Protective immunity to the larval stages of onchocerca volvulus is dependent on Toll-like receptor 4.
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.
Kerepesi
Laura A
LA
Department of Microbiology and Immunology, Thomas Jefferson University, 233 S. 10th St., BLSB 530, Philadelphia, PA 19107, USA.
Leon
Ofra
O
Lustigman
Sarah
S
Abraham
David
D
D000818:Animals; D000917:Antibody Formation; D015801:Helminth Proteins / Q000276:immunology; D007371:Interferon-gamma / Q000378:metabolism; D007814:Larva / Q000276:immunology / Q000648:ultrastructure; D051379:Mice; D008817:Mice, Mutant Strains; D017181:Onchocerca volvulus / Q000254:growth & development / Q000276:immunology* / Q000382:microbiology; D009855:Onchocerciasis / Q000235:genetics / Q000276:immunology*; D013154:Spleen / Q000166:cytology; D013559:Symbiosis; D018418:Th2 Cells / Q000276:immunology; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000502:physiology*; D020577:Wolbachia / Q000276:immunology / Q000648:ultrastructure
D015801:Helminth Proteins; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D007371:Interferon-gamma