Owens Shana M, Sifford Jeffrey M, Li Gang, Murdock Steven J, Salinas Eduardo, Oldenburg Darby, Ghosh Debopam, Stumhofer Jason S, Nookaew Intawat, Manzano Mark, Forrest J Craig
Dept. of Microbiology and Immunology and Center for Microbial Pathogenesis and Host Inflammatory Responses, University of Arkansas for Medical Sciences, Little Rock, AR, USA.
Gunderson Research Institute, LaCrosse, WI, USA.
Nat Commun. 2025 Jan 22;16(1):951. doi: 10.1038/s41467-025-56247-5.
Gammaherpesviruses are DNA tumor viruses that establish lifelong latent infections in lymphocytes. For viruses such as Epstein-Barr virus and murine gammaherpesvirus 68, this is accomplished through a viral gene-expression program that promotes cellular proliferation and differentiation, especially of germinal center B cells. Intrinsic host mechanisms that control virus-driven cellular expansion are incompletely defined. Using a small-animal model of gammaherpesvirus pathogenesis, we demonstrate in vivo that the tumor suppressor p53 is activated specifically in B cells latently infected by murine gammaherpesvirus 68. In the absence of p53, the early expansion of murine gammaherpesvirus 68 latency greatly increases, especially in germinal center B cells, a cell type whose proliferation is conversely restricted by p53. We identify the B cell-specific latency gene M2, a viral promoter of germinal center B cell differentiation, as a viral protein sufficient to elicit a p53-dependent anti-proliferative response caused by Src-family kinase activation. We further demonstrate that Epstein-Barr virus-encoded latent membrane protein 1 similarly triggers a p53 response in primary B cells. Our data highlight a model in which gammaherpesvirus latency gene-expression programs that promote B cell proliferation and differentiation to facilitate viral colonization of the host trigger aberrant cellular proliferation that is controlled by p53.
γ疱疹病毒是在淋巴细胞中建立终身潜伏感染的DNA肿瘤病毒。对于诸如爱泼斯坦-巴尔病毒和鼠γ疱疹病毒68等病毒而言，这是通过一种促进细胞增殖和分化（尤其是生发中心B细胞的增殖和分化）的病毒基因表达程序来实现的。控制病毒驱动的细胞扩张的内在宿主机制尚未完全明确。利用γ疱疹病毒发病机制的小动物模型，我们在体内证明肿瘤抑制因子p53在被鼠γ疱疹病毒68潜伏感染的B细胞中特异性激活。在没有p53的情况下，鼠γ疱疹病毒68潜伏期的早期扩张显著增加，尤其是在生发中心B细胞中，而生发中心B细胞的增殖反过来会受到p53的限制。我们确定B细胞特异性潜伏基因M2，一种生发中心B细胞分化的病毒启动子，是一种足以引发由Src家族激酶激活导致的p53依赖性抗增殖反应的病毒蛋白。我们进一步证明，爱泼斯坦-巴尔病毒编码的潜伏膜蛋白1同样会在原代B细胞中触发p53反应。我们的数据突出了一种模型，即促进B细胞增殖和分化以促进病毒在宿主体内定植的γ疱疹病毒潜伏基因表达程序会引发由p53控制的异常细胞增殖。
