Caspase-7 activation by the Nlrc4/Ipaf inflammasome restricts Legionella pneumophila infection.
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.
Akhter
Anwari
A
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.
Gavrilin
Mikhail A
MA
Frantz
Laura
L
Washington
Songcerae
S
Ditty
Cameron
C
Limoli
Dominique
D
Day
Colby
C
Sarkar
Anasuya
A
Newland
Christie
C
Butchar
Jonathan
J
Marsh
Clay B
CB
Wewers
Mark D
MD
Tridandapani
Susheela
S
Kanneganti
Thirumala-Devi
TD
Amer
Amal O
AO