Journal article
Interleukin 1 alpha Is Critical for Resistance against Highly Virulent Aspergillus fumigatus Isolates
Infection and immunity, Vol.85(12), e00661-17
12/01/2017
DOI: 10.1128/IAI.00661-17
PMCID: PMC5695118
PMID: 28947643
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 1 alpha (IL-1 alpha) 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-1 alpha, in contrast to Af293. The release of IL-1 alpha 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-1 alpha-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-1 alpha-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-1 alpha dependent inflammation and fungal clearance. Third, primary environmental A. fumigatus isolates that rapidly germinate under airway conditions follow the same trend toward IL-1 alpha dependency. Our data support the hypothesis that A. fumigatus phenotypic variation significantly contributes to disease outcomes.
Details
- Title: Subtitle
- Interleukin 1 alpha Is Critical for Resistance against Highly Virulent Aspergillus fumigatus Isolates
- Creators
- Alayna K. Caffrey-Carr - Dartmouth CollegeCaitlin H. Kowalski - Dartmouth CollegeSarah R. Beattie - Dartmouth CollegeNathan A. Blaseg - Montana State UniversityChanell R. Upshaw - Miami UniversityArsa Thammahong - Dartmouth CollegeHannah E. Lust - Dartmouth CollegeYi-Wei Tang - Memorial Sloan Kettering Cancer CenterTobias M. Hohl - Memorial Sloan Kettering Cancer CenterRobert A. Cramer - Dartmouth CollegeJoshua J. Obar - Dartmouth College
- Resource Type
- Journal article
- Publication Details
- Infection and immunity, Vol.85(12), e00661-17
- DOI
- 10.1128/IAI.00661-17
- PMID
- 28947643
- PMCID
- PMC5695118
- NLM abbreviation
- Infect Immun
- ISSN
- 0019-9567
- eISSN
- 1098-5522
- Publisher
- Amer Soc Microbiology
- Number of pages
- 19
- Grant note
- P30 GM106394 / Dartmouth Lung Biology Center for Molecular, Cellular, and Translational Research grant P30 GM103415 / Center for Molecular, Cellular, and Translational Immunological Research grant P30CA008748 / NATIONAL CANCER INSTITUTE; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI) R01 AI081838; R01 AI093808; R21 AI105617 / NIH; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA P30GM106394 / NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of General Medical Sciences (NIGMS) R01AI093808 / NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Allergy & Infectious Diseases (NIAID) P30 CA008748 / NIH/NCI Cancer Center Support grant Dartmouth College Burroughs Wellcome Fund
- Language
- English
- Date published
- 12/01/2017
- Academic Unit
- Stead Family Department of Pediatrics; Infectious Disease (Pediatrics)
- Record Identifier
- 9984354005102771
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