The Role of Flagellar Motility to Innate Immune Recognition of Bacteria

点击翻译按钮获取中文摘要

Abstract The Gram-negative bacteria, which include Pseudomonas aeruginosa, cause substantial morbidity and mortality: bacterial pneumonia, septicemia and chronic disease account for ~15% of the total deaths in the USA. Therefore, it is imperative that we develop a better cellular and molecular understanding of the host interactions with bacterial pathogens, how bacteria avoid or manipulate the host's response, and to develop new strategies to prevent disease and improve patient care. Bacterial swimming motility, conferred by their flagella, has been recognized for over 25 years to influence the ability of bacteria to infect and colonize a host. Importantly, motility is required to initially infect the host, but bacteria must become non-motile to persist during clinical chronic infection. A well-described example is that the loss of P. aeruginosa motility directly correlates with increased bacterial burdens and increased disease severity in Cystic Fibrosis patients. However the underlying reasons for why and how changes in bacterial motility alter the course of infection and disease are unknown. We have recently provided the first formal demonstration that it is loss of bacterial motility, rather than loss of flagellar expression, that confers an advantage towards evasion of immune responses. Specifically, we have shown that loss of bacterial motility, in a variety of bacterial genera, results in bacterial resistance to phagocytosis in vitro and in vivo. Thus motility represents a novel and widespread mechanism by which the innate immune system recognizes and responds to bacteria – and is a mechanism by which bacteria successfully elude immune responses during chronic infection. Therefore this proposal has the central goal of identifying the mechanisms by which immune cells respond to bacterial motility. Our recent finding that phagocyte PI3K and Akt activity are responsive to bacterial flagellar motility identifies novel regulation of an intracellular pathway that determines the phagocytic fate of Pa. We have leveraged this finding to identify two new critical molecular links in this motility-induced signal transduction pathway. Based on our preliminary data, in Specific Aim 1 our working hypothesis is that the Pa motility-stimulated phagocytic signal is transduced through a CIN85/src-family kinase pathway to PI3K/Akt. Our working hypothesis for Specific Aim 2 is that the c-Abl pathway is also responsive to, and required for, motility-induced phagocytosis. Therefore we propose to identify the c-Abl molecule(s) that contribute to motility-induced phagocytosis, and how this pathway functionally intersects with the PI3K/Akt axis. Achievement of these Aims will provide a mechanistic understanding of how loss of bacterial motility enables immune evasion and persistence of infection, and will identify molecular targets which can potentially be targeted to effect the therapeutic clearance of the non-motile, antibiotic-resistant bacteria present in chronic infections.