Journal
CELL HOST & MICROBE
Volume 17, Issue 3, Pages 357-368Publisher
CELL PRESS
DOI: 10.1016/j.chom.2015.01.006
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Funding
- Neoma Boadway Endowed Fellowship
- Paul Barrett Endowed Fellowship
- St. Jude Children's Research Hospital
- European Union Marie-Curie grant [256432]
- ERC grant [281600]
- Fund for Scientific Research - Flanders [G030212N, 1.2.201.10.N.00, 1.5.122.11.N.00]
- NIH
- American Lebanese Syrian Associated Charities (ALSAC)
- European Research Council (ERC) [281600] Funding Source: European Research Council (ERC)
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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-1 beta 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.
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