Authors
Waytashek, C. M., Nelson, E. A., Sessions, K. J., Dalhberg, K., Fondakowski, M., Bubier, J., Usherwood, E. J., Krementsov, D. N.
Abstract
Inefficient host control of infection by gammaherpesviruses is a risk factor for lymphoproliferative disease, autoimmunity, and cancer, yet naturally occurring genetic determinants of viral control remain poorly defined. Previously, we discovered that wild-derived PWD/PhJ (PWD) mice exhibit markedly improved control of murine gammaherpesvirus 68 (MHV-68) replication compared with C57BL/6J (B6) mice. This elite control of viral replication was linked to muted T cell responses, but partially dependent on NK cells. Here, we used genetic approaches to identify host determinants controlling MHV-68 resistance in PWD mice. Analysis of B6PWDF1 and B6PWDF2 populations suggested the existence of a major locus in the PWD genome contributing to MHV-68 resistance. Using B6.ChrPWD chromosome substitution (consomic) mice, we mapped a major resistance locus to Chr 17 and refined the required interval to 27.6-49.4 Mb, including the MHC locus. While B6.Chr17PWD mice recapitulated muted T cell responses observed in PWD mice, they controlled viral burden independent of NK cells and without reduced frequencies of infected germinal center B cells, indicating that resistance of PWD mice comprises multiple genetically and mechanistically distinct pathways. While the NK cell receptor complex on PWD chromosome 6 did not provide protection, genotype-phenotype analysis of the B6PWDF2 cohort revealed additional non-Chr 17-linked loci contributing to viral control. Together, our results identify a novel MHC-linked locus regulating gammaherpesvirus burden with minimal cytotoxic T cell expansion, demonstrating that effective host control of gammaherpesviruses can be achieved by diverse immune mechanisms.
Preprint server:
bioRxiv
The authors list and abstract were imported from bioRxiv on 30 Jun 2026.
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