Host Genetic Variation Has a Profound Impact on Immune Responses Mediating Control of Viral Load in Chronic Gammaherpesvirus Infection.

Autor:	Holt EA; Department of Biomedical and Health Sciences, University of Vermont, Burlington, VT., Waytashek CM; Department of Biomedical and Health Sciences, University of Vermont, Burlington, VT., Sessions KJ; Department of Biomedical and Health Sciences, University of Vermont, Burlington, VT., Asarian L; Department of Medicine, Vermont Center for Immunology and Infectious Diseases, Larner College of Medicine, University of Vermont, Burlington, VT., Lahue KG; Department of Biomedical and Health Sciences, University of Vermont, Burlington, VT., Usherwood EJ; Department of Microbiology and Immunology, The Geisel School of Medicine at Dartmouth College, Lebanon, NH., Teuscher C; Department of Medicine, Vermont Center for Immunology and Infectious Diseases, Larner College of Medicine, University of Vermont, Burlington, VT., Krementsov DN; Department of Biomedical and Health Sciences, University of Vermont, Burlington, VT.
Jazyk:	angličtina
Zdroj:	Journal of immunology (Baltimore, Md. : 1950) [J Immunol] 2023 Nov 15; Vol. 211 (10), pp. 1526-1539.
DOI:	10.4049/jimmunol.2300294
Abstrakt:	Chronic infection with the gammaherpesvirus EBV is a risk factor for several autoimmune diseases, and poor control of EBV viral load and enhanced anti-EBV responses elevate this risk further. However, the role of host genetic variation in the regulation of immune responses to chronic gammaherpesvirus infection and control of viral replication remains unclear. To address this question, we infected C57BL/6J (B6) and genetically divergent wild-derived inbred PWD/PhJ (PWD) mice with murine gammaherpesvirus-68 (MHV-68), a gammaherpesvirus similar to EBV, and determined the effect of latent gammaherpesvirus infection on the CD4 T cell transcriptome. Chronic MHV-68 infection of B6 mice resulted in a dramatic upregulation of genes characteristic of a cytotoxic Th cell phenotype, including Gzmb, Cx3cr1, Klrg1, and Nkg7, a response that was highly muted in PWD mice. Flow cytometric analyses revealed an expansion of CX3CR1+KLRG1+ cytotoxic Th cell-like cells in B6 but not PWD mice. Analysis of MHV-68 replication demonstrated that in spite of muted adaptive responses, PWD mice had superior control of viral load in lymphoid tissue, despite an absence of a defect in MHV-68 in vitro replication in PWD macrophages. Depletion of NK cells in PWD mice, but not B6 mice, resulted in elevated viral load, suggesting genotype-dependent NK cell involvement in MHV-68 control. Taken together, our findings demonstrate that host genetic variation can regulate control of gammaherpesvirus replication through disparate immunological mechanisms, resulting in divergent long-term immunological sequelae during chronic infection. (Copyright © 2023 by The American Association of Immunologists, Inc.)
Databáze:	MEDLINE
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