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

Abstract

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.

Hyperreactive Onchocerciasis is Characterized by a Combination of Th17-Th2 Immune Responses and Reduced Regulatory T Cells

“…This correlates to studies showing an increased likelihood for developing sowda in persons carrying the Arg110 variant of IL-13 which leads to higher IL-13 signalling [30] . Th2 responses in filarial infections are linked to infection resistance [31] , [32] and microfilariae can elicit pro-inflammatory responses when they are degenerated or moribund [33] . Thus, a potential scenario for developing hyperresponsiveness may be that deviated Th2 responses provoke microfilariae death, which in turn induces a Th17 phenotype.…”

The innate host defence against nematode parasites

“…TGF‐β is immunosuppressive and may be an important mediator in reducing gut inflammation creating a more favourable environment for nematode survival. Mice with a point mutation in the TLR4 protein (HeJ mice) showed a heightened type II response to Onchocerca volvulus infection, but had a deficiency in vaccination priming using irradiated larvae, implying that TLR4 was required for a vaccine induced parasite killing mechanism (63).…”

Toll-Like Receptor 2 Regulates CXC Chemokine Production and Neutrophil Recruitment to the Cornea inOnchocerca volvulus/Wolbachia-Induced Keratitis

“…Furthermore, there were no differences in neutrophil recruitment or corneal haze between TLR2 Ϫ/Ϫ and TLR2/ 4 Ϫ/Ϫ mice, indicating that TLR4 does not have a coreceptor role in neutrophil recruitment and development of stromal haze. Although we and others previously implicated TLR4 as an important receptor (6,29,37,41), the current study used TLR4 Ϫ/Ϫ mice on a C57BL/6 background rather than LPShyporesponsive C3H/HeJ mice, and we used more stringently prepared filarial extracts. The absence of TLR4 responsiveness is also consistent with the absence of the enzymes associated with LPS biosynthesis in the Brugia malayi/Wolbachia genomes (14,44).…”