Human airway microfold cells in mucosal immunity to bacterial pathogens

项目摘要/摘要 鼻咽和呼吸道粘膜是防止吸入生物感染的主要屏障。 然而，许多病原体已经适应并可以传播到口腔和呼吸道粘膜以外的地方 导致全身性疾病。这些病原体包括结核分枝杆菌、金黄色葡萄球菌、 肺炎链球菌和炭疽杆菌。这些病原体加在一起导致数百万人死亡 全世界每年，尤其是结核分枝杆菌仍然是一种毁灭性的全球病原体，仅 每年造成200万人死亡，并潜伏感染世界三分之一的人口。呼吸道衬里 粘膜是一种特殊的上皮细胞，其功能是从顶端、粘膜 管腔通向基底外侧间隙。这些细胞被称为微折叠细胞或M细胞，覆盖在粘膜相关的 淋巴组织，巨噬细胞和树突状细胞等待摄取抗原并将其呈递给B细胞和T细胞。 细胞。我们假设结核分枝杆菌已经进化为通过M细胞穿透粘膜，而我们的 初步数据表明，结核分枝杆菌确实利用M细胞来引发疾病。阻断M细胞 开发或分泌结核分枝杆菌毒力因子可防止淋巴转移和 小鼠因结核分枝杆菌感染而死亡。我们将应用遗传学、生化、免疫学和动物 确定M细胞在黏膜和系统抗呼吸道免疫中的功能作用的方法 病原体。因此，在拟议的研究中，我们将(1)描述由 细菌穿过呼吸道M细胞，(2)评估呼吸道M细胞在诱导先天免疫和获得性免疫中的作用 以及(3)利用原代人体组织确定呼吸道M细胞在免疫反应中的作用。这个 拟议的工作预计将确定M细胞如何结合和跨细胞连接结核分枝杆菌和类似细菌， 以及M细胞介导的跨细胞反应对先天和获得性免疫反应的影响。

Project Summary/Abstract The nasopharyngeal and respiratory mucosa represents a primary barrier to infection by inhaled organisms. However, many pathogens have adapted and can disseminate beyond the oral and respiratory mucosa to cause systemic disease. Such pathogens include Mycobacterium tuberculosis, Staphylococcus aureus, Streptococcus pneumonia, and Bacillus anthracis. Together these pathogens account for millions of deaths worldwide every year, and in particular, M. tuberculosis continues to be a devastating global pathogen, alone causing two million deaths annually and latently infecting a third of the world’s population. Lining the respiratory mucosa are specialized epithelial cells that function to transcytose mucosal antigens from the apical, mucosal lumen to the basolateral space. These cells, known as microfold or M-cells, overlie mucosal associated lymphatic tissue where macrophages and dendritic cells await to ingest and present antigens to B-cells and T- cells. We hypothesized that M. tuberculosis has evolved to penetrate the mucosa via M-cells, and our preliminary data indicate that M. tuberculosis indeed utilizes M-cells to initiate disease. Blocking M-cell development or secretion of an M. tuberculosis virulence factor prevents lymph node dissemination and mortality from M. tuberculosis infection in mice. We will apply genetic, biochemical, immunologic and animal approaches to determine the functional role of M-cells in mucosal and systemic immunity against respiratory pathogens. Thus, in the proposed research we will (1) Characterize the transcytosis machinery leveraged by bacteria to cross airway M-cells, (2) Assess the role of airway M-cells in inducing innate and adaptive immunity in mice and (3) Determine the role of airway M-cells in the immune response using primary human tissues. The proposed work is expected to identify how M-cells bind and transcytose M. tuberculosis and similar bacteria, and the consequences of M-cell mediated transcytosis to innate and adaptive immune responses.