Caspase-7 Activation by the Nlrc4/Ipaf Inflammasome Restricts Legionella pneumophila Infection
Open Access
- 3 April 2009
- journal article
- research article
- Published by Public Library of Science (PLoS) in PLoS Pathogens
- Vol. 5 (4), e1000361
- https://doi.org/10.1371/journal.ppat.1000361
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. Legionella pneumophila causes a severe form of pneumonia called Legionnaires' disease. In human macrophages, L. pneumophila establishes special vacuoles that do not fuse with the lysosome and grows intracellularly. However, in mouse macrophages, the bacteria are efficiently delivered to the lysosome for degradation. Importantly, caspase-1 is activated when L. pneumophila infects mouse macrophages, but not when it infects human cells. Caspase-1 activation promotes the fusion of the L. pneumophila vacuole with the lysosome and macrophage death. However, the caspase-1 substrate mediating such effects is unknown. Experiments performed in vitro demonstrate that caspase-7 is a substrate of caspase-1. Yet, it is not known if the reaction takes place within the macrophage, and it is unclear if it has any biological effect. In this study we show that, in mouse macrophages, caspase-7 is activated by L. pneumophila downstream of caspase-1 and requires the host receptors Nlrc4 and Naip5. Remarkably, caspase-7 activation during L. pneumophila infection restricts growth by promoting early macrophage death and efficient delivery of the organism to the lysosome. Consequently, L. pneumophila grows in the macrophages and the lungs of caspase-7−/− mice. Therefore, we demonstrate a novel caspase-7 activation pathway that contributes to the restriction of L. pneumophila infection.Keywords
This publication has 81 references indexed in Scilit:
- Targeted Peptidecentric Proteomics Reveals Caspase-7 as a Substrate of the Caspase-1 InflammasomesMolecular & Cellular Proteomics, 2008
- The Legionella pneumophila replication vacuole: making a cosy niche inside host cellsNature Reviews Microbiology, 2008
- Phagosome maturation: going through the acid testNature Reviews Molecular Cell Biology, 2008
- Executioner caspase-3 and caspase-7 are functionally distinct proteasesProceedings of the National Academy of Sciences of the United States of America, 2008
- Critical function for Naip5 in inflammasome activation by a conserved carboxy-terminal domain of flagellinNature Immunology, 2008
- Mycobacterium tuberculosis Prevents Inflammasome ActivationCell Host & Microbe, 2008
- The NLR Gene Family: A Standard NomenclatureImmunity, 2008
- Legionella pneumophila inhibits macrophage apoptosis by targeting pro-death members of the Bcl2 protein familyProceedings of the National Academy of Sciences of the United States of America, 2007
- LAMP proteins are required for fusion of lysosomes with phagosomesThe EMBO Journal, 2007
- Delivery of proteins into living cells by reversible membrane permeabilization with streptolysin-OProceedings of the National Academy of Sciences of the United States of America, 2001