Neurokinin 1 receptor signaling affects the local innate immune defense against genital herpes virus infection.
We show that genital infection with neurotropic HSV type 2 (HSV-2) induced a significant increase of the neuropeptide substance P (SP) within the genital tract of mice. SP was shown to weakly interfere with the HSV-2 replication. Furthermore, lack of SP signaling through the use of mice deficient in the SP receptor, neurokinin 1 receptor (NK1R), revealed an important role for SP in the innate defense against HSV-2. NK1R-deficient mice had significantly enhanced levels of HSV-2 in the genital tract and in the CNS following infection and a significantly accelerated disease progression, which was associated with an impaired NK cell activity locally in the vagina. Lack of NK1R signaling did, however, not impair the animals' ability to mount a protective immune response to HSV-2 following vaccination with an attenuated virus. Both NK1R+/+ and NK1R-/- mice developed strong HSV-2-specific Th1 T cell responses following vaccination. No genital viral replication was observed in either vaccinated NK1R-deficient or NK1R+/+ control animals following a genital HSV-2 challenge, and all of these animals survived without any symptoms of disease. In conclusion, the present results indicate that SP and NK1R signaling contributes to the innate resistance against HSV-2 infection in mice.
Svensson
Alexandra
A
Department of Rheumatology and Inflammation Research, Göteborg University, Göteborg, Sweden.
Kaim
Joanna
J
Mallard
Carina
C
Olsson
Annika
A
Brodin
Ernst
E
Hökfelt
Tomas
T
Eriksson
Kristina
K
D000818:Animals; D002490:Central Nervous System / Q000473:pathology / Q000821:virology; D005260:Female; D006558:Herpes Genitalis / Q000276:immunology* / Q000378:metabolism / Q000517:prevention & control / Q000821:virology; D022301:Herpes Simplex Virus Vaccines / Q000494:pharmacology; D018258:Herpesvirus 2, Human / Q000187:drug effects / Q000276:immunology / Q000502:physiology; D007113:Immunity, Innate; D066298:In Vitro Techniques; D007694:Killer Cells, Natural / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018040:Receptors, Neurokinin-1 / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D015398:Signal Transduction; D013373:Substance P / Q000378:metabolism / Q000494:pharmacology; D014613:Vaccines, Attenuated / Q000494:pharmacology; D014621:Vagina / Q000276:immunology / Q000378:metabolism / Q000821:virology; D014779:Virus Replication / Q000187:drug effects
D022301:Herpes Simplex Virus Vaccines; D018040:Receptors, Neurokinin-1; D014613:Vaccines, Attenuated; D013373:Substance P