Importance of myeloid differentiation factor 88 in innate and acquired immune protection against genital herpes infection in mice.
Toll-like receptors (TLRs) play an important role as pattern-recognition receptors to sense and respond to pathogens. Our laboratory and others have shown recently that activation of TLR/MyD88 signaling through vaginal administration of CpG oligodeoxynucleotides, either singly or in combination with recombinant glycoprotein from herpes simplex virus type 2 (HSV-2), confers immunity against genital herpes infection. In this study, we have investigated the importance of the myeloid differentiation factor 88 (MyD88), a critical adaptor protein shared by all TLRs, in innate and acquired immunity against genital HSV-2 infection in mice. We demonstrate that MyD88 is essential for innate immune resistance against HSV-2. Thus, MyD88 deficient (MyD88(-/-)) mice show more vaginal HSV-2 titers, more rapid disease progression and earlier death compared to C57Bl/6 mice following a vaginal challenge with high (9 x 10(4) PFU) or low (9 x 10(3) PFU) virus dose. In contrast, use of MyD88 appears dispensable for induction of HSV-specific serum IgG antibody as well as local and systemic cell-mediated immune responses elicited by vaginal immunization with live attenuated thymidine kinase-deficient HSV-2 (HSV-2 TK(-)). Importantly, and similar to immunized C57Bl/6 mice, immunized MyD88(-/-) mice were completely protected against subsequent vaginal challenge with a lethal dose of virulent strain of HSV-2. These results provide evidence that the adaptor protein MyD88 is important for innate early control of genital HSV-2 infection, and that use of MyD88 is not required for induction of acquired immunity following vaginal immunization with HSV-2 TK(-).
Tengvall
Sara
S
Department of Microbiology and Immunology, Institute of Biomedicine, Sahlgrenska Academy at Göteborg University, Medicinaregatan 7A, Box 435, 40530 Göteborg, Sweden.
Harandi
Ali M
AM
D000818:Animals; D000914:Antibodies, Viral / Q000276:immunology; D005260:Female; D006558:Herpes Genitalis / Q000276:immunology*; D018258:Herpesvirus 2, Human / Q000276:immunology*; D022283:Herpesvirus Vaccines / Q000494:pharmacology; D007111:Immunity, Cellular / Q000187:drug effects / Q000502:physiology; D007113:Immunity, Innate / Q000187:drug effects / Q000502:physiology*; D007114:Immunization; D007074:Immunoglobulin G / Q000276:immunology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics / Q000276:immunology*; D009838:Oligodeoxyribonucleotides / Q000276:immunology / Q000494:pharmacology; D015398:Signal Transduction / Q000276:immunology; D051193:Toll-Like Receptors / Q000276:immunology; D014613:Vaccines, Attenuated / Q000494:pharmacology
D000914:Antibodies, Viral; C408982:CPG-oligonucleotide; D022283:Herpesvirus Vaccines; D007074:Immunoglobulin G; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D009838:Oligodeoxyribonucleotides; D051193:Toll-Like Receptors; D014613:Vaccines, Attenuated