The Frustrated Host Response to Legionella pneumophila Is Bypassed by MyD88-Dependent Translation of Pro-inflammatory Cytokines

PLoS Pathogens

Aisling S. Dugan¹  Ralph R. Isberg²  Seblewongel Asrat³ 

[1] 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;Howard Hughes Medical Institute, Boston, Massachusetts, United States of America

关键词: Macrophages;    Legionella pneumophila;    Cytokines;    Protein translation;    Protein synthesis;    Bacterial pathogens;    DNA transcription;    Host cells;   

DOI  :  10.1371/journal.ppat.1004229

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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.

【 授权许可】

CC BY