Wang Guoxun, Zarek Christina, Chang Tyron, Tao Lili, Lowe Alexandria, Reese Tiffany A
Department of Immunology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Department of Immunology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
J Virol. 2021 Mar 25;95(8). doi: 10.1128/JVI.01946-20. Epub 2021 Feb 3.
Gammaherpesviruses, such as Epstein-Barr virus (EBV), Kaposi's sarcoma associated virus (KSHV), and murine γ-herpesvirus 68 (MHV68), establish latent infection in B cells, macrophages, and non-lymphoid cells, and can induce both lymphoid and non-lymphoid cancers. Research on these viruses has relied heavily on immortalized B cell and endothelial cell lines. Therefore, we know very little about the cell type specific regulation of virus infection. We have previously shown that treatment of MHV68-infected macrophages with the cytokine interleukin-4 (IL-4) or challenge of MHV68-infected mice with an IL-4-inducing parasite leads to virus reactivation. However, we do not know if all latent reservoirs of the virus, including B cells, reactivate the virus in response to IL-4. Here we used an approach to address the question of whether all latently infected cell types reactivate MHV68 in response to a particular stimulus. We found that IL-4 receptor expression on macrophages was required for IL-4 to induce virus reactivation, but that it was dispensable on B cells. We further demonstrated that the transcription factor, STAT6, which is downstream of the IL-4 receptor and binds virus 50 N4/N5 promoter in macrophages, did not bind to the virus 50 N4/N5 promoter in B cells. These data suggest that stimuli that promote herpesvirus reactivation may only affect latent virus in particular cell types, but not in others. Herpesviruses establish life-long quiescent infections in specific cells in the body, and only reactivate to produce infectious virus when precise signals induce them to do so. The signals that induce herpesvirus reactivation are often studied only in one particular cell type infected with the virus. However, herpesviruses establish latency in multiple cell types in their hosts. Using murine gammaherpesvirus-68 (MHV68) and conditional knockout mice, we examined the cell type specificity of a particular reactivation signal, interleukin-4 (IL-4). We found that IL-4 only induced herpesvirus reactivation from macrophages, but not from B cells. This work indicates that regulation of virus latency and reactivation is cell type specific. This has important implications for therapies aimed at either promoting or inhibiting reactivation for the control or elimination of chronic viral infections.
γ疱疹病毒，如爱泼斯坦-巴尔病毒（EBV）、卡波西肉瘤相关病毒（KSHV）和鼠γ疱疹病毒68（MHV68），可在B细胞、巨噬细胞和非淋巴细胞中建立潜伏感染，并能诱发淋巴样和非淋巴样癌症。对这些病毒的研究严重依赖永生化B细胞和内皮细胞系。因此，我们对病毒感染的细胞类型特异性调控了解甚少。我们之前已经表明，用细胞因子白细胞介素-4（IL-4）处理感染MHV68的巨噬细胞，或用一种能诱导IL-4的寄生虫感染MHV68感染的小鼠，会导致病毒重新激活。然而，我们不知道病毒的所有潜伏储存库，包括B细胞，是否会响应IL-4而重新激活病毒。在这里，我们采用了一种方法来解决是否所有潜伏感染的细胞类型都会响应特定刺激而重新激活MHV68这个问题。我们发现，IL-4诱导病毒重新激活需要巨噬细胞上表达IL-4受体，但在B细胞上则不需要。我们进一步证明，转录因子STAT6位于IL-4受体下游，在巨噬细胞中与病毒50 N4/N5启动子结合，但在B细胞中不与病毒50 N4/N5启动子结合。这些数据表明，促进疱疹病毒重新激活的刺激可能只影响特定细胞类型中的潜伏病毒，而不影响其他细胞类型中的潜伏病毒。疱疹病毒在体内特定细胞中建立终身静止感染，只有在精确信号诱导时才重新激活产生感染性病毒。诱导疱疹病毒重新激活的信号通常只在感染该病毒的一种特定细胞类型中进行研究。然而，疱疹病毒在其宿主的多种细胞类型中建立潜伏状态。利用鼠γ疱疹病毒68（MHV68）和条件性基因敲除小鼠，我们研究了特定重新激活信号白细胞介素-4（IL-4）的细胞类型特异性。我们发现，IL-4仅能诱导巨噬细胞中的疱疹病毒重新激活，而不能诱导B细胞中的疱疹病毒重新激活。这项工作表明，病毒潜伏和重新激活的调控具有细胞类型特异性。这对于旨在促进或抑制重新激活以控制或消除慢性病毒感染的治疗具有重要意义。
