title: Caspase-7 activation by the Nlrc4/Ipaf inflammasome restricts Legionella pneumophila infection.
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.
authors.affiliation: Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine, Center for Microbial Interface Biology and the Department of Internal Medicine, Ohio State University, Columbus, OH, USA.
authors.forename: Anwari
authors.initials: A
authors.lastname: Akhter
authors.forename: Mikhail A
authors.initials: MA
authors.lastname: Gavrilin
authors.forename: Laura
authors.initials: L
authors.lastname: Frantz
authors.forename: Songcerae
authors.initials: S
authors.lastname: Washington
authors.forename: Cameron
authors.initials: C
authors.lastname: Ditty
authors.forename: Dominique
authors.initials: D
authors.lastname: Limoli
authors.forename: Colby
authors.initials: C
authors.lastname: Day
authors.forename: Anasuya
authors.initials: A
authors.lastname: Sarkar
authors.forename: Christie
authors.initials: C
authors.lastname: Newland
authors.forename: Jonathan
authors.initials: J
authors.lastname: Butchar
authors.forename: Clay B
authors.initials: CB
authors.lastname: Marsh
authors.forename: Mark D
authors.initials: MD
authors.lastname: Wewers
authors.forename: Susheela
authors.initials: S
authors.lastname: Tridandapani
authors.forename: Thirumala-Devi
authors.initials: TD
authors.lastname: Kanneganti
authors.forename: Amal O
authors.initials: AO
authors.lastname: Amer