Alteration of innate immunity by HCV core

描述（由申请人提供）：人类丙型肝炎病毒（HCV）感染几乎总是与病毒持续存在相关，导致肝细胞癌和自身免疫性疾病的发生。在慢性HCV患者中，包括IL-12和IFN-g的产生在内的细胞免疫应答严重受损。此外，HCV诱导的免疫抑制与对细菌和其他肠道病毒感染的易感性增加有关。因此，HCV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。 为了理解HCV的免疫逃避机制并设计治疗和改善免疫的策略，我们鉴定了HCV核心蛋白作为抑制IL- 12产生的免疫调节分子。此外，我们成功地证明了HCV核心和补体受体（gClqR）之间的新的相互作用。Clq是gClqR的配体，在先天免疫以及适应性免疫的调节中起关键作用。有趣的是，细胞外核心蛋白与巨噬细胞上的gClqR的结合诱导SHP-1募集和SOCS 1 mRNA表达。SHP-1和SOCS 1都在抑制炎症细胞因子产生的细胞内信号传导中发挥作用。基于这些发现，我们假设可溶性核心蛋白与巨噬细胞上的gClqR的结合导致IL-12产生的SHP-1和/或SOCS 1依赖性抑制。 在本提案中，我们将首先确定招募到HCV核心/gC 1 qR复合物中以抑制IL- 12产生的蛋白质。其次，我们将表征SHP-1和SOCS 1在通过HCV核心/gClqR接合抑制IL-12产生中的作用。第三，我们将分析HCV核心/gC 1 qR接合抑制IL-12产生的机制。本文的研究将有助于阐明HCV核心蛋白诱导免疫抑制的机制。此外，它们将为合理设计新的治疗药物以阻断HCV诱导的免疫抑制作用提供基础。

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.