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Michele Swanson

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Primary Appointment: Microbiology and Immunology
Primary PIBS Dept.: Microbiology and Immunology
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  Legionella pneumophila is an opportunistic human pathogen whose natural reservoir is fresh water amoebae. Remarkably, traits that promote amoebae infection also confer virulence in the human lung. When inhaled, this gram-negative bacterium can colonize alveolar macrophages and cause the severe pneumonia, Legionnaires' Disease. Because L. pneumophila is amenable to genetic analysis, it is a powerful tool to investigate the mechanisms that govern the fate of microbes that have been ingested by phagocytes.

To persist in fresh water reservoirs, L. pneumophila alternates between an intracellular replicative form and an extracellular transmissive form. When the transmissive form is ingested by a phagocyte, L. pneumophila isolates its vacuole from the endosomal network. We determined that L. pneumophila developmentally regulates its surface glycoconjugates and sheds LPS-rich vesicles that can block phagosome-lysosome fusion. Within its stalled phagosome, the bacterium exits lag phase, down-regulates transmission factors, and converts to a replicative form. As a prerequisite to differentiation, intracellular L. pneumophila must first acquire the essential amino acid threonine via PhtA, a transporter of the Major Facilitator Superfamily. Currently we are examining the function of other members of the Pht family that are encoded by L. pneumophila, Coxiella burnetii, and Francisella tularensis.

Once the nutrient supply is consumed by the intracellular progeny, a stringent response mechanism triggers L. pneumophila differentiation to the transmissive form. In particular, either the amino acid-sensor RelA or the fatty acid-sensor SpoT synthesize (p)ppGpp, a second messenger that positively activates the sigma factors RpoS and FliA and the two component regulator LetA/S. In collaboration with the Buchrieser laboratory, particular regulatory mutants are used as tools to identify replication- and transmission-specific pathways by genome microarray analysis.

Despite its ability to replicate in amoebae and in human macrophages, L. pneumophila does not establish infection in mice. By applying bacterial and mouse mutants, we discovered that mouse macrophages recognize cytosolic flagellin by a pathway that requires the NOD-containing protein Naip5 and the enzyme caspase 1. Consequently, mouse macrophages activate either autophagy or a pro-inflammatory cell death as innate immune responses that contain L. pneumophila infection in both tissue culture and mouse models of Legionnairesí disease. By applying bacterial and mouse genetics, we are investigating how macrophages coordinate autophagy and pyroptosis as barriers to cytosolic infection.

By exploiting our knowledge of L. pneumophila differentiation, we aim to learn when, how and where its stimulators of autophagy and inhibitors of phagosome maturation are expressed, then identify the corresponding molecules. Knowledge of the mechanisms that govern the fate of microbes and microbial products in macrophages can inform the design of new strategies to prevent and to treat a wide variety of infectious diseases.