Mycobacterium tuberculosis protein ESAT‐6 is a potent activator of the NLRP3/ASC inflammasome |
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| Authors: | Bibhuti B. Mishra Pedro Moura‐Alves Avinash Sonawane Nir Hacohen Gareth Griffiths Luis F. Moita Elsa Anes |
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| Affiliation: | 1. Centro de Patogénese Molecular, Unidade dos Retrovírus e Infec??es Associadas e Instituto de Medicina Molecular, Faculdade de Farmácia, Universidade de Lisboa, Lisboa, Portugal.;2. Present address: Department of Molecular Genetics and Microbiology, University of Massachusetts Medical School, Worcester, MA 01655, USA.;3. Cell Biology of the Immune System Unit, Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, 1649‐028 Lisboa, Portugal.;4. Graduate Program in Basic and Applied Biology, Abel Salazar Institute of Biomedical Sciences, University of Porto, 4099‐003 Porto, Portugal.;5. Department of Molecular Biosciences, University of Oslo, PO Box 1041, Blindern, 0316 Oslo, Norway.;6. Center for Immunology and Inflammatory Diseases, Division of Rheumatology, Allergy, and Immunology, Massachusetts General Hospital, Charlestown, MA 02129, USA.;7. Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA. |
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| Abstract: | Interleukin‐1β (IL‐1β) represents one of the most important mediators of inflammation and host responses to infection. Mycobacterium tuberculosis (Mtb), the causative agent of human tuberculosis, induces IL‐1β secretion at the site of infection, but the underlying mechanism(s) are poorly understood. In this work we show that Mtb infection of macrophages stimulates caspase‐1 activity and promotes the secretion of IL‐1β. This stimulation requires live intracellular bacteria expressing a functional ESX‐1 secretion system. ESAT‐6, an ESX‐1 substrate implicated in membrane damage, is both necessary and sufficient for caspase‐1 activation and IL‐1β secretion. ESAT‐6 promotes the access of other immunostimulatory agents such as AG85 into the macrophage cytosol, indicating that this protein may contribute to caspase‐1 activation largely by perturbing host cell membranes. Using a high‐throughput shRNA‐based screen we found that numerous NOD‐like receptors (NLRs) and CARD domain‐containing proteins (CARDs) were important for IL‐1β secretion upon Mtb infection. Most importantly, NLRP3, ASC and caspase‐1 form an infection‐inducible inflammasome complex that is essential for IL‐1β secretion. In summary, we show that recognition of Mtb infection by the NLRP3 inflammasome requires the activity of the bacterial virulence factor ESAT‐6, and the subsequent IL‐1β response is regulated by a number of NLR/CARD proteins. |
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