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Chapter 76 : Inflammatory Immune Response to Cytosolic Flagellin Protects Mice from Legionella pneumophila Infection
Category: Bacterial Pathogenesis
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Legionella pneumophila has earned a reputation as a public scourge, and rightly so. With the goal of identifying the molecular basis of L. pneumophila pathogenesis, investigators quickly turned to animal models. By exploiting the observation that susceptibility to L. pneumophila behaves as a single Mendelian trait, the Dietrich and Gross laboratories identified naip5 as a critical determinant of mouse resistance to this pathogen. Based on these and other pioneering pathology and immunology studies in the 1980s and 1990s, workers in the field today continue to depend on small animal models to investigate the host-pathogen interactions that govern the outcome of L. pneumophila infection. Flagellar-based motility is mediated by a sophisticated organelle whose components are strictly regulated and whose assembly is carefully orchestrated. Extracellular flagellin is recognized by a receptor on the surface of eukaryotic cells, Toll-like receptor 5 ( TLR-5; 17). Knowing that bacterial flagellins trigger a rapid, proinflammatory innate immune response, the authors postulated that lysis of macrophages by motile L. pneumophila was not a pathogen tactic, but rather a host defense. L. pneumophila can induce apoptosis in numerous cell types, including human peripheral blood monocytes, human monocyte, epithelial and T cell lines, and mouse alveolar macrophages and epithelial cells. If the macrophage response to flagellin is indeed a host mechanism to combat infection, the authors postulated that L. pneumophila that lack flagellin would escape the Naip5.
L. pneumophila requires fla-gellin but not motility to induce macrophage death. After centrifugation with two-fold dilutions of the strains indicated, A/J mouse macrophages and microbes were incubated for 1 h, and then viability was determined by Alamar Blue reduction. Shown are mean percent of viable macrophages ± standard error pooled from three or more experiments in multiplicity of infection bins of two-fold dilutions; the middle value for each bin is indicated. WT, wild-type L. pneumophila strain Lp02; dotA mutants lack type IV secretion but are fully motile; flaA mutants lack the structural protein flagellin; flaA mutants secrete but do not assemble flagellin; fliD dotA mutants lack motility and type IV secretion but secrete flagellin protein.
Secretion of IL-1β by macrophages in response to L. pneumophila is controlled by Naip5 and caspase-1. After infecting the macrophages shown for 1 h with wild-type L. pneumophila at the multiplicity of infection indicated, secreted interleukin-1p was quantified. Where indicated, macrophages were treated for 1 h before and during the infection with 100 μM Ac-YVAD-cmk, an inhibitor of caspase-1.
Model for the innate immune response of mice to L. pneumophila infection. See text for details.
Recognition of flagellin by mouse macrophages restricts L. pneumophila infection