Abstract
Abstract Irgm1 is an IFN-inducible GTPase that mediates host resistance to a variety of intracellular pathogens, and also modulates the LPS response in cultured macrophages. Whether Irgm1 regulates innate immune lung responses and controls host defense against extracellular pathogens is undetermined. We hypothesized that Irgm1 would regulate host defense against extracellular bacteria that cause pneumonia. Compared to wildtype, naïve Irgm1-/- mice had elevated expression of cytokines and chemokines in the lung parenchyma and bronchoalveolar lavage fluid, consistent with steady state inflammation. Moreover, naïve Irgm1-/- lungs displayed abnormal bronchiolocentric lymphocytic infiltration. Compared to wildtype, Irgm1-/- mice had increased influx of PMNs into the airspace after exposure to LPS and S. pneumoniae, but not K. pneumoniae. Bronchoalveolar lavage fluid chemokines, cytokines, and protein concentration (marker of microvascular injury) were all higher in Irgm1-/- mice after LPS and S. pneumonia. Irgm1-/- mice had lower lung CFUs after infection with S. pneumoniae, indicating enhanced pathogen clearance. Irgm1-/- mice also had increased survival after lung infection with S. pneumoniae but not K. pneumonaie. In conclusion, Irgm1-/- mice have an enhanced lung response to LPS and S. pneumoniae, but not K. pneumonaie, implicating a selective role for Irgm1 in host defense. Whether these responses derive from the Irgm1-/- basal lung phenotype is yet to be determined.
Published Version
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