Mast cell dependent inflammatory cascade during influenza A virus infection

描述（由申请人提供）：呼吸道是许多病原体的主要入口。甲型流感病毒（IAV）是季节性病毒性呼吸道感染的主要原因。由静脉注射引起的疾病不仅对经济有重大影响，而且仅在美国每年就有36000人死亡，170万人住院治疗。此外，禽流感有可能造成全球大流行病，其发病率和死亡率要高得多。与IAV感染相关的发病率和死亡率被认为是显著的免疫病理的结果。很明显，IAV菌株引起的肺部疾病的严重程度不同。因此，我们实验室的长期目标是了解由IAV感染的免疫反应引起的保护和宿主损伤之间的微妙平衡。肺部抵抗病原体的最初防线包括肺泡上皮细胞、内皮细胞、组织常驻肺泡巨噬细胞、树突状细胞和肥大细胞。然而，肥大细胞在呼吸道病毒感染中的作用尚未得到充分的研究。重要的是，我们的数据表明，肥大细胞以病毒株特异性的方式启动流感病毒诱导的炎症免疫病理是至关重要的；然而，肥大细胞在呼吸道清除IAV中并不起关键作用。此外,

DESCRIPTION (provided by applicant): The respiratory tract is a major portal of entry for many pathogens. Influenza A virus (IAV) is a major cause of seasonal viral respiratory infections. Not only do IAV-induced illnesses have a significant economic impact, but there are also ~36,000 deaths and ~1.7 million hospitalizations each year in the United States alone. Moreover, IAV has the potential to cause global pandemics, which have significantly greater morbidity and mortality. Morbidity and mortality associated with IAV infections is thought be the result of significant immunopathology. It is well defined that IAV strains vary in the severity of lung disease they induce. Thus, the long-term goal of our laboratory is to understand the fine balance between protection and host damage caused by immune responses to IAV infection. The initial lines of defense against pathogens in the lungs include alveolar epithelial cells, endothelial cells, tissue resident alveolar macrophages, dendritic cells, and mast cells. However, the role of the mast cell has been under explored during respiratory viral infection. Importantly, our data demonstrate that mast cells are critical for initiating the inflammatory immunopathology induced by influenza virus in a virus strain-specific manner; however, mast cells did not play a critical role in the clearance of IAV from the respiratory tract. Furthermore, others have reported that during IAV infection of humans significantly elevated levels of histamine can be detected coincident with IAV induced symptoms. Thus, mast cells are likely to participate in the immune response to IAV infection, but what their role is has not been elucidated. This proposal has three specific aims which will test the role of mast cells during IAV infection and elucidate the molecular mechanisms responsible for their activation, recruitment, and activity. In specific aim 1, we will identify which receptors modulate mast cell activity in response to IAV and determine the role of newly recruited mast cell progenitors in the IAV-induced lung inflammation. In specific aim 2, we will define the key mast cell effectors that are critical for inducing the inflammation- induced pulmonary injury during respiratory IAV infection. In specific aim 3, we will define the role of the IAV hemaggultinin in initiating the mast cell-dependent IAV immune response. Completion of these three aims will offer novel insights into the mechanisms of mast cell activation and function during respiratory viral infection. In conclusion, understanding mast cells and IAV strain specificity contributions to the inflammatory response will not only be crucial in the development and appropriate use of novel host-targeted therapeutics to limit IAV-induced host damage and morbidity, but will also provide novel regions of viral proteins which could be targeted by novel anti-viral therapeutics.