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Infection and Immunity, December 2005, p. 8291-8297, Vol. 73, No. 12
0019-9567/05/$08.00+0     doi:10.1128/IAI.73.12.8291-8297.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Protective Immunity to the Larval Stages of Onchocerca volvulus Is Dependent on Toll-Like Receptor 4

Department of Microbiology and Immunology, Thomas Jefferson University, 233 S. 10th Street, Philadelphia, Pennsylvania 19104,¹ The Lindsley F. Kimball Research Institute, New York Blood Center, 310 East 67th Street, New York, New York 10021²

Received 9 December 2004/ Returned for modification 30 January 2005/ Accepted 16 August 2005

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.

Editor: J. F. Urban, Jr.

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