title: The frustrated host response to Legionella pneumophila is bypassed by MyD88-dependent translation of pro-inflammatory cytokines.
abstract: Many pathogens, particularly those that require their host for survival, have devised mechanisms to subvert the host immune response in order to survive and replicate intracellularly. Legionella pneumophila, the causative agent of Legionnaires' disease, promotes intracellular growth by translocating proteins into its host cytosol through its type IV protein secretion machinery. At least 5 of the bacterial translocated effectors interfere with the function of host cell elongation factors, blocking translation and causing the induction of a unique host cell transcriptional profile. In addition, L. pneumophila also interferes with translation initiation, by preventing cap-dependent translation in host cells. We demonstrate here that protein translation inhibition by L. pneumophila leads to a frustrated host MAP kinase response, where genes involved in the pathway are transcribed but fail to be translated due to the bacterium-induced protein synthesis inhibition. Surprisingly, few pro-inflammatory cytokines, such as IL-1α and IL-1β, bypass this inhibition and get synthesized in the presence of Legionella effectors. We show that the selective synthesis of these genes requires MyD88 signaling and takes place in both infected cells that harbor bacteria and neighboring bystander cells. Our findings offer a perspective of how host cells are able to cope with pathogen-encoded activities that disrupt normal cellular process and initiate a successful inflammatory response.
authors: Howard Hughes Medical Institute, Boston, Massachusetts, United States of America; Department of Molecular Biology and Microbiology, Tufts University School of Medicine, Boston, Massachusetts, United States of America; Graduate Program in Molecular Microbiology, Sackler School of Graduate Biomedical Science, Tufts University School of Medicine, Boston, Massachusetts, United States of America.
authors: Seblewongel
authors: S
authors: Asrat
authors: Department of Molecular Biology and Microbiology, Tufts University School of Medicine, Boston, Massachusetts, United States of America.
authors: Aisling S
authors: AS
authors: Dugan
authors: Howard Hughes Medical Institute, Boston, Massachusetts, United States of America; Department of Molecular Biology and Microbiology, Tufts University School of Medicine, Boston, Massachusetts, United States of America.
authors: Ralph R
authors: RR
authors: Isberg
mesh_terms: D000818:Animals; D006801:Humans; D053582:Interleukin-1alpha / Q000235:genetics / Q000276:immunology*; D053583:Interleukin-1beta / Q000235:genetics / Q000276:immunology*; D016952:Legionella pneumophila / Q000276:immunology*; D007877:Legionnaires' Disease / Q000235:genetics / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics / Q000276:immunology*; D014176:Protein Biosynthesis / Q000235:genetics / Q000276:immunology*; D020298:U937 Cells
chemical_list: C508584:IL1A protein, human; C508585:IL1B protein, human; C587672:IL1B protein, mouse; D053582:Interleukin-1alpha; D053583:Interleukin-1beta; C507779:MYD88 protein, human; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88