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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\u03b1 (IL-1\u03b1) 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\u03b1, in contrast to Af293. The release of IL-1\u03b1 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\u03b1-dependent inflammation is supported by three independent experimental lines. First, pregermination of Af293 prior to\n            <jats:italic>in vivo<\/jats:italic>\n            challenge drives greater lung damage and an IL-1\u03b1-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\u03b1-dependent inflammation and fungal clearance. Third, primary environmental\n            <jats:named-content content-type=\"genus-species\">A. fumigatus<\/jats:named-content>\n            isolates that rapidly germinate under airway conditions follow the same trend toward IL-1\u03b1 dependency. Our data support the hypothesis that\n            <jats:named-content content-type=\"genus-species\">A. fumigatus<\/jats:named-content>\n            phenotypic variation significantly contributes to disease outcomes.\n          <\/jats:p>","DOI":"10.1128\/iai.00661-17","type":"journal-article","created":{"date-parts":[[2017,9,26]],"date-time":"2017-09-26T00:30:33Z","timestamp":1506385833000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":65,"title":["Interleukin 1\u03b1 Is Critical for Resistance against Highly Virulent Aspergillus fumigatus Isolates"],"prefix":"10.1128","volume":"85","author":[{"given":"Alayna K.","family":"Caffrey-Carr","sequence":"first","affiliation":[{"name":"Montana State University, Department of Microbiology and Immunology, Bozeman, Montana, USA"},{"name":"Geisel School of Medicine at Dartmouth, Department of Microbiology and Immunology, Lebanon, New Hampshire, 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