Michele S. Swanson

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.

Our genetic, microbiological, and cell biological studies support the following working model for the encounter between mouse macrophages and L. pneumophila. To persist in fresh water reservoirs, L. pneumophila alternates between an intracellular replicative form and an extracellular transmissive form. When a transmissive cell is ingested by a phagocyte, L. pneumophila isolates its vacuole from the endosomal network. However, bacterial flagellin that escapes the phagosome during type IV secretion activates the macrophage inflammasome and triggers innate defense pathways. As a consequence, mouse macrophages can undergo a proinflammatory cell death and recognize the paused pathogen phagosome as cargo for autophagy, a broadly conserved mechanism to engulf defective organelles within endoplasmic reticulum for delivery the lysosomes. To avoid degradation, L. pneumophila slows maturation of its vacuole. As one mechanism to survive within phagocytes, L. pneumophila developmentally regulates its surface glycoconjugates and sheds LPS-rich vesicles that can inhibit fusion with lysosomes. Within its stalled vacuole, 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 essential amino acids. For example, only when threonine is obtained via PhtA, a transporter of the Major Facilitator Superfamily, do intracellular bacteria re-enter the cell cycle.

Once the nutrient supply is consumed by the intracellular progeny, a stringent response mechanism triggers L. pneumophila differentiation to the transmissive form. The sensor RelA synthesizes ppGpp, a second messenger that positively activates the sigma factors RpoS and FliA, the two-component regulatory system LetA/S, and the co-activator LetE. In particular LetA/S induces bacterial differentiation by relieving repression likely mediated at the post-transcriptional level by CsrA. One target of CsrA repression is the flagellar sigma factor FliA. In addition to motility, L. pneumophila requires the flagellar sigma factor to inhibit phagosome maturation, produce pigment, modify the composition of its surface, and induce pro-inflammatory death of macrophages. Thus, as a response to starvation, L. pneumophila coordinates exit from exponential phase with expression of an array of traits that promote transmission to a new host. Within another phagocyte, the cycle repeats.

By exploiting knowledge of L. pneumophila differentiation, we aim to understand how flagellin and other microbial products trigger autophagy and proinflammatory cell death and how the pathogens retard delivery of their phagosome to the lysosomes. Knowledge of the mechanisms that govern the fate of microbes in macrophages can inform the design of new strategies to prevent and to treat a wide variety of infectious diseases.

Councilor, Society for Leukocyte Biology (2006-09)
Chair-elect/Chair, American Society for Microbiology, Microbial Pathogenesis Division B (2007-09)
Vice-Chair/Chair, FASEB Summer Research Conference, "Microbial Pathogenesis: Mechanisms of Infectious Disease" (2007-09)
Editor, Molecular Biology and Microbiology Reviews (2006-)
Editorial Board, Infection and Immunity (2001-06); Autophagy (2005-)
Waxman Foundation for Microbiology Lecture Program (2004-06)
President's Advisory Commission on Women's Issues, University of Michigan (2006-)
Board Member, Women's Intercollegiate Sports Endowment & Resource, Yale University (2005-)
Ad hoc Reviewer, Journals
Molecular Microbiology, Cellular Microbiology, Microbial Pathogenesis, Trends in Microbiology, Microbiology, Journal of Bacteriology, Current Biology, Proceedings of the National Academy Science, Nature, Nature Reviews Microbiology, Science, Journal of Experimental Medicine, Journal of Virology
Ad hoc Reviewer, Grant Agencies
North Carolina Biotechnology Center, National Science Foundation, University of Michigan Biomedical Research Council, Wellcome Trust
Ad hoc Member, NIH Study Sections
2001-National Institutes of Health, NIAID Bacteriology and Mycology-2
2001-National Institutes of Health, NIAID Special Emphasis Panel
"Ecology of Infectious Diseases"
2003-National Institutes of Health, NIAID Bacteriology and Mycology-1
2006-National Institutes of Health, NIAID, Host Interactions with Bacterial Pathogens