KSHV interactions with host nuclear innate response components

真核生物有一系列的防御机制来识别、反应和控制 他们每天都会遇到无数的病原体和有害物质。先天免疫反应是 以非特定方式回应和防御的第一道防线之一。KSHV是一个性爱的 在美国和西方国家传播，并在撒哈拉以南非洲的生命早期感染。在……里面 免疫抑制的人，KSHV与炎症相关的恶性肿瘤有病因学联系 如卡波西氏肉瘤(KS)、原发性渗出性B细胞淋巴瘤(PEL)和多中心性Castleman 疾病(MCD)。细胞因子如IL-1β、肿瘤坏死因子-α、干扰素-γ和IL-6以及病毒基因产物被建议用于 推动KS、PEL和MCD的发展和进步。KSHV感染内皮细胞诱导 与KS/PEL/MCD病变微环境相似的炎性细胞因子和生长因子。 我们推测，KSHV对先天PRR的持续激活可能是慢性 炎症见于KS、PEL和MCD病变。因此，我们的总体目标是定义先天免疫 对KSHV的反应，并确定其在KSHV生物学中的作用。 我们已经证明了在KSHV新发感染人皮肤时所激发的细胞因子谱。 微血管内皮细胞与KS/PEL/MCD损伤微环境相同，并有利于 培养上清液中分泌炎性IL-1β和IL-18细胞因子。IL-1β和IL-18前体 通过激活的caspase-1进行处理。Caspase-1，合成为proaspase-1，由自身催化裂解 由感知危险信号的传感器蛋白--适配器形成的分子平台“炎症体” 分子Asc和Proaspase-1。先天反应是否识别和响应染色体外 核中的DS-环状KSHV基因组(和其他DNA病毒)尚不清楚。我们的研究是第一次 证明了IFI16是一种高度保守的核蛋白，参与转录的机制未知。 是KSHV、EBV和HSV-1基因组的天然核感受器。后续研究表明，IFI16 在KSHV的潜伏期维护中起作用。基于这些研究，我们扩展了我们最初的 假说和假说“IFI16与细胞核中不同的蛋白质形成复合体，介导不同的 包括先天感知DNA和KSHV利用/颠覆IFI16及其相关的功能 我们令人兴奋的初步研究支持这一假说。为了检验这一假说，我们 制定了两个重点突出、相互关联的主要具体目标。这些研究具有重要意义，因为 阐明IFI16及其相关蛋白在KSHV潜伏期中的作用将允许更深层次的 对其发病机制的了解将有助于该途径的治疗操作以控制KSHV 感染、炎症和相关的恶性肿瘤。

Eukaryotic organisms have an array of defense mechanisms to recognize, respond and control the numerous pathogens and harmful substances that they encounter every day. The Innate immune response is one of the first lines of defense to respond and defend in a non-specific manner. KSHV is a sexually transmitted agent in the USA and Western countries, and infects early during life in sub-Saharan Africa. In immune-suppressed individuals, KSHV is etiologically associated with inflammation associated malignancies such as Kaposi’s sarcoma (KS), primary effusion B-cell lymphoma (PEL), and Multicentric Castleman’s disease (MCD). Cytokines such as IL-1β, TNF-α, IFN-γ and IL-6 as well as viral gene products are proposed to drive KS, PEL and MCD development and progression. KSHV infection of endothelial cells induces inflammatory cytokines and growth factors which are similar to the microenvironments of KS/PEL/MCD lesions. We hypothesize that constant activation of innate PRRs by KSHV could be one of the reasons for the chronic inflammation seen in KS, PEL and MCD lesions. Hence, our overall goals are to define the innate immune response against KSHV and to determine its role in KSHV’s biology. We have shown that the cytokine profiles elicited during de novo KSHV infection of human dermal microvascular endothelial cells are identical to the KS/PEL/MCD lesion microenvironments and pro- inflammatory IL-1β and IL-18 cytokines are secreted in the supernatants. IL-1β and IL-18 pro-forms undergo processing by activated caspase-1. Caspase-1, synthesized as procaspase-1, is auto-catalytically cleaved by the molecular platform “inflammasome” that is formed by a sensor protein sensing the danger signal, adaptor molecule ASC and procaspase-1. Whether innate responses recognize and respond to the extra-chromosomal ds-circular KSHV genome (and other DNA viruses) in the nuclei were not known. Our studies for the first time demonstrated that IFI16, a highly conserved nuclear protein involved in transcription by unknown mechanism, is an innate nuclear sensor of KSHV, EBV and HSV-1 genomes. Follow up studies have revealed that IFI16 plays a role in latency maintenance of KSHV. Based on these studies we have extended our original hypothesis and hypothesize that "IFI16 is in complex with different proteins in the nucleus to mediate different functions including innate sensing of episomal DNA and KSHV utilizes/subverts IFI16 and its associated proteins for its latency". Our exciting preliminary studies supports this hypothesis. To test this hypothesis, we have formulated two major focused and interlinked specific aims. These studies are significant since elucidating the role of IFI16 and its associated proteins in the nucleus in KSHV’s latency will allow a deeper understanding of its pathogenesis which will facilitate therapeutic manipulation of this pathway to control KSHV infection, inflammation and the associated malignancies.