Concerted Activation of the AIM2 and NLRP3 Inflammasomes Orchestrates Host Protection against Aspergillus Infection
Open accessAbstract
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.
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Balanced activation of inflammatory responses followed the combined activation of AIM2 and NLRP3 inflammasomes in macrophages, and other myeloid cells in the lung play important roles in protection against invasive disease in a mouse model of infection with swollen A. fumigatus conidia.
“Balanced activation of inflammatory responses followed the combined activation of the interferon-inducible protein AIM2 and NLRP3 inflammasomes in macrophages, and other myeloid cells in the lung play important roles in protection against invasive disease in a mouse model of infection with swollen A. fumigatus conidia (268).”
From Aspergillus fumigatus and Aspergillosis in 2019 (2019) · cites this paper as [268]
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References 58 · Cited by 272
- Authors
- Karki, R., Man, S. M., Malireddi, R. K. S., Gurung, P., Vogel, P., Lamkanfi, M., & Kanneganti, T.-D.
- Affiliations
- St. Jude Children's Research Hospital (US)
- Vlaams Instituut voor Biotechnologie (BE)
- Corresponding author
- Kanneganti, Thirumala-Devi
- ORCID
- Venue
- Cell Host & Microbe
- Publisher
- Elsevier BV
- Published
- 2015-03
- Volume
- 17
- Issue
- 3
- Pages
- 357-368
- ISSN
- 1931-3128 (ISSN-L)
- PMC
- PMC4359672
- OpenAlex
- W2083392874
- Cited by
- 272
- References
- 58
- Citations by year
- 2026: 10 · 2025: 19 · 2024: 13 · 2023: 29 · 2022: 24 · 2021: 26 · 2020: 27 · 2019: 21 · 2018: 32 · 2017: 32 · 2016: 30 · 2015: 8
- FWCI
- 14.77
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell Host & Microbe (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Ghent University Academic Bibliography (Ghent University) (submittedVersion)
- Seoul National University Open Repository (Seoul National University) (submittedVersion)
- Funders
- National Cancer Institute (R01CA163507, P30CA021765)
- National Institute of Allergy and Infectious Diseases (R01AI101935)
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (R01AR056296)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Inflammasome and immune disorders
- Health Sciences › Medicine › Infectious Diseases › Antifungal resistance and susceptibility
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Keywords
- AIM2 inflammasome, NLRP3 inflammasome, Aspergillus fumigatus, invasive pulmonary aspergillosis, caspase-1, caspase-8, IL-1β, IL-18, host defense against fungi, immunocompromised patients
- MeSH terms
- NLR Family, Pyrin Domain-Containing 3 Protein, Animals, Aspergillosis, Aspergillus fumigatus, Carrier Proteins, DNA-Binding Proteins, Mice, Knockout, Mice, Inflammasomes
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