The Zika ThreatASM Acts to Counter Zika Virus Outbreak.
Legionella pneumophila, a genetic probe of macrophage function innate and adaptive immune responses are initiated when macrophages ingest microbes. To investigate the mechanisms that govern the outcome of this encounter, the Swanson lab exploits a bacterial pathogen as a genetic probe of macrophage function. Legionella pneumophila is an opportunistic human pathogen whose natural reservoir is amoebae in water and soil. When inhaled, the gram-negative bacteria can colonize alveolar macrophages and cause the severe pneumonia, Legionnaires' disease.
Metabolic cues govern virulence expression. To persist in the environment, L. pneumophila alternates between distinct cell types. A replicative cell grows within vacuoles of amoebae and macrophages, and a motile and resilient transmissive form is equipped to escape a spent host and primed to invade a naive one. By applying genetic, biochemical and cell biological methods, Swanson's lab has identified a number of metabolic cues that govern the pathogen's lifecycle. To resume replication, intracellular L. pneumophila rely on Phagosomal transporter proteins to obtain essential metabolites and the bacterial enzyme SpoT to degrade the alarmone guanosine tetraphosphate (ppGpp). Once the intracellular progeny have exhausted the local nutrient supply, ppGpp accumulates and cooperates with other regulatory proteins to coordinate bacterial expression of transmissive traits, including cytotoxicity, motility, stress resistance, and the capacity to block phagosome-lysosome fusion. By coupling cellular differentiation to its metabolic state, L. pneumophila swiftly acclimates to stresses encountered in its host or the environment, thereby enhancing its overall fitness.
Autophagy and pyroptosis, two barriers to infection. Although L. pneumophila can replicate in human macrophages and fresh water amoebae, mice are naturally resistant to infection. Accordingly, the laboratory exploits a mouse infection model to investigate how the innate immune system detects and responds to infection by intracellular pathogens. Genetic analysis of human Crohn's disease, the plant response to tobacco mosaic virus, and mouse restriction of L. pneumophila infection each indicate that cells coordinately regulate autophagy and programmed cell death to combat infection. Likewise, by applying bacterial and mouse genetics and cell biological methods they have discovered that, in response to cytosolic contamination with flagellin, NOD-like receptor proteins equip mouse macrophages first to induce autophagy to capture and eliminate intracellular microbes or, at higher infection burdens, to undergo pyroptosis, a failsafe caspase-1-dependent pro-inflammatory cell death.