A gammaherpesvirus cooperates with interferon-alpha/beta-induced IRF2 to halt viral replication, control reactivation, and minimize host lethality.
A gammaherpesvirus cooperates with interferon-alpha/beta-induced IRF2 to halt viral replication, control reactivation, and minimize host lethality.
复制标题
γ掌病毒与干扰素 - α/β诱导的IRF2合作，以停止病毒复制，控制重新激活并最大程度地减少宿主致死性。
DOI：
10.1371/journal.ppat.1002371
复制
发表时间：
2011-11
期刊：
影响因子：
6.7
通讯作者：
Barton ES
中科院分区：
文献类型：
--
作者：
Mandal P;Krueger BE;Oldenburg D;Andry KA;Beard RS;White DW;Barton ES
伽马疱疹病毒，包括 Epstein-Barr 病毒 (EBV) 和卡波西肉瘤相关疱疹病毒 (KSHV)，在记忆 B 淋巴细胞中建立潜伏期，并促进免疫功能低下个体的淋巴增殖性疾病。防止伽马疱疹病毒再激活和肿瘤发生的精确免疫机制尚不清楚。鼠伽马疱疹病毒 68 (MHV68) 与 EBV 和 KSHV 密切相关，I 型 (α/β) 干扰素 (IFNαβ) 通过未知机制调节 B 细胞和巨噬细胞的 MHV68 重新激活。在这里，我们证明，在没有可检测到的 MHV68 复制的情况下，IFNβ 在潜伏感染期间高度上调。我们在 MHV68 M2 基因启动子中发现了一个干扰素刺激反应元件 (ISRE)，该元件在体内潜伏期与 IFNαβ 诱导的转录抑制子 IRF2 结合。 M2 蛋白调节 B 细胞信号传导以促进潜伏期的建立和重新激活。缺乏 M2 ISRE (ISREΔ) 的病毒过度表达 M2 mRNA，并表现出体内不受控制的急性复制、较高的潜伏病毒载量以及异常高的潜伏期再激活。 ISREΔ突变体的这些表型是B细胞特异性的，需要IRF2，并且与急性病毒性肺炎模型中毒力的显着增加相关。因此，我们确定了一种机制，伽马疱疹病毒以令人惊讶的合作方式颠覆宿主 IFNαβ 信号传导，直接抑制病毒复制和重新激活并强制潜伏，从而最大限度地减少急性宿主疾病。由于我们发现多种啮齿动物、灵长类动物和人类伽马疱疹病毒的主要淋巴细胞潜伏基因的 ISRE 5'，因此我们提出，合作颠覆 IFNαβ 诱导的 IRF 以促进潜伏感染是一种古老的策略，可确保稳定、致病性最低的病毒-宿主关系。疱疹病毒在称为潜伏期的非复制状态下建立终生感染。在免疫受损期间，疱疹病毒可能会重新激活并导致严重的疾病，包括癌症。我们研究了干扰素 α/β (IFNαβ)（抗病毒免疫基因家族）抑制鼠伽马疱疹病毒 68 (MHV68) 重新激活的机制。 MHV68 与 Epstein-Barr 病毒和卡波西肉瘤相关疱疹病毒、与多种癌症相关的人类伽马疱疹病毒有关。我们令人惊讶地发现，在潜伏期，MHV68 与 IFNαβ 合作抑制其自身复制。具体来说，重新激活所需的病毒基因已进化为可直接被 IFNαβ 诱导的转录因子 IRF2 抑制。一旦病毒复制触发足够的 IFNαβ 产生，该病毒基因的表达就会减少，重新激活效率也会降低。这种策略可以保护宿主的健康，因为无法响应 IRF2 的突变病毒会不受控制地复制并且毒性更强。 IFNαβ 的病毒感应也具有潜在的颠覆性，因为它允许 MHV68 检测局部免疫静止期，在此期间它可以重新激活并传播到新宿主。因此，我们强调了病毒与宿主共同进化的新途径，以合作颠覆抗病毒免疫反应。这些观察结果可能揭示抑制疱疹病毒再激活或消除疱疹病毒相关肿瘤的药物的新靶点。
The gammaherpesviruses, including Epstein-Barr virus (EBV) and Kaposi's sarcoma-associated herpesvirus (KSHV), establish latency in memory B lymphocytes and promote lymphoproliferative disease in immunocompromised individuals. The precise immune mechanisms that prevent gammaherpesvirus reactivation and tumorigenesis are poorly defined. Murine gammaherpesvirus 68 (MHV68) is closely related to EBV and KSHV, and type I (alpha/beta) interferons (IFNαβ) regulate MHV68 reactivation from both B cells and macrophages by unknown mechanisms. Here we demonstrate that IFNβ is highly upregulated during latent infection, in the absence of detectable MHV68 replication. We identify an interferon-stimulated response element (ISRE) in the MHV68 M2 gene promoter that is bound by the IFNαβ-induced transcriptional repressor IRF2 during latency in vivo. The M2 protein regulates B cell signaling to promote establishment of latency and reactivation. Virus lacking the M2 ISRE (ISREΔ) overexpresses M2 mRNA and displays uncontrolled acute replication in vivo, higher latent viral load, and aberrantly high reactivation from latency. These phenotypes of the ISREΔ mutant are B-cell-specific, require IRF2, and correlate with a significant increase in virulence in a model of acute viral pneumonia. We therefore identify a mechanism by which a gammaherpesvirus subverts host IFNαβ signaling in a surprisingly cooperative manner, to directly repress viral replication and reactivation and enforce latency, thereby minimizing acute host disease. Since we find ISREs 5′ to the major lymphocyte latency genes of multiple rodent, primate, and human gammaherpesviruses, we propose that cooperative subversion of IFNαβ-induced IRFs to promote latent infection is an ancient strategy that ensures a stable, minimally-pathogenic virus-host relationship. Herpesviruses establish life-long infection in a non-replicating state termed latency. During immune compromise, herpesviruses can reactivate and cause severe disease, including cancer. We investigated mechanisms by which interferons alpha/beta (IFNαβ), a family of antiviral immune genes, inhibit reactivation of murine gammaherpesvirus 68 (MHV68). MHV68 is related to Epstein-Barr virus and Kaposi's sarcoma-associated herpesvirus, human gammaherpesviruses associated with multiple cancers. We made the surprising discovery that during latency, MHV68 cooperates with IFNαβ to inhibit its own replication. Specifically, a viral gene required for reactivation has evolved to be directly repressed by an IFNαβ-induced transcription factor, IRF2. Once virus replication has triggered sufficient IFNαβ production, expression of this viral gene is reduced and reactivation efficiency decreases. This strategy safeguards the health of the host, since a mutant virus that cannot respond to IRF2 replicates uncontrollably and is more virulent. Viral sensing of IFNαβ is also potentially subversive, since it allows MHV68 to detect periods of localized immune quiescence during which it can reactivate and spread to a new host. Thus, we highlight a novel path of virus-host coevolution, toward cooperative subversion of the antiviral immune response. These observations may illuminate new targets for drugs to inhibit herpesvirus reactivation or eliminate herpesvirus-associated tumors.
登录
查看更多内容
影响因子：
56.9
作者：
Chatterjee, M;Osborne, J;Moore, PS
通讯作者：
Moore, PS
影响因子：
32.4
作者：
Hida, S;Ogasawara, K;Taniguchi, T
通讯作者：
Taniguchi, T
影响因子：
5.4
作者：
Gargano, Lisa M.;Forrest, J. Craig;Speck, Samuel H.
通讯作者：
Speck, Samuel H.
影响因子：
5.4
作者：
Adler, H;Messerle, M;Koszinowski, UH
通讯作者：
Koszinowski, UH
影响因子：
4.4
作者：
Flaño, E;Jia, QM;Blackman, MA
通讯作者：
Blackman, MA