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.