Host Genetic Variation Has a Profound Impact on Immune Responses Mediating Control of Viral Load in Chronic Gammaherpesvirus Infection.
J Immunol
; 211(10): 1526-1539, 2023 11 15.
Article
en En
| MEDLINE
| ID: mdl-37819784
ABSTRACT
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.
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Gammaherpesvirinae
/
Infecciones por Herpesviridae
Tipo de estudio:
Risk_factors_studies
Límite:
Animals
Idioma:
En
Revista:
J Immunol
Año:
2023
Tipo del documento:
Article