B Cell-Specific Expression of Ataxia-Telangiectasia Mutated Protein Kinase Promotes Chronic Gammaherpesvirus Infection.
B Cell-Specific Expression of Ataxia-Telangiectasia Mutated Protein Kinase Promotes Chronic Gammaherpesvirus Infection.
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B 细胞特异性表达共济失调毛细血管扩张突变蛋白激酶促进慢性伽马疱疹病毒感染。
DOI：
10.1128/jvi.01103-17
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发表时间：
2017
影响因子：
5.4
通讯作者：
Tarakanova,VeraL
中科院分区：
文献类型：
--
作者：
Darrah,EricJ;Kulinski,JosephM;Mboko,WadzanaiP;Xin,Gang;Malherbe,LaurentP;Gauld,StephenB;Cui,Weiguo;Tarakanova,VeraL
宿主细胞途径的操纵是γ疱疹病毒（包括小鼠γ疱疹病毒68（MHV 68））采用的策略，以协商慢性感染。共济失调-毛细血管扩张突变（ATM）在γ疱疹病毒感染中起着独特但尚未完全理解的作用，因为它具有前病毒和抗病毒作用。慢性γ疱疹病毒感染在具有全局ATM不足的宿主中控制不佳，无论宿主是小鼠还是人。相反，ATM促进体外几种γ疱疹病毒的复制、再激活和潜伏期建立，表明ATM在感染细胞培养物中是前病毒。ATM的前病毒作用在体内也是明显的，因为骨髓特异性ATM表达在病毒潜伏期建立期间促进MHV 68再活化。为了更好地了解宿主ATM和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ATM，这是一种对慢性γ疱疹病毒感染至关重要的细胞类型。B细胞特异性ATM缺陷减弱了由于ATM缺陷B细胞的分化受损而导致的病毒潜伏期的建立。此外，我们发现，在长期感染期间，腹膜B-1 B b，而非相关的B-1 a、B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表达对于在长期感染期间支持病毒从腹膜细胞再活化是必要的。因此，我们的研究揭示了ATM作为促进B细胞慢性γ-疱疹病毒感染的宿主因子的作用。重要提示γ-疱疹病毒感染大多数人群并与癌症有关，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前病毒和抗病毒作用。此外，对慢性感染过程中这些作用的相互作用还缺乏足够的了解。在这项研究中，我们表明，ATM表达脾B细胞是有效建立γ疱疹病毒潜伏期所必需的。我们还表明，ATM表达腹膜B细胞是需要促进病毒在长期感染的再活化。因此，我们的研究确定了慢性γ疱疹病毒感染过程中B细胞特异性ATM表达的前病毒作用。
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 gammaherpesvirusesin vitro, suggesting that ATM is proviral in the context of infected cell cultures. The proviral role of ATM is also evidentin vivo, 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.IMPORTANCEGammaherpesviruses 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 rolesin vivoduring 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.