Host microRNA control of gammaherpesvirus latency

伽马疱疹病毒在免疫抑制人群中会导致重要的疾病，这是由于它们的能力 在B淋巴细胞中建立潜伏感染。我们已经学到了很多关于病毒基因表达和 潜伏期内宿主细胞生物学的操纵。然而，我们的知识仍然有一个显著的差距 关于有效建立体内潜伏感染所需的宿主细胞因素。我们的研究已经 发现缺乏microRNA-155(miR-155)的小鼠在建立潜伏期的能力方面存在明显缺陷 小鼠伽玛疱疹病毒感染后的感染。在本应用程序中，我们将确定 这种影响，因为这将增加我们对有效潜伏感染所需的宿主细胞因子的了解 伽马疱疹病毒在真实的活体环境中。在我们的第一个具体目标中，我们将测试miR- 155以B细胞固有的方式发挥作用，并检测其对潜伏感染和从 延迟。我们还将确定miR-155影响潜伏期的分子机制。这个 第二个特定目的是研究miR-155在卵泡辅助CD4T细胞分化和功能中的作用，AS 这种细胞类型已被证明对潜伏的MHV-68感染的放大是必不可少的。在第三节 具体目的我们将确定miR-155是否是由MHV-68介导的必要的慢性疾病。这些 实验将提供重要的体内和机制数据，以补充目前的体外证据 MiR-155在人类伽马疱疹病毒潜伏感染中的关键作用。我们的数据还将揭示 MiR-155是否是一个潜在的靶点，可以通过治疗来减少潜在的病毒负担 有患严重伽马疱疹病毒相关疾病风险的个人。

Gammaherpesviruses cause important diseases in immunosuppressed populations, which is due to their ability to establish a latent infection in B lymphocytes. We have learned much about viral gene expression and manipulation of host cell biology during latency. However there is still a notable gap in our knowledge regarding host cell factors required for the efficient establishment of latent infection in vivo. Our research has discovered that mice lacking microRNA-155 (miR-155) have a marked defect in their ability to establish latent infection following murine gammaherpesvirus infection. In this application we will determine the mechanism for this effect, as this will increase our understanding of host cell factors required for efficient latent infection by gammaherpesviruses in an authentic in vivo environment. In our first Specific Aim, we will test whether miR- 155 is acting in a B cell intrinsic fashion, and examine its effect on latent infection and reactivation from latency. We will also determine the molecular mechanisms underlying the effect of miR-155 on latency. The second Specific Aim examines the role of miR-155 in follicular helper CD4 T cell differentiation and function, as this cell type has been shown to be essential for the amplification of latent MHV-68 infection. In the third Specific Aim we will determine whether miR-155 is necessary chronic disease mediated by MHV-68. These experiments will provide important in vivo and mechanistic data to complement current in vitro evidence for a critical role for miR-155 in latent infection with the human gammaherpesviruses. Our data will also reveal whether miR-155 is a potential target that could be manipulated therapeutically to reduce latent virus burden in individuals at risk of severe gammaherpesvirus-related disease.