Immunogenetic determinants of HSV-2 infection and disease
JOURNAL OF IMMUNOLOGY(2022)
Abstract
Abstract Herpes simplex virus-2 (HSV-2) is one of the most prevalent sexually transmitted infections, and can result in life-long, chronic disease. Disease severity, frequency of reactivation, and shedding rates vary between individuals, though little is known about how host genes regulate tissue-specific immune responses. We have previously used the Collaborative Cross (CC) mouse model system, which incorporates the extent of genetic variation found in the human genome, to better model the diversity of outcomes found in human viral infections, so we next probed the CC to identify host genetic regions that regulate viral shedding and disease following HSV-2 infection, as well as tissue-specific immune responses. We performed a screen of mice from different CC strains to assess viral titers and disease following vaginal HSV-2 infection, and then used this data to perform quantitative trait loci (QTL) mapping to identify chromosomal regions linked to vaginal viral shedding rates and levels, as well as virus-associated clinical disease. In parallel experiments, we assessed lymphoid, nervous system, and mucosal immune cell frequencies at innate, adaptive, and memory response timepoints. We observed a distinctive suppressive signature on vaginal Tregs compared to lymph node Tregs, at various times following HSV-2 infection. Additionally, these suppressive responses varied in mice with either higher viral titers, or more tissue inflammation, highlighting the interplay between host immune response and viral infection kinetics. Understanding host factors that contribute to HSV shedding, clinical disease, and immune responses may provide critical insights for developing new preventive strategies or interventions to HSV-2 infection. Supported by grant R21 AI152559-01 from the NIH
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Key words
immunogenetic determinants,infection,disease
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