Concerted activation of the AIM2 and NLRP3 inflammasomes orchestrates host protection against Aspergillus infection.

Abstract

Invasive pulmonary aspergillosis is a leading cause of infection-associated mortality in immunocompromised individuals. Aspergillus fumigatus infection produces ligands that could activate inflammasomes, but the contribution of these host defenses remains unclear. We show that two inflammasome receptors, AIM2 and NLRP3, recognize intracellular A. fumigatus and collectively induce protective immune responses. Mice lacking both AIM2 and NLRP3 fail to confine Aspergillus hyphae to inflammatory foci, leading to widespread hyphal dissemination to lung blood vessels. These mice succumb to infection more rapidly than WT mice or mice lacking a single inflammasome receptor. AIM2 and NLRP3 activation initiates assembly of a single cytoplasmic inflammasome platform, composed of the adaptor protein ASC along with caspase-1 and caspase-8. Combined actions of caspase-1 and caspase-8 lead to processing of pro-inflammatory cytokines IL-1β and IL-18 that critically control the infection. Thus, AIM2 and NLRP3 form a dual cytoplasmic surveillance system that orchestrates responses against A. fumigatus infection.

• Authors: Rajendra Karki, Si Ming Man, R K Subbarao Malireddi, Prajwal Gurung, Peter Vogel, Mohamed Lamkanfi, Thirumala-Devi Kanneganti
• Journal: Cell host & microbe (Cell Host Microbe) Vol. 17 Issue 3 Pg. 357-368 (Mar 11 2015) ISSN: 1934-6069 [Electronic] United States
• PMID: 25704009 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 Elsevier Inc. All rights reserved.

Chemical References

• Aim2 protein, mouse
• Carrier Proteins
• DNA-Binding Proteins
• Inflammasomes
• NLR Family, Pyrin Domain-Containing 3 Protein
• Nlrp3 protein, mouse

Topics

• Animals
• Aspergillosis (immunology, microbiology)
• Aspergillus fumigatus (immunology)
• Carrier Proteins (metabolism)
• DNA-Binding Proteins (metabolism)
• Inflammasomes (metabolism)
• Mice
• Mice, Knockout
• NLR Family, Pyrin Domain-Containing 3 Protein