T cell response kinetics determines neuroinfection outcomes during murine HSV infection
Aisha G. Lee, Jason M. Scott, Maria Rita Fabbrizi, Xiaoping Jiang, Dorothy K. Sojka, Mark J. Miller, Megan T. Baldridge, Wayne M. Yokoyama, Haina Shin
Aisha G. Lee, Jason M. Scott, Maria Rita Fabbrizi, Xiaoping Jiang, Dorothy K. Sojka, Mark J. Miller, Megan T. Baldridge, Wayne M. Yokoyama, Haina Shin
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Research Article Immunology Infectious disease

T cell response kinetics determines neuroinfection outcomes during murine HSV infection

Abstract

Herpes simplex virus-2 (HSV-2) and HSV-1 both can cause genital herpes, a chronic infection that establishes a latent reservoir in the nervous system. Clinically, the recurrence frequency of HSV-1 genital herpes is considerably less than HSV-2 genital herpes, which correlates with reduced neuronal infection. The factors dictating the disparate outcomes of HSV-1 and HSV-2 genital herpes are unclear. In this study, we show that vaginal infection of mice with HSV-1 leads to the rapid appearance of mature DCs in the draining lymph node, which is dependent on an early burst of NK cell–mediated IFN-γ production in the vagina that occurs after HSV-1 infection but not HSV-2 infection. Rapid DC maturation after HSV-1 infection, but not HSV-2 infection, correlates with the accelerated generation of a neuroprotective T cell response and early accumulation of IFN-γ–producing T cells at the site of infection. Depletion of T cells or loss of IFN-γ receptor (IFN-γR) expression in sensory neurons both lead to a marked loss of neuroprotection only during HSV-1, recapitulating a prominent feature of HSV-2 infection. Our experiments reveal key differences in host control of neuronal HSV-1 and HSV-2 infection after genital exposure of mice, and they define parameters of a successful immune response against genital herpes.

Authors

Aisha G. Lee, Jason M. Scott, Maria Rita Fabbrizi, Xiaoping Jiang, Dorothy K. Sojka, Mark J. Miller, Megan T. Baldridge, Wayne M. Yokoyama, Haina Shin

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Figure 7

T cells and IFN-γ are critical for reducing neuronal viral burden after HSV-1 but not HSV-2 infection.

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T cells and IFN-γ are critical for reducing neuronal viral burden after ...
(A) Eight-week-old C57BL/6J female mice were treated with Depo-Provera. Mice were injected i.p. with a combination of CD4+ and CD8+ T cell–depleting antibodies or with an isotype control at 1 and 3 days prior to and 1 d.p.i. (B) Representative plots show efficiency of T cell depletion at 6 d.p.i. in vagina. Top row shows isotype control; bottom shows mice treated with depleting antibodies. Left columns of plots are gated on live, NK1.1– cells and show CD4+ (left 2) and CD8+ (middle 2) T cells with corresponding FMO controls. Right column of plots are gated on total live cells from the vagina and show the presence or absence of HSV-specific T cells. (C) Replicating virus was measured by plaque assay in vaginal washes collected on 2 (left graph) or 6 (right graph) d.p.i. from T cell–depleted (n = 9) or isotype-treated controls (n = 10). (D) Replicating virus was measured by plaque assay in the lumbar-sacral DRG at 6 d.p.i. from T cell–depleted or isotype-treated controls. (E) Replicating virus was measured by plaque assay at 2 (left graph) and 6 (right graph) d.p.i. in vaginal washes from IFN-γR CKO (n = 6-7) or littermate controls (n = 5–6). (F) Replicating virus was measured by plaque assay at 6 d.p.i. in lumbar-sacral ganglia IFN-γR CKO or littermate controls. Data are pooled from 3 (A–D) or 2 (E–F) independent experiments. Horizontal lines show mean; vertical bars show 95% CI. Statistical significance was measured by 2-way ANOVA with Bonferroni multiple comparisons test on log-transformed data. *P < 0.05, **P < 0.01, ***P < 0.005, ****P < 0.001.