Immunity to vacuolar bacterial pathogens, pathogen discrimination pathways of the immune system, mechanisms of Legionella pathogenesis, and biogenesis of the Legionella intracellular niche
Faced with an invading microorganism, innate immune cells must rapidly determine its pathogenic potential to tailor their anti-microbial response. For the host, overreaction to avirulent bacteria is just as hazardous as inadequate response to a pathogen. The specialized immune pathways tasked with discriminating innocuous members of the resident microbiota from disease-causing pathogens are fundamentally important for immune function. We use the human pathogen Legionella pneumophila to determine how the process of pathogen discrimination functions at the molecular level. Legionella is the etiological agent of Legionnaires’ disease - a devastating atypical pneumonia. An obligate intracellular pathogen, Legionella manipulates immune phagocytes by injecting over 300 bacterial proteins directly in the host cytoplasm via a type IV secretion system (T4SS). The T4SS promotes Legionella virulence, however it also benefits the host by facilitating pathogen discrimination through the inadvertent release of bacterial molecules in the cytoplasm of infected cells. This process, in turn, promotes the robust inflammatory response required for Legionella clearance. Recently, we uncovered that the central metabolic checkpoint kinase mTOR linked the process of pathogen discrimination with inflammation. Our data support the idea that mTOR functions as a molecular rheostat switch that dials in an appropriate inflammatory response depending upon the treat levels of the invading Legionella. Infections with virulent strains dialed down the rheostat to boost anti-microbial capacity through increased inflammation and autophagy responses; conversely, the rheostat was turned up in response to avirulent strains to maintain the synthesis of anti-inflammatory cytokines and keep inflammation in check. Our research goals are to determine: (i) how signals from immunosurveillance networks modulate the mTOR rheostat during infection; (ii) what factors control the dialing mechanism of the rheostat and (iii) how oscillations in mTOR activity promote asynchronous translation of pro- vs. anti-inflammatory cytokines.