Reddy Sandeep Steven, Foreman Hui-Chen Chang, Sioux Thubten Ozula, Park Gee Ho, Poli Valeria, Reich Nancy C, Krug Laurie T
Department of Molecular Genetics and Microbiology, Stony Brook University, Stony Brook, New York, USA.
Department of Molecular Biotechnology and Health Sciences, University of Torino, Turin, Italy.
mBio. 2016 Aug 2;7(4):e00723-16. doi: 10.1128/mBio.00723-16.
A challenging property of gammaherpesviruses is their ability to establish lifelong persistence. The establishment of latency in B cells is thought to involve active virus engagement of host signaling pathways. Pathogenic effects of these viruses during latency or following reactivation can be devastating to the host. Many cancers, including those associated with members of the gammaherpesvirus family, Kaposi's sarcoma-associated herpesvirus and Epstein-Barr virus, express elevated levels of active host signal transducer and activator of transcription-3 (STAT3). STAT3 is activated by tyrosine phosphorylation in response to many cytokines and can orchestrate effector responses that include proliferation, inflammation, metastasis, and developmental programming. However, the contribution of STAT3 to gammaherpesvirus pathogenesis remains to be completely understood. This is the first study to have identified STAT3 as a critical host determinant of the ability of gammaherpesvirus to establish long-term latency in an animal model of disease. Following an acute infection, murine gammaherpesvirus 68 (MHV68) established latency in resident B cells, but establishment of latency was dramatically reduced in animals with a B cell-specific STAT3 deletion. The lack of STAT3 in B cells did not impair germinal center responses for immunoglobulin (Ig) class switching in the spleen and did not reduce either total or virus-specific IgG titers. Although ablation of STAT3 in B cells did not have a global effect on these assays of B cell function, it had long-term consequences for the viral load of the host, since virus latency was reduced at 6 to 8 weeks postinfection. Our findings establish host STAT3 as a mediator of gammaherpesvirus persistence.
The insidious ability of gammaherpesviruses to establish latent infections can have detrimental consequences for the host. Identification of host factors that promote viral latency is essential for understanding latency mechanisms and for therapeutic interventions. We provide the first evidence that STAT3 expression is needed for murine gammaherpesvirus 68 to establish latency in primary B cells during an active immune response to infection. STAT3 deletion in B cells does not impair adaptive immune control of the virus, but loss of STAT3 in B cells has a long-lasting impact on viral persistence. These results indicate a potential therapeutic benefit of STAT3 inhibitors for combating gammaherpesvirus latency and, thereby, associated pathologies.
γ疱疹病毒的一个具有挑战性的特性是它们能够建立终身持续性感染。B细胞中潜伏期的建立被认为涉及病毒对宿主信号通路的主动参与。这些病毒在潜伏期或再激活后的致病作用对宿主可能是毁灭性的。许多癌症，包括与γ疱疹病毒家族成员卡波西肉瘤相关疱疹病毒和爱泼斯坦-巴尔病毒相关的癌症，都表达高水平的活性宿主信号转导和转录激活因子3（STAT3）。STAT3在响应多种细胞因子时通过酪氨酸磷酸化被激活，并能协调包括增殖、炎症、转移和发育编程在内的效应反应。然而，STAT3对γ疱疹病毒发病机制的贡献仍有待完全了解。这是第一项在疾病动物模型中确定STAT3是γ疱疹病毒建立长期潜伏期能力的关键宿主决定因素的研究。急性感染后，鼠γ疱疹病毒68（MHV68）在驻留B细胞中建立潜伏期，但在B细胞特异性STAT3缺失的动物中，潜伏期的建立显著减少。B细胞中缺乏STAT3并不损害脾脏中免疫球蛋白（Ig）类别转换的生发中心反应，也不降低总IgG或病毒特异性IgG滴度。虽然B细胞中STAT3的缺失对这些B细胞功能检测没有全局影响，但它对宿主病毒载量有长期影响，因为感染后6至8周病毒潜伏期缩短。我们的发现确立了宿主STAT3作为γ疱疹病毒持续性感染的介导因子。
γ疱疹病毒建立潜伏感染的隐匿能力可能对宿主产生有害后果。识别促进病毒潜伏的宿主因子对于理解潜伏机制和治疗干预至关重要。我们提供了首个证据，表明在对感染的主动免疫反应期间，鼠γ疱疹病毒68在原代B细胞中建立潜伏期需要STAT3表达。B细胞中STAT3的缺失并不损害对病毒的适应性免疫控制，但B细胞中STAT3的缺失对病毒持续性有持久影响。这些结果表明STAT3抑制剂在对抗γ疱疹病毒潜伏期及相关病理方面具有潜在的治疗益处。
