title: IL-1R signaling enables bystander cells to overcome bacterial blockade of host protein synthesis.
abstract: 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.
authors.affiliation: Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104.
authors.forename: Alan M
authors.initials: AM
authors.lastname: Copenhaver
authors.affiliation: Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104.
authors.forename: Cierra N
authors.initials: CN
authors.lastname: Casson
authors.affiliation: Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104.
authors.forename: Hieu T
authors.initials: HT
authors.lastname: Nguyen
authors.affiliation: Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104.
authors.forename: Matthew M
authors.initials: MM
authors.lastname: Duda
authors.affiliation: Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104 sunshin@mail.med.upenn.edu.
authors.forename: Sunny
authors.initials: S
authors.lastname: Shin
mesh_terms: D000818:Animals; D051940:B7-2 Antigen / Q000096:biosynthesis; D016207:Cytokines / Q000096:biosynthesis; D005260:Female; D054884:Host-Pathogen Interactions / Q000276:immunology; D007113:Immunity, Innate; D018836:Inflammation Mediators / Q000378:metabolism; D007375:Interleukin-1 / Q000378:metabolism; D016952:Legionella pneumophila / Q000276:immunology / Q000472:pathogenicity; D007877:Legionnaires' Disease / Q000276:immunology / Q000382:microbiology; D008264:Macrophages / Q000276:immunology / Q000382:microbiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053573:Receptors, Interleukin-1 Type I / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D014774:Virulence / Q000276:immunology
chemical_list: D051940:B7-2 Antigen; C497965:Cd86 protein, mouse; D016207:Cytokines; C583355:IL1R1 protein, mouse; D018836:Inflammation Mediators; D007375:Interleukin-1; D053573:Receptors, Interleukin-1 Type I; D014409:Tumor Necrosis Factor-alpha
keywords: IL-1; IL-1R; L. pneumophila; TNF; type IV secretion system