Autophagy Genes Enhance Murine Gammaherpesvirus 68 Reactivation from Latency by Preventing Virus-Induced Systemic Inflammation.
Autophagy Genes Enhance Murine Gammaherpesvirus 68 Reactivation from Latency by Preventing Virus-Induced Systemic Inflammation.
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DOI：
10.1016/j.chom.2015.12.010
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发表时间：
2016-01-13
影响因子：
30.3
通讯作者：
Virgin HW
中科院分区：
文献类型：
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作者：
Park S;Buck MD;Desai C;Zhang X;Loginicheva E;Martinez J;Freeman ML;Saitoh T;Akira S;Guan JL;He YW;Blackman MA;Handley SA;Levine B;Green DR;Reese TA;Artyomov MN;Virgin HW
在慢性病毒感染后调节全身炎症的宿主基因还不完全清楚。小鼠γ疱疹病毒68（MHV 68）感染的特征是在巨噬细胞中潜伏，再活化被干扰素-γ（IFN-γ）抑制。使用溶菌酶-M-cre（LysMcre）表达系统，我们发现，删除自噬相关（Atg）基因Fip 200，beclin 1，Atg 14，Atg 16 l1，Atg 7，Atg 3和Atg 5，在骨髓腔室，抑制MHV 68在巨噬细胞中的再激活。Atg 5缺陷并没有改变从B细胞的再激活，并没有解释从巨噬细胞的再激活的影响，在生产性病毒复制或建立潜伏期的改变。相反，慢性MHV 68感染引发了全身炎症增加，IFN-γ的T细胞产生增加，以及Atg基因缺陷小鼠巨噬细胞中IFN-γ诱导的转录特征。IFN-γ的中和作用可部分逆转Atg 5相关的再激活缺陷。因此，髓样细胞中的Atg基因抑制了病毒诱导的全身性炎症，创造了一个促进MHV 68从潜伏期有效再激活的环境。髓样细胞中的自噬（Atg）基因抑制病毒触发的全身性炎症Atg基因调节的全身性炎症抑制疱疹病毒再活化干扰素-γ在Atg基因突变背景下控制疱疹病毒再活化Park et al.报道了髓样细胞中的典型自噬基因调节由慢性鼠γ疱疹病毒感染诱导的全身炎症水平。在自噬基因缺乏的情况下，全身炎症增加的一个后果是抑制潜伏感染的巨噬细胞中疱疹病毒的再活化。
Host genes that regulate systemic inflammation upon chronic viral infection are incompletely understood. Murine gammaherpesvirus 68 (MHV68) infection is characterized by latency in macrophages, and reactivation is inhibited by interferon-γ (IFN-γ). Using a lysozyme-M-cre (LysMcre) expression system, we show that deletion of autophagy-related (Atg) genes Fip200, beclin 1, Atg14, Atg16l1, Atg7, Atg3, and Atg5, in the myeloid compartment, inhibited MHV68 reactivation in macrophages. Atg5 deficiency did not alter reactivation from B cells, and effects on reactivation from macrophages were not explained by alterations in productive viral replication or the establishment of latency. Rather, chronic MHV68 infection triggered increased systemic inflammation, increased T cell production of IFN-γ, and an IFN-γ-induced transcriptional signature in macrophages from Atg gene-deficient mice. The Atg5-related reactivation defect was partially reversed by neutralization of IFN-γ. Thus Atg genes in myeloid cells dampen virus-induced systemic inflammation, creating an environment that fosters efficient MHV68 reactivation from latency. Autophagy (Atg) genes in myeloid cells inhibit virus-triggered systemic inflammation Atg gene-regulated systemic inflammation inhibits herpesvirus reactivation Interferon-γ controls herpesvirus reactivation in the setting of Atg gene mutations Park et al. report that canonical autophagy genes in myeloid cells regulate the level of systemic inflammation induced by chronic murine gammaherpesvirus infection. One consequence of increased systemic inflammation in the setting of autophagy-gene deficiency is the inhibition of reactivation of the herpesvirus from latently infected macrophages.