Gammaherpesvirus-driven plasma cell differentiation regulates virus reactivation from latently infected B lymphocytes.
Gammaherpesvirus-driven plasma cell differentiation regulates virus reactivation from latently infected B lymphocytes.
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DOI：
10.1371/journal.ppat.1000677
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发表时间：
2009-11
期刊：
影响因子：
6.7
通讯作者：
Speck SH
中科院分区：
文献类型：
--
作者：
Liang X;Collins CM;Mendel JB;Iwakoshi NN;Speck SH
γ疱疹病毒慢性感染其宿主，并与淋巴增生性疾病和淋巴瘤以及几种其他类型的癌症的发展密切相关。维持慢性γ疱疹病毒感染的机制知之甚少，特别是，对控制γ疱疹病毒在体内从潜伏感染的B细胞再活化的机制知之甚少。最近的证据表明，浆细胞分化与通过浆细胞特异性转录因子XBP-1 s诱导的立即早期病毒转录激活因子的人γ疱疹病毒EBV和KSHV的再活化有关。我们现在将这些发现扩展到记录γ疱疹病毒基因产物在调节浆细胞分化和病毒再活化中的作用。我们以前已经表明，鼠γ疱疹病毒68（MHV 68）基因产物M2是病毒复制在允许的细胞，但在潜伏感染的B细胞的病毒再激活中起着关键作用。在这里，我们表明，在感染野生型MHV 68的小鼠中，病毒感染的浆细胞（约100%）。8%的病毒感染的脾细胞在病毒潜伏期的峰值）占脾细胞外植体后观察到的大部分再活化。相比之下，在用M2无效MHV 68感染的小鼠中，在潜伏期的峰值处不存在病毒感染的浆细胞。此外，我们表明，M2蛋白可以驱动浆细胞分化的B淋巴瘤细胞系中没有任何其他MHV 68基因产物。因此，M2在MHV 68再活化中的作用可归因于其操纵浆细胞分化的能力，提供了一种新的病毒策略来调节潜伏感染的B细胞中的γ疱疹病毒再活化。我们假设，M2代表一类新的疱疹病毒基因产物（再活化调节剂），不直接参与病毒复制，而是通过操纵细胞环境提供一个再活化环境，以促进病毒再活化。γ疱疹病毒与淋巴瘤的发展有关，特别是在免疫抑制的个体中，以及与几种其他类型的癌症有关。像所有疱疹病毒一样，一旦宿主被感染，这些病毒就不能被清除，因此，受感染的个体终生携带这些病毒。疱疹病毒用于慢性感染其宿主的重要策略之一是它们能够建立被称为潜伏期的大部分静止形式的感染，其中不产生子代病毒。重要的是，所有疱疹病毒都有能力从潜伏期出现并复制，这一过程被称为再激活。γ-疱疹病毒主要存在于称为B淋巴细胞的白色血细胞群体中，其在分化为浆细胞时产生抗体以响应感染。值得注意的是，最近已经显示，对于人γ疱疹病毒、爱泼斯坦-巴尔病毒和卡波西肉瘤相关疱疹病毒，潜伏感染的B淋巴细胞的病毒再活化涉及感染的B淋巴细胞分化为浆细胞。在这里，使用一个小动物模型的γ疱疹病毒感染，我们表明，浆细胞分化也与鼠γ疱疹病毒68的再激活。此外，我们表明，这需要一种由病毒编码的蛋白质，它能够驱动浆细胞分化。因此，我们的研究不仅证实了浆细胞分化在γ疱疹病毒从B淋巴细胞再活化中的重要性，而且还提供了该过程受病毒蛋白控制的证据。
Gammaherpesviruses chronically infect their host and are tightly associated with the development of lymphoproliferative diseases and lymphomas, as well as several other types of cancer. Mechanisms involved in maintaining chronic gammaherpesvirus infections are poorly understood and, in particular, little is known about the mechanisms involved in controlling gammaherpesvirus reactivation from latently infected B cells in vivo. Recent evidence has linked plasma cell differentiation with reactivation of the human gammaherpesviruses EBV and KSHV through induction of the immediate-early viral transcriptional activators by the plasma cell-specific transcription factor XBP-1s. We now extend those findings to document a role for a gammaherpesvirus gene product in regulating plasma cell differentiation and thus virus reactivation. We have previously shown that the murine gammaherpesvirus 68 (MHV68) gene product M2 is dispensable for virus replication in permissive cells, but plays a critical role in virus reactivation from latently infected B cells. Here we show that in mice infected with wild type MHV68, virus infected plasma cells (ca. 8% of virus infected splenocytes at the peak of viral latency) account for the majority of reactivation observed upon explant of splenocytes. In contrast, there is an absence of virus infected plasma cells at the peak of latency in mice infected with a M2 null MHV68. Furthermore, we show that the M2 protein can drive plasma cell differentiation in a B lymphoma cell line in the absence of any other MHV68 gene products. Thus, the role of M2 in MHV68 reactivation can be attributed to its ability to manipulate plasma cell differentiation, providing a novel viral strategy to regulate gammaherpesvirus reactivation from latently infected B cells. We postulate that M2 represents a new class of herpesvirus gene products (reactivation conditioners) that do not directly participate in virus replication, but rather facilitate virus reactivation by manipulating the cellular milieu to provide a reactivation competent environment. Gammaherpesviruses are associated with the development of lymphomas, particularly in immunosuppressed individuals, as well as several other types of cancers. Like all herpesviruses, once a host is infected these viruses cannot be cleared and, as such, infected individuals harbor these viruses for life. One of the important strategies utilized by herpesviruses to chronically infect their host is their ability to establish a largely quiescent form of infection referred to as latency, in which no progeny virus is produced. Importantly, all herpesviruses have the capacity to emerge from latency and replicate, a process referred to as reactivation. Gammaherpesviruses largely persist in a population of white blood cells called B lymphocytes which, upon differentiation into plasma cells, produce antibodies in response to infection. Notably, it has been recently shown for the human gammaherpesviruses, Epstein-Barr virus and Kaposi's sarcoma-associated herpesvirus, that virus reactivation from latently infected B lymphocytes involves differentiation of the infected B lymphocytes to plasma cells. Here, using a small animal model of gammaherpesvirus infection, we show that plasma cell differentiation is also associated with reactivation of murine gammaherpesvirus 68. Furthermore, we show that this requires a protein encoded by the virus which is able to drive plasma cell differentiation. Thus, our studies not only confirm the importance of plasma cell differentiation in gammaherpesvirus reactivation from B lymphocytes, but also provide evidence that this process is controlled by a viral protein.
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