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- Title
Caspase-7 Activation by the Nlrc4/Ipaf Inflammasome Restricts Legionella pneumophila Infection.
- Authors
Akhter, Anwari; Gavrilin, Mikhail A.; Frantz, Laura; Washington, Songcerae; Ditty, Cameron; Limoli, Dominique; Day, Colby; Sarkar, Anasuya; Newland, Christie; Butchar, Jonathan; Marsh, Clay B.; Wewers, Mark D.; Tridandapani, Susheela; Kanneganti, Thirumala-Devi; Amer, Amal O.
- Abstract
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.
- Subjects
LEGIONNAIRES' disease; ETIOLOGY of diseases; LEGIONELLA pneumophila; PROTEOLYTIC enzymes; INFECTION prevention; APOPTOSIS prevention; ANIMAL disease models; THERAPEUTICS
- Publication
PLoS Pathogens, 2009, Vol 5, Issue 4, p1
- ISSN
1553-7366
- Publication type
Article
- DOI
10.1371/journal.ppat.1000361