The Role Of Innate Immunity Genes In Viral Infection and Disease Progression

本项目旨在研究呼吸道合胞病毒（RSV）感染易感性和疾病进展的机制。 RSV是美国和世界上导致婴幼儿住院的主要病毒性呼吸道疾病。 为什么一些以前健康的婴儿发展LRI（细支气管炎和肺炎），而其他人保持无症状或仅在RSV感染后发展上呼吸道症状，原因尚不清楚。 有证据表明，小婴儿肺实质的既往损伤程度可能在疾病严重程度中发挥作用，因为患有慢性肺病的儿童具有RSV LRI的高风险。 然而，大多数住院治疗发生在以前健康的婴儿中。 在RSV LRI期间可引起肺损伤的另一个潜在重要因素是先天免疫。 RSV LRI期间的肺浸润主要由嗜中性粒细胞和巨噬细胞组成，受病毒影响的小气道（10-300微米）的损伤可能容易导致小气道管腔中的碎片积聚、炎症和水肿，并损害通气。 此外，大多数患有RSV相关喘鸣的婴儿对b2-支气管扩张剂没有反应，但可能受益于减少水肿/炎症的吸入α-激动剂。 此外，高水平的CXC趋化因子（特别是MIP-1 a、MCP-1和IL-8）与RSV疾病严重程度增加相关。 氧化应激在呼吸道RSV感染的发病机制中的作用已被提出。 NF-E2相关因子2（Nrf 2）是通过抗氧化/防御基因诱导保护气道免受氧化损伤、炎症和免疫反应的关键调节因子。 我们已经开始研究Nrf 2在RSV感染和RSV介导的损伤中的作用，使用Nrf 2缺陷型（Nrf 2-/-）和野生型（Nrf 2 +/+）小鼠鼻内用RSV或媒介物处理。 结果支持氧化应激在RSV诱导的疾病的发病机制中的关键作用以及Nrf 2在宿主防御RSV中的重要性。 与此同时，我们正在使用传统的定位克隆方法以及单倍型作图来鉴定小鼠中的候选RSV易感基因。 我们与Fernando Polack（Johns霍普金斯）合作，招募了2003年6月1日至2005年5月31日期间在阿根廷布宜诺斯艾利斯的五家医院和诊所感染RSV的婴儿和幼儿的前瞻性队列。 这些婴儿和儿童已被广泛表征为RSV相关疾病表型，并已从所有参与个体中提取DNA。 我们目前正在调查候选先天免疫和抗氧化基因的多态性（基于上述研究）是否与感染儿童的疾病严重程度相关。

This project has been designed to investigate the mechanisms of susceptibility to respiratory syncytial virus (RSV) infection and disease progression. RSV is the leading viral respiratory cause of hospitalization in infants and young children in the United States and in the world. The reason why some previously healthy infants develop LRI (bronchiolitis and pneumonia) while others remain asymptomatic or only develop upper respiratory tract symptoms after RSV infection is not well understood. Evidence exists that the degree of previous injury of the lung parenchyma in small infants could play a role in disease severity, as children with chronic lung disease are at high risk of RSV LRI. However, the majority of hospitalizations occur in previously healthy infants. Another potentially important factor that can cause lung injury during RSV LRI is innate immunity. The pulmonary infiltration during RSV LRI is composed overwhelmingly by neutrophils and macrophages and damage to the small airways (10-300 microns) affected by the virus could easily cause debris accumulation in the lumen, inflammation and edema of the small airways, and compromise ventilation. Further, most infants with RSV-associated wheezing do not respond to b2-bronchodilators, but may benefit from inhaled a-agonists that decrease edema/inflammation. Additionally, high levels of CXC chemokines (particularly MIP-1a, MCP-1 and IL-8) have been associated with increased RSV disease severity. A role for oxidative stress has been suggested in the pathogenesis of airway RSV infection. NF-E2-related factor 2 (Nrf2) is a key regulator of airway protection against oxidative injury, inflammation, and immune responses via antioxidant/defense gene induction. We have begun to investigate the role of Nrf2 in RSV infection and RSV-mediated injury using Nrf2-deficient (Nrf2-/-) and wild type (Nrf2+/+) mice intranasally treated with RSV or vehicle. Results support a key role oxidant stress in the pathogenesis of RSV-induced disease and the importance of Nrf2 in host defense against RSV. In parallel, we are using traditional positional cloning approaches as well as haplotype mapping to identify candidate RSV susceptibility genes in the mouse. In collaboration with Fernando Polack (Johns Hopkins) we have recruited a prospective cohort of infants and young children who were infected with RSV between June 1 2003 and May 31 2005 at five hospitals and clinic in Buenos Aires, Argentina. These infants and children have been characterized extensively for RSV-related disease phenotypes, and DNA has been extracted from all participating individuals. We are currently investigating whether polymorphisms in candidate innate immunity and antioxidant genes (based on studies described above) associate with disease severity in infected children.