Complementary immune roles for infected and uninfected cells during Legionella pneumophila infection.

摘要

The innate immune system responds to virulent pathogens, yet many pathogens manipulate host-signaling pathways, which should limit immune activation. The intracellular bacterium Legionella pneumophila is the cause of the severe pneumonia Legionnaire's disease. L. pneumophila encodes a type IV secretion system (T4SS) to translocate bacterial proteins into the cytosol of infected host cells. Several of these bacterial effectors (Lgt1, Lgt2, Lgt3, SidI, SidL, Pkn5, and Lpg1489) inactivate host cell elongation factors involved in protein translation. Despite the ability of L. pneumophila to block host protein translation, inflammatory cytokines are still made during infection both in vivo and in vitro. It is unclear how infected cells can mount a cytokine response when host protein synthesis is blocked. By creating a fluorescence resonance energy transfer-based system to track the activity of the T4SS in infected host cells, this study investigates how innate immune cells produce cytokines during L. pneumophila infection. In vitro, cells targeted by the T4SS of L. pneumophila are poor producers of cytokines critical for control of infection, such as TNF, IL-6, IL-12, and do not express CD86 in response to infection. Instead, uninfected, bystander cells produce these cytokines. Infected host cells do produce IL-1alpha; and IL-1beta; de novo and transcribe many proinflammatory genes. During pulmonary infection, alveolar macrophages and neutrophils are targeted by the T4SS for translocation and contain viable L. pneumophila. These cells provide a niche for bacterial replication during infection, but also secrete IL-1 in response to virulent bacteria. Uninfected alveolar macrophages, neutrophils, as well as inflammatory monocytes and dendritic cells produce TNF during L. pneumophila infection in vivo. Inflammatory monocytes and dendritic cells also increase CD86 expression during infection. Importantly, this bystander TNF production and CD86 expression requires IL-1 signaling, as mice deficient for the IL-1R have diminished levels of TNF and CD86 expression during infection. These data suggest that infected cells have mechanisms to overcome protein synthesis inhibition to produce IL-1 and that uninfected bystander cells are important contributors to the immune response during infection with L. pneumophila. This mechanism of immune activation has broad significance as many other bacterial pathogens manipulate host cell processes, including immune cell signaling.