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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

Laura A. Kerepesi,1 Ofra Leon,1 Sarah Lustigman,2 and David Abraham1*

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.

* Corresponding author. Mailing address: Department of Microbiology and Immunology, Thomas Jefferson University, 233 S. 10th St., BLSB 530, Philadelphia, PA 19107. Phone: (215) 503-8917. Fax: (215) 923-9248. E-mail: david.abraham{at}jefferson.edu.

Editor: J. F. Urban, Jr.

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.



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