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）感染的易感性机制和疾病进展。在美国和世界上，RSV是导致婴幼儿住院治疗的主要呼吸道病毒。为什么一些以前健康的婴儿在感染RSV后出现LRI（毛细支气管炎和肺炎），而另一些婴儿没有症状或仅出现上呼吸道症状的原因尚不清楚。有证据表明，小婴儿以前肺实质损伤的程度可能在疾病严重程度中起作用，因为患有慢性肺病的儿童是RSV LRI的高危人群。然而，大多数住院发生在以前健康的婴儿中。另一个可能在RSV LRI期间引起肺损伤的重要因素是先天免疫。RSV LRI期间肺浸润主要由中性粒细胞和巨噬细胞组成，病毒对小气道（10-300微米）的损伤容易引起腔内碎片堆积，小气道炎症和水肿，影响通气。此外，大多数与rsv相关的喘息婴儿对b2支气管扩张剂没有反应，但可能受益于吸入减少水肿/炎症的a激动剂。此外，高水平的CXC趋化因子（特别是MIP-1a、MCP-1和IL-8）与RSV疾病严重程度增加有关。

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.