Schmalzriedt Damon L, Johansen Erika R, Aurubin Carlie A, Rahlf Cade R, Stuart Bradey, Sahoo Daisy, Tarakanova Vera L
Department of Microbiology and Immunology, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.
Medical Scientist Training Program, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.
J Virol. 2025 Jul 22;99(7):e0075725. doi: 10.1128/jvi.00757-25. Epub 2025 May 30.
Lipid metabolism has emerged as an important regulator of acute viral infections by affecting viral replication and the host immune response. In contrast, the role of host lipid metabolism during chronic viral infection has been less explored. The current study aims to define the role of scavenger receptor class B type I (SR-BI), a primary physiologic receptor for high-density lipoprotein (HDL), during natural gammaherpesvirus infection. Gammaherpesviruses are highly prevalent cancer-associated pathogens that induce and manipulate germinal center responses to establish life-long infection of B cells. Importantly, gammaherpesvirus-infected germinal center B cells are thought to be the target of viral transformation. In this study, we found that global SR-BI deficiency led to increased gammaherpesvirus lytic gene expression in the lungs during the acute stage of infection. Chronic gammaherpesvirus infection of the SR-BI-deficient host was associated with exaggerated germinal center responses and increased differentiation of self-reactive B cells that persisted during the long-term stage of chronic infection. Interestingly, SR-BI-deficient germinal center B cells, although more numerous, failed to support efficient gammaherpesvirus infection. The exaggerated germinal center response was also observed following immunization of the SR-BI-deficient host, unveiling the novel role of SR-BI as a negative regulator of physiological and gammaherpesvirus-driven germinal center responses.
Lipid metabolism affects diverse acute viral infections. In contrast, less is known about the effect of lipid metabolism on chronic virus infection, including in the context of an intact host. Host lipid homeostasis is maintained via a combination of endogenous lipid synthesis that takes place in most cell types and cellular interaction with exogenous, circulating lipids. This study focuses on defining the interaction between SR-BI, a primary HDL receptor, and natural gammaherpesvirus infection. We found that SR-BI deficiency led to increased expression of lytic gammaherpesvirus genes during acute gammaherpesvirus replication in the lungs. Importantly, chronic gammaherpesvirus infection unveiled the physiological role of SR-BI as a negative regulator of the germinal center response, a B cell differentiation process that is critical for physiological B cell responses and that is manipulated by gammaherpesviruses to establish chronic infection.
脂质代谢已成为急性病毒感染的重要调节因子，可影响病毒复制和宿主免疫反应。相比之下，宿主脂质代谢在慢性病毒感染中的作用尚未得到充分研究。本研究旨在确定B类I型清道夫受体（SR-BI）在自然感染γ疱疹病毒期间的作用，SR-BI是高密度脂蛋白（HDL）的主要生理受体。γ疱疹病毒是高度流行的与癌症相关的病原体，可诱导和操纵生发中心反应以建立B细胞的终身感染。重要的是，感染γ疱疹病毒的生发中心B细胞被认为是病毒转化的靶标。在本研究中，我们发现整体SR-BI缺陷导致感染急性期肺部γ疱疹病毒裂解基因表达增加。SR-BI缺陷宿主的慢性γ疱疹病毒感染与生发中心反应过度和自身反应性B细胞分化增加有关，这些变化在慢性感染的长期阶段持续存在。有趣的是，SR-BI缺陷的生发中心B细胞虽然数量更多，但无法支持有效的γ疱疹病毒感染。在对SR-BI缺陷宿主进行免疫后也观察到生发中心反应过度，揭示了SR-BI作为生理和γ疱疹病毒驱动的生发中心反应的负调节因子的新作用。
脂质代谢影响多种急性病毒感染。相比之下，脂质代谢对慢性病毒感染的影响，包括在完整宿主的情况下，了解较少。宿主脂质稳态通过大多数细胞类型中发生的内源性脂质合成以及细胞与外源性循环脂质的相互作用来维持。本研究重点确定主要HDL受体SR-BI与自然γ疱疹病毒感染之间的相互作用。我们发现，在肺部急性γ疱疹病毒复制期间，SR-BI缺陷导致γ疱疹病毒裂解基因表达增加。重要的是，慢性γ疱疹病毒感染揭示了SR-BI作为生发中心反应负调节因子的生理作用，生发中心反应是一种对生理性B细胞反应至关重要的B细胞分化过程，γ疱疹病毒会操纵该过程以建立慢性感染。
