1R signaling enables bystander cells to overcome bacterial blockade of host protein synthesis

The innate immune system is critical for host defense against microbial pathogens, yet many pathogens express virulence factors that impair immune function. Here, we used the bacterial pathogen Legionella pneumophila to understand how the immune system successfully overcomes pathogen subversion mechanisms. L. pneumophila replicates within macrophages by using a type IV secretion system to translocate bacterial effectors into the host cell cytosol. As a consequence of effector delivery, host protein synthesis is blocked at several steps, including translation initiation and elongation. Despite this translation block, infected cells robustly produce proinflammatory cytokines, but the basis for this is poorly understood. By using a reporter system that specifically discriminates between infected and uninfected cells within a population, we demonstrate here that infected macrophages produced IL-1α and IL-1β, but were poor producers of IL-6, TNF, and IL-12, which are critical mediators of host protection. Uninfected bystander cells robustly produced IL-6, TNF, and IL-12, and this bystander response required IL-1 receptor (IL-1R) signaling during early pulmonary infection. Our data demonstrate functional heterogeneity in production of critical protective cytokines and suggest that collaboration between infected and uninfected cells enables the immune system to bypass pathogen-mediated translation inhibition to generate an effective immune response. Significance Pathogens use virulence factors to inhibit key immune cell functions and would be expected to impair immune responses to infection. However, immune responses are still generated against infection, suggesting that the immune system has evolved mechanisms for overcoming pathogenic activity. Here, we demonstrate that cells infected with Legionella pneumophila synthesize IL-1 despite a pathogen-imposed block in host translation, but are unable to produce other critical cytokines. IL-1 signaling allows uninfected bystander cells to produce protective cytokines. Our data thus demonstrate a key role for communication between infected and uninfected bystander cells in overcoming pathogenic activities. This mechanism of immune activation has broad significance for our understanding of how successful immune responses are generated against pathogens.