Interleukin 16 contributes to gammaherpesvirus pathogenesis by inhibiting viral reactivation
Interleukin 16 contributes to gammaherpesvirus pathogenesis by inhibiting viral reactivation
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白细胞介素 16 通过抑制病毒再激活促进伽马疱疹病毒发病机制
DOI：
10.1371/journal.ppat.1008701
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发表时间：
2020-07-01
期刊：
影响因子：
6.7
通讯作者：
Liang, Xiaozhen
中科院分区：
文献类型：
--
作者：
Liu, Shuai;Lei, Zhangmengxue;Liang, Xiaozhen
伽马疱疹病毒已经进化出各种策略，利用宿主细胞因子或信号通路来建立终身潜伏感染。与人类伽马疱疹病毒Epstein-Barr病毒类似，小鼠伽马疱疹病毒68(MHV68)在感染实验小鼠的过程中建立并维持记忆B细胞的潜伏期。我们之前已经证明，MHV68可以使胎肝来源的B细胞永生化，当注射到免疫缺陷小鼠中时，这些B细胞会导致淋巴瘤。在这里，我们发现白介素16(IL16)是在MHV68永生化的B细胞中表达最丰富的细胞因子，并表明MHV68感染上调了IL16的表达。IL16对MHV68裂解感染并不重要，但在潜伏期重新激活MHV68中起关键作用。IL16缺乏增加了MHV68永生化B细胞中MHV68裂解基因的表达，并增强了脾潜伏期的重新激活。相关地，IL16缺乏增加了MHV68感染浆细胞的频率，这可归因于增强的MHV68重新激活。此外，与TPA介导的Kaposi肉瘤相关疱疹病毒的裂解复制类似，IL16缺乏显著诱导Tyr705 STAT3去磷酸化和上调p21的表达，这可以被酪氨酸磷酸酶抑制剂原钒酸所抵消。重要的是，原钒酸强烈阻断IL16缺乏介导的MHV68裂解基因的表达。这些数据表明，病毒诱导的IL16并不直接参与MHV68的裂解复制，而是通过部分通过STAT3-p21轴抑制病毒的重新激活以促进潜伏感染。
Gammaherpesviruses have evolved various strategies to take advantage of host cellular factors or signaling pathways to establish a lifelong latent infection. Like the human gammaherpesvirus Epstein-Barr virus, murine gammaherpesvirus 68 (MHV68) establishes and maintains latency in the memory B cells during infection of laboratory mice. We have previously shown that MHV68 can immortalize fetal liver-derived B cells that induce lymphomas when injected into immunodeficient mice. Here we identify interleukin 16 (IL16) as a most abundantly expressed cytokine in MHV68-immortalized B cells and show that MHV68 infection elevates IL16 expression. IL16 is not important for MHV68 lytic infection but plays a critical role in MHV68 reactivation from latency. IL16 deficiency increases MHV68 lytic gene expression in MHV68-immortalized B cells and enhances reactivation from splenic latency. Correlatively, IL16 deficiency increases the frequency of MHV68-infected plasma cells that can be attributed to enhanced MHV68 reactivation. Furthermore, similar to TPA-mediated lytic replication of Kaposi's sarcoma-associated herpesvirus, IL16 deficiency markedly induces Tyr705 STAT3 de-phosphorylation and elevates p21 expression, which can be counteracted by the tyrosine phosphatase inhibitor orthovanadate. Importantly, orthovanadate strongly blocks MHV68 lytic gene expression mediated by IL16 deficiency. These data demonstrate that virus-induced IL16 does not directly participate in MHV68 lytic replication, but rather inhibits virus reactivation to facilitate latent infection, in part through the STAT3-p21 axis.