Nonhematopoietic Cells Are Key Players in Innate Control of Bacterial Airway Infection

Abstract

Airborne pathogens encounter several hurdles during host invasion, including alveolar macrophages (AMs) and airway epithelial cells (AECs) and their products. Although growing evidence indicates pathogen-sensing capacities of epithelial cells, the relative contribution of hematopoietic versus nonhematopoietic cells in the induction of an inflammatory response and their possible interplay is still poorly defined in vivo in the context of infections with pathogenic microorganisms. In this study, we show that nonhematopoietic cells, including AECs, are critical players in the inflammatory process induced upon airway infection with Legionella pneumophila, and that they are essential for control of bacterial infections. Lung parenchymal cells, including AECs, are not infected themselves by L. pneumophila in vivo but rather act as sensors and amplifiers of inflammatory cues delivered by L. pneumophila-infected AM. We identified AM-derived IL-1β as the critical mediator to induce chemokine production in nonhematopoietic cells in the lung, resulting in swift and robust recruitment of infection-controlling neutrophils into the airways. These data add a new level of complexity to the coordination of the innate immune response to L. pneumophila and illustrate how the cross talk between leukocytes and nonhematopoietic cells contributes to efficient host protection.

Alveolar Macrophages and Neutrophils Are the Primary Reservoirs for Legionella pneumophila and Mediate Cytosolic Surveillance of Type IV Secretion

“…S5A and B in the supplemental material), consistent with previous studies indicating that neutrophil recruitment is T4SS dependent (20,28,30,60 identified alveolar macrophages as being positive for T4SS-mediated injection, but we also could identify injected cells that expressed high levels of Ly6G and were negative for MHC-II (Fig. 3B).…”

“…In vivo, alveolar macrophages and neutrophils in the airway space and lung tissue were the primary recipients of T4SS-translocated effectors and harbored viable bacteria. Consistent with the critical role of immune sensing of T4SS activity in triggering host cytokine production, alveolar macrophages and neutrophils from mice infected with T4SS-competent L. pneumophila, but not T4SS-deficient bacteria, secreted the cytokines TNF and IL-1␣, which are known to be important for immune-mediated clearance of infection (28)(29)(30). We did not observe T4SS-mediated injection into other lung cell populations, including airway epithelial cells and dendritic cells, suggesting that these cells are not a primary intracellular niche for L. pneumophila and do not directly participate in cytosolic immunosurveillance of T4SS activity during lung infection.…”

“…However, it is unknown whether other immune phago-cytes in the lung, such as neutrophils, inflammatory monocytes, or dendritic cells, also receive T4SS-translocated effectors and contribute to the immune response or support L. pneumophila survival. Previous studies have demonstrated that in addition to alveolar macrophages, L. pneumophila can be detected in neutrophils during pulmonary infection (30). Neutrophils are thought to be highly bactericidal, and their presence in the lung and airway space during pulmonary L. pneumophila infection correlates with lower bacterial burden (20,28,(32)(33)(34).…”

“…Cytosolic detection of T4SS activity also is required for the robust secretion of inflammasome-independent cytokines, such as tumor necrosis factor (TNF) (25)(26)(27). The IL-1 family cytokines and TNF are critical for host defense against L. pneumophila (20,(28)(29)(30). Thus, the cells that interact with L. pneumophila in the lung and receive T4SS-translocated effectors may have a dual role during in vivo infection, in that they can enable intracellular survival of the pathogen and also contribute directly to the immune response by detecting T4SS-translocated products.…”

Identification of Protective B Cell Antigens of Legionella pneumophila

“…pneumophila infection induces a strong innate immune response, which is pivotal for the initial control of a primary L. pneumophila infection (22)(23)(24)(25). Furthermore, L. pneumophila infection also elicits an adaptive immune response that was shown to protect guinea pigs from lethal secondary L. pneumophila challenge (26,27).…”