. Interestingly, in vitro culturing of CD4+ T cells from infected wild‐type mice with granulocyte–macrophage colony‐stimulating factor‐derived TLR2−/− dendritic cells resulted in an overall diminished cytokine profile to filarial antigens. Hence, triggering TLR4 or TLR2 during chronic filarial infection has a significant impact on patency and efficient CD4+ T‐cell responses, respectively.

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Patency of Litomosoides sigmodontis infection depends on Toll‐like receptor 4 whereas Toll‐like receptor 2 signalling influences filarial‐specific CD4⁺ T‐cell responses

et al. 2016

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Protective Immunity to the Larval Stages ofOnchocerca volvulusIs Dependent on Toll-Like Receptor 4

et al. 2005

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Toll-like receptor 4 (TLR4) has been shown to be important for the induction of Th2-dependent immune responses in mice. Protective immunity against larval Onchocerca volvulus in mice depends on the development of a Th2 immune response mediated by both interleukin-4 (IL-4) and IL-5. In addition, O. volvulus contains the rickettsial endosymbiont Wolbachia, which has molecules with lipopolysaccharide-like activities that also signal through TLR4. We therefore hypothesized that protective immunity to O. volvulus would not develop in C3H/HeJ mice which have a mutation in the Tlr4 gene (TLR4 mutant), either because of a decreased Th2 response to the larvae or because of the absence of a response to Wolbachia. TLR4-mutant mice were immunized against O. volvulus with irradiated third-stage larvae, and it was observed that Th2 responses were elevated based on increased IL-5 production, total immunoglobulin E (IgE) levels, antigen-specific IgG1 response, and eosinophil recruitment. Protective immunity, however, did not develop in the TLR4-mutant mice. The Th1 response, as measured by gamma interferon production from spleen cells, was comparable in both wild-type and TLR4-mutant mice. Furthermore, antibody responses to Wolbachia were absent in both wild-type and TLR4-mutant mice. Therefore, the defect in the development of a protective immune response against O. volvulus in TLR4-mutant mice is not due to loss of Th2 immunity or the response to Wolbachia but is due to an unidentified TLR4-dependent larval killing mechanism.

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Wolbachia Endosymbionts: An Achilles’ Heel of Filarial Nematodes

Hoerauf¹,

Pfarr²

2007

Issues in Infectious Diseases

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Filarial worm infections of humans cause morbidity and even death in developing countries of the tropics. Current antifilarial drug therapies target only the first-stage larvae, requiring many years of annual/biannual treatment. Another problem with controlling filarial infections is the lack of any alternative drugs that can be used in the current mass drug administration programs should resistance develop. Wolbachia, endosymbiotic bacteria that are found in most of the human filarial worms are excellent targets for the discovery of new antifilarial drugs because of their requirement for worm embryogenesis, development and adult survival. Targeting of Wolbachia with antirickettsial drugs has lead to the recommendation of doxycycline for use on an individual basis and may be recommended in areas where resistance to current drugs may develop. More evidence that eliminating the endobacteria reduces adverse reactions to current drug therapies and even reduces early stages of pathology is also accruing. Thus, research is underway to discover new drugs, preferably those already approved for use in humans, that have antiwolbachial activity and work in a shorter time and which can be given to all members of the population. 'Two urns on Jove's high throne have ever stood,The source of evil one, and one of good; From thence the cup of mortal man he fills, Blessings to these, to those distributes ills;To most he mingles both.' HomerFilarial nematode infections are endemic in more than 90 countries of the tropics. In these countries, 200 million individuals are infected and 1.3 billion people are at risk of infection [1][2][3]. The number of people infected is higher than

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Immunopathogenesis of <I>Onchocerca volvulus</I> keratitis (river blindness): a novel role for TLR4 and endosymbiotic <I>Wolbachia</I> bacteria

Cited by 6 publications

References 30 publications

Patency of Litomosoides sigmodontis infection depends on Toll‐like receptor 4 whereas Toll‐like receptor 2 signalling influences filarial‐specific CD4⁺ T‐cell responses

Patency of Litomosoides sigmodontis infection depends on Toll‐like receptor 4 whereas Toll‐like receptor 2 signalling influences filarial‐specific CD4⁺ T‐cell responses

Protective Immunity to the Larval Stages ofOnchocerca volvulusIs Dependent on Toll-Like Receptor 4

Wolbachia Endosymbionts: An Achilles’ Heel of Filarial Nematodes

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Immunopathogenesis of <I>Onchocerca volvulus</I> keratitis (river blindness): a novel role for TLR4 and endosymbiotic <I>Wolbachia</I> bacteria

Cited by 6 publications

References 30 publications

Patency of Litomosoides sigmodontis infection depends on Toll‐like receptor 4 whereas Toll‐like receptor 2 signalling influences filarial‐specific CD4+ T‐cell responses

Patency of Litomosoides sigmodontis infection depends on Toll‐like receptor 4 whereas Toll‐like receptor 2 signalling influences filarial‐specific CD4+ T‐cell responses

Protective Immunity to the Larval Stages ofOnchocerca volvulusIs Dependent on Toll-Like Receptor 4

Wolbachia Endosymbionts: An Achilles’ Heel of Filarial Nematodes

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Resources

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Patency of Litomosoides sigmodontis infection depends on Toll‐like receptor 4 whereas Toll‐like receptor 2 signalling influences filarial‐specific CD4⁺ T‐cell responses

Patency of Litomosoides sigmodontis infection depends on Toll‐like receptor 4 whereas Toll‐like receptor 2 signalling influences filarial‐specific CD4⁺ T‐cell responses