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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-? 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-?-producing T cells at the site of infection. Depletion of T cells or loss of IFN-? receptor (IFN-?R) 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.

SUBMITTER: Lee AG

PROVIDER: S-EPMC7141405 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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T cell response kinetics determines neuroinfection outcomes during murine HSV infection.

Lee Aisha G AG Scott Jason M JM Fabbrizi Maria Rita MR Jiang Xiaoping X Sojka Dorothy K DK Miller Mark J MJ Baldridge Megan T MT Yokoyama Wayne M WM Shin Haina H

JCI insight 20200312 5

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 ...[more]

PMID: 32161194

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Project description:For Samples 1-8 and 11-18: The innate immune sensor retinoic acid-inducible gene-I (RIG-I) detects double-stranded RNA derived from RNA viruses, and recent studies have demonstrated that RIG-I also plays a role in the antiviral response to DNA viruses. To identify the physiological RNA species that are recognized by RIG-I during HSV-1 infection, we purified the RNAs that co-immunoprecipitated with FLAG-tagged RIG-I in transfected human embryonic kidney (HEK) 293T cells that had been infected with a recombinant HSV-1 (hereafter referred to as HSV-1 mut) containing a mutation (K220A) in the viral serine/threonine protein kinase US3 that abolishes its catalytic activity, as the viral kinase is known to antagonize type-I IFN responses. As controls, RNA species bound to FLAG-RIG-I in uninfected cells and RNA bound to FLAG-GFP from both HSV-1 mut-infected and uninfected cells were also purified. RIG-I-bound RNA and total RNA extracted from uninfected and HSV-1 mut-infected cells were analyzed by RNAseq, and the resulting sequences were mapped to both the HSV-1F-strain and human genome (hg38). This analysis revealed that several human transcripts were highly enriched in the RIG-I-bound fraction from infected cells; in contrast, the enrichment of viral sequences was low. The cellular transcripts that were most abundant in the RIG-I fraction were predominantly non-coding RNAs from different subclasses, as well as some coding RNAs. For Samples 9 and 10: HSV-1 infection is known to induces changes in the transcriptional profile of the infected cell. To analyze global changes in RNA transcript levels in infected cells, total RNA was extracted from HEK 293T cells that were infected with wild-type (WT) HSV-1. For comparison, total RNA was extracted from HEK 293T cells that remained uninfected. Next, RNAseq analysis was performed. The resulting sequences were mapped to the human genome, and gene inductions were calculated and normalized to uninfected samples to determine changes in gene expression upon infection.

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T cell response kinetics determines neuroinfection outcomes during murine HSV infection.

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T cell response kinetics determines neuroinfection outcomes during murine HSV infection.

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