Caspase-7 Activation by the Nlrc4/Ipaf Inflammasome Restricts Legionella pneumophila Infection

PLoS Pathogens

Thirumala-Devi Kanneganti¹  Anasuya Sarkar²  Mark D. Wewers²  Clay B. Marsh²  Cameron Ditty²  Christie Newland²  Jonathan Butchar²  Anwari Akhter²  Amal O. Amer²  Colby Day²  Dominique Limoli²  Susheela Tridandapani²  Mikhail A. Gavrilin²  Laura Frantz²  Songcerae Washington² 

[1] Department of Immunology, St Jude Children's Research Hospital, Memphis, Tennessee, United States of America;Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine, Center for Microbial Interface Biology and the Department of Internal Medicine, Ohio State University, Columbus, Ohio, United States of America

关键词: Legionella pneumophila;    Macrophages;    Apoptosis;    Flagellin;    Lysosomes;    Salmonellosis;    Intracellular pathogens;    Phagosomes;   

DOI  :  10.1371/journal.ppat.1000361

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

Legionella pneumophila (L. pneumophila), the causative agent of a severe form of pneumonia called Legionnaires' disease, replicates in human monocytes and macrophages. Most inbred mouse strains are restrictive to L. pneumophila infection except for the A/J, Nlrc4−/− (Ipaf−/−), and caspase-1−/− derived macrophages. Particularly, caspase-1 activation is detected during L. pneumophila infection of murine macrophages while absent in human cells. Recent in vitro experiments demonstrate that caspase-7 is cleaved by caspase-1. However, the biological role for caspase-7 activation downstream of caspase-1 is not known. Furthermore, whether this reaction is pertinent to the apoptosis or to the inflammation pathway or whether it mediates a yet unidentified effect is unclear. Using the intracellular pathogen L. pneumophila, we show that, upon infection of murine macrophages, caspase-7 was activated downstream of the Nlrc4 inflammasome and required caspase-1 activation. Such activation of caspase-7 was mediated by flagellin and required a functional Naip5. Remarkably, mice lacking caspase-7 and its macrophages allowed substantial L. pneumophila replication. Permissiveness of caspase-7−/− macrophages to the intracellular pathogen was due to defective delivery of the organism to the lysosome and to delayed cell death during early stages of infection. These results reveal a new mechanism for caspase-7 activation downstream of the Nlrc4 inflammasome and present a novel biological role for caspase-7 in host defense against an intracellular bacterium.

【 授权许可】

CC BY