Nod1 and Nod2 regulation of pulmonary immunity to Legionella pneumophila (135.77)

Abstract

Abstract The role of Nod1 and Nod2 in pulmonary innate immune responses is poorly understood. We hypothesized that Nod1 and Nod2 regulate non-redundant and specific immune responses during murine in vivo infection with Legionella pneumophila (Lp). We first examined whether Nod1 and Nod2 regulate detection of Lp in HEK293 cells transfected with luciferase reporter constructs and either Nod1 or Nod2. Heat-killed Lp stimulated NF-κB and interferon-β-dependent promoter activity in cells transfected with either Nod1 or Nod2. To examine the role of Nod1 and Nod2 during in vivo infection, we exposed Nod1-/- and Nod2-/- and C57Bl/6 control mice to aerosolized Lp. Bronchoalveolar lavage fluid from Nod1-/- animals had decreased neutrophils compared to wild type animals at 4 and 24 hours post-infection. Furthermore, monocyte recruitment was also impaired at 24 hours. In addition Nod1-/- mice had increased lung bacterial loads at 72 hours in comparison to wild type and Nod2-/- mice. In contrast, there was no reproducible difference in cytokines in Nod1-/- lung homogenates at 4 hours and 24 hours. Conversely, Nod2-/- mice had impaired neutrophil cell recruitment at 24 hours, and only a trend to increased organism burden at 72 hours (p=0.07). Nod2-/- animals, however, showed reproducible impairment in cytokine production from lung homogenates. Lung histologic sections at later time points (3-7 days) had no detectable differences in inflammation in Nod1-/- or Nod2-/- mice in comparison to wild type mice. Overall these data indicate that Nod1 regulates early inflammatory cell recruitment of both neutrophils and monocytes to the alveolar space without detectable differences in inflammatory cytokine productions or changes in lung histology at later time points.