Darrah Eric J, Kulinski Joseph M, Mboko Wadzanai P, Xin Gang, Malherbe Laurent P, Gauld Stephen B, Cui Weiguo, Tarakanova Vera L
Microbiology and Immunology, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.
Blood Research Institute, Blood Center of Wisconsin, Milwaukee, Wisconsin, USA.
J Virol. 2017 Sep 12;91(19). doi: 10.1128/JVI.01103-17. Print 2017 Oct 1.
Manipulation of host cellular pathways is a strategy employed by gammaherpesviruses, including mouse gammaherpesvirus 68 (MHV68), in order to negotiate a chronic infection. Ataxia-telangiectasia mutated (ATM) plays a unique yet incompletely understood role in gammaherpesvirus infection, as it has both proviral and antiviral effects. Chronic gammaherpesvirus infection is poorly controlled in a host with global ATM insufficiency, whether the host is a mouse or a human. In contrast, ATM facilitates replication, reactivation, and latency establishment of several gammaherpesviruses , suggesting that ATM is proviral in the context of infected cell cultures. The proviral role of ATM is also evident , as myeloid-specific ATM expression facilitates MHV68 reactivation during the establishment of viral latency. In order to better understand the complex relationship between host ATM and gammaherpesvirus infection, we depleted ATM specifically in B cells, a cell type critical for chronic gammaherpesvirus infection. B cell-specific ATM deficiency attenuated the establishment of viral latency due to compromised differentiation of ATM-deficient B cells. Further, we found that during long-term infection, peritoneal B-1b, but not related B-1a, B cells display the highest frequency of gammaherpesvirus infection. While ATM expression did not affect gammaherpesvirus tropism for B-1 B cells, B cell-specific ATM expression was necessary to support viral reactivation from peritoneal cells during long-term infection. Thus, our study reveals a role of ATM as a host factor that promotes chronic gammaherpesvirus infection of B cells. Gammaherpesviruses infect a majority of the human population and are associated with cancer, including B cell lymphomas. ATM is a unique host kinase that has both proviral and antiviral roles in the context of gammaherpesvirus infection. Further, there is insufficient understanding of the interplay of these roles during chronic infection. In this study, we show that ATM expression by splenic B cells is required for efficient establishment of gammaherpesvirus latency. We also show that ATM expression by peritoneal B cells is required to facilitate viral reactivation during long-term infection. Thus, our study defines a proviral role of B cell-specific ATM expression during chronic gammaherpesvirus infection.
操纵宿主细胞通路是γ疱疹病毒采用的一种策略，包括小鼠γ疱疹病毒68（MHV68），以便促成慢性感染。共济失调毛细血管扩张症突变基因（ATM）在γ疱疹病毒感染中发挥着独特但尚未完全了解的作用，因为它兼具促进病毒和抗病毒的作用。在全球ATM功能不全的宿主中，无论是小鼠还是人类，慢性γ疱疹病毒感染都难以得到有效控制。相反，ATM促进了几种γ疱疹病毒的复制、再激活和潜伏建立，这表明在感染细胞培养的背景下，ATM具有促进病毒的作用。ATM的促病毒作用也很明显，因为髓系特异性ATM表达在病毒潜伏建立期间促进了MHV68的再激活。为了更好地理解宿主ATM与γ疱疹病毒感染之间的复杂关系，我们专门在B细胞中耗尽了ATM，B细胞是慢性γ疱疹病毒感染的关键细胞类型。B细胞特异性ATM缺陷由于ATM缺陷B细胞分化受损而减弱了病毒潜伏的建立。此外，我们发现，在长期感染期间，腹膜B-1b细胞而非相关的B-1a细胞显示出最高频率的γ疱疹病毒感染。虽然ATM表达不影响γ疱疹病毒对B-1 B细胞的嗜性，但B细胞特异性ATM表达是长期感染期间支持腹膜细胞病毒再激活所必需的。因此，我们的研究揭示了ATM作为一种宿主因子在促进B细胞慢性γ疱疹病毒感染中的作用。γ疱疹病毒感染了大多数人群，并与癌症相关，包括B细胞淋巴瘤。ATM是一种独特的宿主激酶，在γ疱疹病毒感染的背景下具有促进病毒和抗病毒的作用。此外，对于这些作用在慢性感染期间的相互作用了解不足。在这项研究中，我们表明脾B细胞的ATM表达是γ疱疹病毒潜伏有效建立所必需的。我们还表明，腹膜B细胞的ATM表达是长期感染期间促进病毒再激活所必需的。因此，我们的研究确定了B细胞特异性ATM表达在慢性γ疱疹病毒感染期间的促病毒作用。
