Details

Autor(en) / Beteiligte

• Mishra, Bibhuti B
• Moura-Alves, Pedro
• Sonawane, Avinash
• Hacohen, Nir
• Griffiths, Gareth
• Moita, Luis F
• Anes, Elsa

Titel

Mycobacterium tuberculosis protein ESAT-6 is a potent activator of the NLRP3/ASC inflammasome

Ist Teil von

• Cellular microbiology, 2010-08, Vol.12 (8), p.1046-1063

Ort / Verlag

Oxford, UK: Oxford, UK : Blackwell Publishing Ltd

Erscheinungsjahr

2010

Quelle

Access via Wiley Online Library

Beschreibungen/Notizen

• 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.