Format

Send to

Choose Destination
Infect Immun. 2017 Nov 17;85(12). pii: e00661-17. doi: 10.1128/IAI.00661-17. Print 2017 Dec.

Interleukin 1α Is Critical for Resistance against Highly Virulent Aspergillus fumigatus Isolates.

Author information

1
Montana State University, Department of Microbiology and Immunology, Bozeman, Montana, USA.
2
Geisel School of Medicine at Dartmouth, Department of Microbiology and Immunology, Lebanon, New Hampshire, USA.
3
Department of Microbiology, Miami University, Oxford, Ohio, USA.
4
Department of Laboratory Medicine, Clinical Microbiology Service, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
5
Department of Medicine, Infectious Disease Service, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
6
Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
7
Geisel School of Medicine at Dartmouth, Department of Microbiology and Immunology, Lebanon, New Hampshire, USA joshua.j.obar@dartmouth.edu.

Abstract

Heterogeneity among Aspergillus fumigatus isolates results in unique virulence potential and inflammatory responses. How these isolates drive specific immune responses and how this affects fungally induced lung damage and disease outcome are unresolved. We demonstrate that the highly virulent CEA10 strain is able to rapidly germinate within the immunocompetent lung environment, inducing greater lung damage, vascular leakage, and interleukin 1α (IL-1α) release than the low-virulence Af293 strain, which germinates with a lower frequency in this environment. Importantly, the clearance of CEA10 was consequently dependent on IL-1α, in contrast to Af293. The release of IL-1α occurred by a caspase 1/11- and P2XR7-independent mechanism but was dependent on calpain activity. Our finding that early fungal conidium germination drives greater lung damage and IL-1α-dependent inflammation is supported by three independent experimental lines. First, pregermination of Af293 prior to in vivo challenge drives greater lung damage and an IL-1α-dependent neutrophil response. Second, the more virulent EVOL20 strain, derived from Af293, is able to germinate in the airways, leading to enhanced lung damage and IL-1α-dependent inflammation and fungal clearance. Third, primary environmental A. fumigatus isolates that rapidly germinate under airway conditions follow the same trend toward IL-1α dependency. Our data support the hypothesis that A. fumigatus phenotypic variation significantly contributes to disease outcomes.

KEYWORDS:

Aspergillus fumigatus; IL-1; aspergillosis; innate immunity; invasive fungal infection; lung defense; lung infection; mucosal immunity; neutrophils; respiratory pathogens

PMID:
28947643
PMCID:
PMC5695118
DOI:
10.1128/IAI.00661-17
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for HighWire Icon for PubMed Central
Loading ...
Support Center