Viral immune evasion from the NK cell Ly49H activation receptor

NK细胞Ly49H激活受体的病毒免疫逃避

• 批准号: nhmrc : 303212
• 负责人: A/Pr Anthony Scalzo
• 金额: $ 15.95万
• 依托单位: The University of Western Australia
• 依托单位国家: 澳大利亚
• 项目类别: NHMRC Project Grants
• 财政年份: 2004
• 资助国家: 澳大利亚
• 起止时间: 2004-01-01 至 2006-12-31
• 项目状态: 已结题
• 来源: https://researchdata.edu.au/viral-immune-evasion-activation-receptor/99624
• 关键词: Viral; immune; evasion; NK; cell

Infection with human cytomegalovirus (HCMV) remains a significant health problem for individuals whose immune systems are immunocompromised (transplant patients and AIDS patients) or poorly developed (such as the foetus and newborn children). While drugs are available to treat HCMV infection the emergence of viral drug escape mutants means there is a medical necessity to develop new therapies and vaccines against this agent. As a basis for this it is important to develop a better understand the host-virus relationship to rationally design appropriate treatments. As HCMV is species specific and does not infect experimental animals, the murine cytomegalovirus (MCMV) in mice is widely used as a model for HCMV disease. MCMV infection is controlled by both innate and adaptive arms of the host's immune response. Natural killer (NK) cells constitute an important frontline defence against MCMV and understanding how they are activated is of importance to harnessing them for anti-viral control measures. Recently we have shown that NK cells are activated via the interaction of an NK cell activation receptor (Ly49H) with a MCMV-encoded ligand (m157). However, we have also found that MCMV can rapidly mutate its m157 gene to evade effective NK cell control and that wild populations of MCMV have foms of m157 that don't bind to Ly49H. Other studies suggest that m157 can bind to inhibitory NK cell receptors, such as Ly49I, and inactivate the NK cell response. This study seeks to understand the dynamics of the m157-Ly49H and m157-Ly49I interactions. As HCMV infection is also regulated at early stages by NK cells, an understanding of how CMV can rapidly mutate its m157 gene to avoid interaction with Ly49H-expressing NK cells has important implications for understanding human disease caused by HCMV, in terms of potential viral escape from NK cell surveillance.

人巨细胞病毒（HCMV）感染仍然是免疫系统受损（移植患者和艾滋病患者）或发育不良（如胎儿和新生儿）的个体的重要健康问题。虽然药物可用于治疗HCMV感染，但病毒药物逃逸突变体的出现意味着有必要开发针对该药剂的新疗法和疫苗。作为此的基础，重要的是要更好地了解宿主-病毒关系，以合理设计适当的治疗方法。由于HCMV具有种属特异性，不感染实验动物，因此小鼠巨细胞病毒（MCMV）被广泛用作HCMV疾病的模型。MCMV感染受宿主免疫应答的先天性和适应性两方面控制。自然杀伤（NK）细胞构成了MCMV的重要前线防御，了解它们如何被激活对于利用它们进行抗病毒控制措施至关重要。最近，我们已经表明，NK细胞通过NK细胞活化受体（Ly 49 H）与MCMV编码的配体（m157）的相互作用而被活化。然而，我们还发现MCMV可以快速突变其m157基因以逃避有效的NK细胞控制，并且MCMV的野生群体具有不与Ly 49 H结合的m157形式。其他研究表明，m157可以结合抑制性NK细胞受体，如Ly 49 I，并抑制NK细胞反应。本研究旨在了解m157-Ly 49 H和m157-Ly 49 I相互作用的动力学。由于HCMV感染在早期阶段也受NK细胞的调控，因此了解CMV如何快速突变其m157基因以避免与表达Ly 49 H的NK细胞相互作用，对于了解HCMV引起的人类疾病具有重要意义。