Cell Intrinsic Immune Control of KSHV

卡波西肉瘤相关疱疹病毒(KSHV)是一种致癌的伽马疱疹病毒，也是一种与艾滋病相关的病原体。KSHV与卡波西氏肉瘤(KS)、原发性渗出性淋巴瘤(PEL)和多中心性Castleman病有关。KSHV相关疾病更常发生在免疫受损的个体中，表明疾病进展与宿主免疫系统之间存在复杂的关系。已证实细胞内的免疫感受器，特别是DNA感受器Toll样受体9(TLR9)和环状GMP-AMP合成酶(CGAS)能够感知KSHV的感染。然而，尚不清楚RNA传感器，如RIG-I样受体RIG-I和MDA5是否参与宿主对KSHV的防御。这项建议中的数据表明，RIG-I和MDA5对PEL中KSHV裂解重新激活施加了显著的限制。利用高通量转录组学，我们定义了在KSHV裂解感染PEL过程中被RIG-I和MDA5识别的RNA，这一建议建立在我们的观察基础上。这些研究将使我们能够(目的1)确定RLR相关RNA对KSHV限制的贡献，(目的2)确定KSHV编码的蛋白如何影响RIG-I和MDA5的感知，以及(目的3)确定KSHV感染过程中MDA5激活的确切机制。这些研究的完成将提供关于细胞内在免疫反应在KSHV感染过程中如何被激活的基础知识。

Kaposi’s sarcoma-associated herpesvirus (KSHV) is an oncogenic gamma-herpesvirus and an AIDS-associated pathogen. KSHV is associated with Kaposi’s sarcoma (KS), primary effusion lymphoma (PEL), and multicentric Castleman’s disease. KSHV-associated disease occurs more commonly in immunocompromised individuals, indicating an intricate relationship between disease progression and the host immune system. It is well established that cell intrinsic immune sensors, and in particular the DNA sensors Toll-like receptor 9 (TLR9) and cyclic GMP-AMP synthase (cGAS), sense KSHV infection. However, it is less clear whether RNA sensors, such as the RIG-I like receptors RIG-I and MDA5, participate in host defense against KSHV. Data within this proposal demonstrate that RIG-I and MDA5 impose a significant restriction on KSHV lytic reactivation in PEL. Using high- throughput transcriptomics we have defined the RNAs that are recognized by RIG-I and MDA5 during KSHV lytic infection in PEL, and this proposal builds upon our observations. These studies will enable us to (Aim 1) determine the contribution of RLR-associated RNAs to KSHV restriction, (Aim 2) determine how KSHV-encoded proteins impact RIG-I and MDA5 sensing, and (Aim 3) identify the precise mechanism of MDA5 activation during KSHV infection. Completion of these studies will provide fundamental knowledge regarding how the cell intrinsic immune response is activated during KSHV infection.