Department of Biomedical and Health Sciences, University of Vermont, Burlington, VT.
Department of Medicine, Vermont Center for Immunology and Infectious Diseases, Larner College of Medicine, University of Vermont, Burlington, VT.
J Immunol. 2023 Nov 15;211(10):1526-1539. doi: 10.4049/jimmunol.2300294.
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.
慢性感染γ疱疹病毒 EBV 是几种自身免疫性疾病的危险因素，EBV 病毒载量控制不佳和增强的抗 EBV 反应进一步增加了这种风险。然而，宿主遗传变异在调节对慢性γ疱疹病毒感染的免疫反应和控制病毒复制中的作用尚不清楚。为了解决这个问题，我们用类似于 EBV 的γ疱疹病毒鼠γ疱疹病毒-68（MHV-68）感染 C57BL/6J（B6）和遗传差异的野生来源近交系 PWD/PhJ（PWD）小鼠，并确定潜伏性 MHV-68 感染对 CD4 T 细胞转录组的影响。B6 小鼠的慢性 MHV-68 感染导致具有细胞毒性 Th 细胞表型特征的基因显著上调，包括 Gzmb、Cx3cr1、Klrg1 和 Nkg7，而 PWD 小鼠的反应则高度沉默。流式细胞术分析显示，B6 小鼠中 CX3CR1+KLRG1+细胞毒性 Th 样细胞扩增，而 PWD 小鼠则没有。对 MHV-68 复制的分析表明，尽管适应性反应被抑制，PWD 小鼠仍能更好地控制淋巴组织中的病毒载量，尽管 PWD 巨噬细胞中 MHV-68 的体外复制没有缺陷。PWD 小鼠而非 B6 小鼠中 NK 细胞的耗竭导致病毒载量升高，表明基因型依赖的 NK 细胞参与了 MHV-68 的控制。总之，我们的研究结果表明，宿主遗传变异可以通过不同的免疫机制调节γ疱疹病毒的复制控制，导致慢性感染期间出现不同的长期免疫后果。
