Alteration of innate immunity by HCV core

描述(申请人提供)：人类感染丙型肝炎病毒(丙型肝炎病毒)几乎总是与病毒持续存在有关，这会导致肝细胞癌和自身免疫性疾病的发展。在慢性丙型肝炎患者中，包括产生IL-12和干扰素-g在内的细胞免疫反应严重受损。此外，丙型肝炎病毒诱导的免疫抑制与细菌和其他肠道病毒感染的易感性增加有关。因此，丙型肝炎病毒很可能进化出一种策略，通过编码能够抑制宿主免疫反应的基因产物来避免宿主免疫监视。 为了了解丙型肝炎病毒逃避免疫的机制(S)，并设计治疗和改进免疫的策略，我们确定丙型肝炎病毒核心蛋白是一种免疫调节分子，可以抑制IL-12的产生。此外，我们还成功地证明了丙型肝炎病毒核心蛋白与补体受体(GClqR)之间的一种新的相互作用。Clq是gClqR的配体，在先天免疫和获得性免疫调节中发挥重要作用。有趣的是，细胞外核心蛋白与巨噬细胞上gClqR的结合诱导了SHP-1的募集和SOCS1mRNA的表达。SHP-1和SOCS1在抑制炎性细胞因子产生的细胞内信号转导中发挥作用。基于这些发现，我们推测，可溶性核心蛋白与巨噬细胞上的gClqR结合导致SHP-1和/或SOCS1依赖的IL-12产生抑制。 在这项建议中，我们将首先确定招募到丙型肝炎病毒核心/gC1qR复合体的抑制IL-12产生的蛋白(S)。其次，我们将研究SHP-1和SOCS1在丙型肝炎病毒核心/gClqR参与抑制IL-12产生中的作用。第三，我们将分析丙型肝炎病毒核心/gC1qR结合抑制IL-12产生的机制。这些研究将有助于阐明丙型肝炎病毒核心蛋白诱导免疫抑制的机制。此外，它们还将为合理设计新型治疗药物以阻断丙型肝炎病毒诱导的免疫抑制作用提供依据。

DESCRIPTION (provided by applicant): Hepatitis C virus (HCV) infection in humans is almost invariably associated with viral persistence, which leads to the development of hepatocellular carcinoma and autoimmune disease. In chronic HCV patients, cellular immune responses including the production of IL-12 and IFN-g are severely impaired. In addition, HCV-induced immune suppression is associated with increased susceptibility to bacteria and other enteric viral infections. Thus, HCV most likely evolved a strategy to avoid host immune surveillance by encoding gene products, which are capable of dampening host immune responses. To understand the mechanism(s) of immune evasion by HCV and to design strategies for therapeutics and improved immunization, we identified the HCV core protein as an immunomodulatory molecule to inhibit IL- 12 production. In addition, we successfully demonstrated a novel interaction between HCV core and complement receptor (gClqR). Clq is a ligand for gClqR and plays a critical role in innate immunity, as well as, regulation of adaptive immunity. Intriguingly, the binding of extracellular core protein to gClqR on macrophages induced SHP-1 recruitment and SOCS1 mRNA expression. Both SHP-1 and SOCS1 play a role in suppressing intracellular signaling for inflammatory cytokine production. Based on these findings, we hypothesize that the binding of soluble core protein to the gClqR on macrophages leads to SHP-1 and/or SOCSl-dependent suppression of IL-12 production. In this proposal, we will first determine protein(s) recruited to HCV core/gC1qR complex for inhibition of IL- 12 production. Second, we will characterize the role of SHP-1 and SOCS1 in inhibition of IL-12 production by HCV core/gClqR engagement. Third, we will analyze the mechanism responsible for inhibition of IL-12 production by HCV core/gC1qR engagement. The studies proposed here will help to elucidate the mechanisms of HCV core-induced immunosuppression. In addition, they will provide a basis for the rational design of novel therapeutic agents to block the action of HCV-induced immunosuppression.