Department of Microbiology and Immunology, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.
Versiti Blood Research Institute, Milwaukee, Wisconsin, USA.
J Virol. 2020 Jun 16;94(13). doi: 10.1128/JVI.00399-20.
Gammaherpesviruses are ubiquitous pathogens that are associated with cancers, including B cell lymphomas. These viruses are unique in that they infect naive B cells and subsequently drive a robust polyclonal germinal center response in order to amplify the latent reservoir and to establish lifelong infection in memory B cells. The gammaherpesvirus-driven germinal center response in combination with robust infection of germinal center B cells is thought to precipitate lymphomagenesis. Importantly, host and viral factors that selectively affect the gammaherpesvirus-driven germinal center response remain poorly understood. Global deficiency of antiviral tumor-suppressive nterferon egulatory actor (IRF-1) selectively promotes the murine gammaherpesvirus 68 (MHV68)-driven germinal center response and expansion of the viral latent reservoir. To determine the extent to which antiviral effects of IRF-1 are B cell intrinsic, we generated mice with conditional IRF-1 deficiency. Surprisingly, B cell-specific IRF-1 deficiency attenuated the establishment of chronic infection and the germinal center response, indicating that MHV68 may, in a B cell-intrinsic manner, usurp IRF-1 to promote the germinal center response and expansion of the latent reservoir. Further, we found that B cell-specific IRF-1 deficiency led to reduced levels of active tyrosine phosphatase SHP1, which plays a B cell-intrinsic proviral function during MHV68 infection. Finally, results of this study indicate that the antiviral functions of IRF-1 unveiled in MHV68-infected mice with global IRF-1 deficiency are mediated via IRF-1 expression by non-B cell populations. Gammaherpesviruses establish lifelong infection in over 95% of all adults and are associated with B cell lymphomas. The virus's manipulation of the germinal center response and B cell differentiation to establish lifelong infection is thought to also precipitate malignant transformation, through a mechanism that remains poorly understood. The host transcription factor IRF-1, a well-established tumor suppressor, selectively attenuates MHV68-driven germinal center response, a phenotype that we originally hypothesized to occur in a B cell-intrinsic manner. In contrast, in testing, B cell-intrinsic IRF-1 expression promoted the MHV68-driven germinal center response and the establishment of chronic infection. Our report highlights the underappreciated multifaceted role of IRF-1 in MHV68 infection and pathogenesis.
γ疱疹病毒是普遍存在的病原体，与癌症有关，包括 B 细胞淋巴瘤。这些病毒的独特之处在于它们感染幼稚 B 细胞，随后驱动强烈的多克隆生发中心反应，以扩增潜伏储库并在记忆 B 细胞中建立终身感染。γ疱疹病毒驱动的生发中心反应加上生发中心 B 细胞的强烈感染，被认为是引发淋巴瘤发生的原因。重要的是，宿主和病毒因素选择性地影响γ疱疹病毒驱动的生发中心反应仍然知之甚少。抗病毒肿瘤抑制干扰素调节因子 1（IRF-1）的全球缺乏选择性地促进了小鼠γ疱疹病毒 68（MHV68）驱动的生发中心反应和病毒潜伏储库的扩张。为了确定 IRF-1 的抗病毒作用在多大程度上是 B 细胞内在的，我们生成了条件性 IRF-1 缺陷的小鼠。令人惊讶的是，B 细胞特异性 IRF-1 缺陷减弱了慢性感染和生发中心反应的建立，表明 MHV68 可能以 B 细胞内在的方式篡夺 IRF-1 来促进生发中心反应和潜伏储库的扩张。此外，我们发现 B 细胞特异性 IRF-1 缺陷导致活性酪氨酸磷酸酶 SHP1 水平降低，SHP1 在 MHV68 感染期间发挥 B 细胞内在的前病毒功能。最后，这项研究的结果表明，在具有全局 IRF-1 缺陷的 MHV68 感染小鼠中揭示的 IRF-1 的抗病毒功能是通过非 B 细胞群体的 IRF-1 表达介导的。γ疱疹病毒在超过 95%的所有成年人中建立终身感染，并与 B 细胞淋巴瘤有关。病毒对生发中心反应和 B 细胞分化的操纵，以建立终身感染，被认为也通过一种仍知之甚少的机制引发恶性转化。宿主转录因子 IRF-1 是一种成熟的肿瘤抑制剂，选择性地减弱 MHV68 驱动的生发中心反应，这一表型我们最初假设是在 B 细胞内在的方式发生的。相比之下，在测试中，B 细胞内在的 IRF-1 表达促进了 MHV68 驱动的生发中心反应和慢性感染的建立。我们的报告强调了 IRF-1 在 MHV68 感染和发病机制中的多方面作用。
