{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T05:27:06Z","timestamp":1790659626010,"version":"4.1.0"},"reference-count":51,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2020,5,29]],"date-time":"2020-05-29T00:00:00Z","timestamp":1590710400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["HL117181"],"award-info":[{"award-number":["HL117181"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["HL140398"],"award-info":[{"award-number":["HL140398"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["AI135803"],"award-info":[{"award-number":["AI135803"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R41AI124997"],"award-info":[{"award-number":["R41AI124997"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000738","name":"U.S. Department of Veterans Affairs","doi-asserted-by":"publisher","award":["I01BX004828"],"award-info":[{"award-number":["I01BX004828"]}],"id":[{"id":"10.13039\/100000738","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JoF"],"abstract":"<jats:p>Filamentous fungi of the Aspergillus genus and others have long been linked to the induction of type 2 immunity that underlies IgE-mediated hypersensitivity responses. This unique immune response is characterized by the production of the allergy-associated T helper cell type 2 (Th2) and Th17 cytokines interleukin 4 (IL-4), IL-13, and IL-17 that drive IgE, eosinophilia, airway hyperresponsiveness and other manifestations of asthma. Proteinases secreted by filamentous fungi promote type 2 immunity, but the mechanism by which this occurs has long remained obscure. Through detailed biochemical analysis of household dust, microbiological dissection of human airway secretions, and extensive modeling in mice, our laboratory has assembled a detailed mechanistic description of how type 2 immunity evolves after exposure to fungi. In this review we summarize three key discoveries: (1) fungal proteinases drive the type 2 immune response; (2) the relationship between fungi, proteinases, and type 2 immunity is explained by airway mycosis, a form of non-invasive fungal infection of the airway lumen; and (3) the innate component of proteinase-driven type 2 immunity is mediated by cleavage of the clotting protein fibrinogen. Despite these advances, additional work is required to understand how Th2 and Th17 responses evolve and the role that non-filamentous fungi potentially play in allergic diseases.<\/jats:p>","DOI":"10.3390\/jof6020074","type":"journal-article","created":{"date-parts":[[2020,6,1]],"date-time":"2020-06-01T11:49:21Z","timestamp":1591012161000},"page":"74","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Airway Mycosis and the Regulation of Type 2 Immunity"],"prefix":"10.3390","volume":"6","author":[{"given":"John Morgan","family":"Knight","sequence":"first","affiliation":[{"name":"Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX 77030, USA"},{"name":"Michael E. DeBakey VA Center for Translational Research on Inflammatory Diseases, Baylor College of Medicine, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yifan","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5985-4148","authenticated-orcid":false,"given":"Kelsey","family":"Mauk","sequence":"additional","affiliation":[{"name":"Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jill","family":"Weatherhead","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA"},{"name":"Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9942-6188","authenticated-orcid":false,"given":"Sara","family":"Anvari","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Farrah","family":"Kheradmand","sequence":"additional","affiliation":[{"name":"Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX 77030, USA"},{"name":"Michael E. DeBakey VA Center for Translational Research on Inflammatory Diseases, Baylor College of Medicine, Houston, TX 77030, USA"},{"name":"Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA"},{"name":"Biology of Inflammation Center, Baylor College of Medicine, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David B.","family":"Corry","sequence":"additional","affiliation":[{"name":"Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX 77030, USA"},{"name":"Michael E. DeBakey VA Center for Translational Research on Inflammatory Diseases, Baylor College of Medicine, Houston, TX 77030, USA"},{"name":"Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA"},{"name":"Biology of Inflammation Center, Baylor College of Medicine, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,5,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1016\/bs.ai.2019.05.002","article-title":"Airway mycosis in allergic airway disease","volume":"142","author":"Li","year":"2019","journal-title":"Adv. Immunol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"2386596","DOI":"10.1155\/2016\/2386596","article-title":"Valuing the Economic Costs of Allergic Rhinitis, Acute Bronchitis, and Asthma from Exposure to Indoor Dampness and Mold in the US","volume":"2016","author":"Mudarri","year":"2016","journal-title":"J. Environ. Public Health"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1055\/s-0037-1607981","article-title":"Advances and Evolving Concepts in Allergic Asthma","volume":"39","author":"Tung","year":"2018","journal-title":"Semin. Respir. Crit. Care Med."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"2261","DOI":"10.1126\/science.282.5397.2261","article-title":"Requirement for IL-13 independently of IL-4 in experimental asthma","volume":"282","author":"Grunig","year":"1998","journal-title":"Science"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"2258","DOI":"10.1126\/science.282.5397.2258","article-title":"Interleukin-13: Central mediator of allergic asthma","volume":"282","author":"Luyimbazi","year":"1998","journal-title":"Science"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"2455","DOI":"10.1056\/NEJMoa1304048","article-title":"Dupilumab in persistent asthma with elevated eosinophil levels","volume":"368","author":"Wenzel","year":"2013","journal-title":"N. Engl. J. Med."},{"key":"ref_7","first-page":"930","article-title":"Immunological and clinical findings in workers and consumers exposed to enzymes of Bacillus subtilis","volume":"66","author":"Pepys","year":"1973","journal-title":"Proc. R. Soc. Med."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1111\/j.1365-2222.1973.tb01318.x","article-title":"Clinical and immunological responses to enzymes of Bacillus subtilis in factory workers and consumers","volume":"3","author":"Pepys","year":"1973","journal-title":"Clin. Allergy"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"445","DOI":"10.1111\/j.1365-2222.1988.tb02894.x","article-title":"Asthma caused by bromelain: An occupational allergy","volume":"18","author":"Gailhofer","year":"1988","journal-title":"Clin. Allergy"},{"key":"ref_10","first-page":"302","article-title":"Occupational asthma after inhalation of dust of the proteolytic enzyme, papain","volume":"32","author":"Milne","year":"1975","journal-title":"Br. J. Ind. Med."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"83","DOI":"10.2332\/allergolint.O-07-507","article-title":"Protease activity of allergenic pollen of cedar, cypress, juniper, birch and ragweed","volume":"57","author":"Gunawan","year":"2008","journal-title":"Allergol. Int."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"288","DOI":"10.2174\/187152808786848379","article-title":"Should we target allergen protease activity to decrease the burden of allergic airway inflammation?","volume":"7","author":"Vliagoftis","year":"2008","journal-title":"Inflamm. Allergy Drug Targets"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"496","DOI":"10.1038\/ni.1719","article-title":"Divergent functions for airway epithelial matrix metalloproteinase 7 and retinoic acid in experimental asthma","volume":"10","author":"Goswami","year":"2009","journal-title":"Nat. Immunol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"375","DOI":"10.1038\/s41590-018-0067-5","article-title":"Environmental allergens induce allergic inflammation through proteolytic maturation of IL-33","volume":"19","author":"Cayrol","year":"2018","journal-title":"Nat. Immunol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1172\/JCI5844","article-title":"Der p 1 facilitates transepithelial allergen delivery by disruption of tight junctions","volume":"104","author":"Wan","year":"1999","journal-title":"J. Clin. Investig."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"5904","DOI":"10.4049\/jimmunol.169.10.5904","article-title":"A protease-activated pathway underlying Th cell type 2 activation and allergic lung disease","volume":"169","author":"Kheradmand","year":"2002","journal-title":"J. Immunol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"334","DOI":"10.1016\/j.jaci.2007.04.025","article-title":"A new mechanism regulating the initiation of allergic airway inflammation","volume":"120","author":"Kiss","year":"2007","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"6000","DOI":"10.4049\/jimmunol.180.9.6000","article-title":"Fungal proteases induce Th2 polarization through limited dendritic cell maturation and reduced production of IL-12","volume":"180","author":"Martin","year":"2008","journal-title":"J. Immunol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"310","DOI":"10.1038\/ni1558","article-title":"A mechanism for the initiation of allergen-induced T helper type 2 responses","volume":"9","author":"Sokol","year":"2008","journal-title":"Nat. Immunol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"507","DOI":"10.1111\/j.1365-2362.2009.02112.x","article-title":"Serine protease activity of Per a 10 augments allergen-induced airway inflammation in a mouse model","volume":"39","author":"Sudha","year":"2009","journal-title":"Eur. J. Clin. Investig."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"292","DOI":"10.1007\/s10875-008-9261-9","article-title":"Serine protease activity of Cur l 1 from Curvularia lunata augments Th2 response in mice","volume":"29","author":"Tripathi","year":"2009","journal-title":"J. Clin. Immunol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1369","DOI":"10.1016\/j.jaci.2010.02.035","article-title":"Human rhinovirus proteinase 2A induces TH1 and TH2 immunity in patients with chronic obstructive pulmonary disease","volume":"125","author":"Singh","year":"2010","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"3164","DOI":"10.4049\/jimmunol.0903812","article-title":"Mucosal allergic sensitization to cockroach allergens is dependent on proteinase activity and proteinase-activated receptor-2 activation","volume":"186","author":"Arizmendi","year":"2011","journal-title":"J. Immunol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"L605","DOI":"10.1152\/ajplung.00359.2010","article-title":"Alternaria alternata serine proteases induce lung inflammation and airway epithelial cell activation via PAR2","volume":"300","author":"Boitano","year":"2011","journal-title":"Am. J. Physiol. Lung Cell. Mol. Physiol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"792","DOI":"10.1126\/science.1240342","article-title":"Cleavage of fibrinogen by proteinases elicits allergic responses through Toll-like receptor 4","volume":"341","author":"Millien","year":"2013","journal-title":"Science"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"6763","DOI":"10.1038\/ncomms7763","article-title":"A fungal protease allergen provokes airway hyper-responsiveness in asthma","volume":"6","author":"Balenga","year":"2015","journal-title":"Nat. Commun."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"504","DOI":"10.1038\/mi.2009.102","article-title":"Link between allergic asthma and airway mucosal infection suggested by proteinase-secreting household fungi","volume":"2","author":"Porter","year":"2009","journal-title":"Mucosal Immunol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"S158","DOI":"10.3109\/13693786.2010.509743","article-title":"Respiratory tract allergic disease and atopy: Experimental evidence for a fungal infectious etiology","volume":"49","author":"Porter","year":"2011","journal-title":"Med. Mycol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1181","DOI":"10.1016\/S0140-6736(69)92166-7","article-title":"Allergic reactions of the lungs to enzymes of Bacillus subtilis","volume":"1","author":"Pepys","year":"1969","journal-title":"Lancet"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"443","DOI":"10.1111\/j.1365-2222.1979.tb02507.x","article-title":"Allergic reactions, including asthma, to the pineapple protease bromelain following occupational exposure","volume":"9","author":"Baur","year":"1979","journal-title":"Clin. Allergy"},{"key":"ref_31","first-page":"232","article-title":"Allergic bronchopulmonary aspergillosis: Evidence of limited tissue invasion","volume":"111","author":"Riley","year":"1975","journal-title":"Am. Rev. Respir. Dis."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1016\/0002-9343(77)90240-6","article-title":"Evidence that Aspergillus fumigatus growing in the airway of man can be a potent stimulus of specific and nonspecific IgE formation","volume":"63","author":"Patterson","year":"1977","journal-title":"Am. J. Med."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1016\/j.clim.2012.11.005","article-title":"Tracheobronchial mycosis in a retrospective case-series study of five status asthmaticus patients","volume":"146","author":"Mak","year":"2013","journal-title":"Clin. Immunol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"325","DOI":"10.1016\/j.jaci.2014.04.028","article-title":"Airway surface mycosis in chronic TH2-associated airway disease","volume":"134","author":"Porter","year":"2014","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"264","DOI":"10.1002\/iid3.215","article-title":"Benefits of Antifungal Therapy in Asthma Patients with Airway Mycosis: A Retrospective Cohort Analysis","volume":"6","author":"Li","year":"2018","journal-title":"Immun. Inflamm. Dis."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"4459","DOI":"10.1128\/IAI.05209-11","article-title":"Necessary and sufficient role for T helper cells to prevent fungal dissemination during mucosal airway infection","volume":"79","author":"Porter","year":"2011","journal-title":"Infect. Immun."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1164\/rccm.200805-737OC","article-title":"Randomized controlled trial of oral antifungal treatment for severe asthma with fungal sensitization: The Fungal Asthma Sensitization Trial (FAST) study","volume":"179","author":"Denning","year":"2009","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"541","DOI":"10.1016\/S0091-6749(99)70321-0","article-title":"Treatment of late-onset asthma with fluconazole","volume":"104","author":"Ward","year":"1999","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"410","DOI":"10.1038\/nm.1946","article-title":"House dust mite allergen induces asthma via Toll-like receptor 4 triggering of airway structural cells","volume":"15","author":"Hammad","year":"2009","journal-title":"Nat. Med."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"585","DOI":"10.1038\/nature07548","article-title":"Allergenicity resulting from functional mimicry of a Toll-like receptor complex protein","volume":"457","author":"Trompette","year":"2009","journal-title":"Nature"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"597","DOI":"10.1002\/cbf.1697","article-title":"House dust mite regulate the lung inflammation of asthmatic mice through TLR4 pathway in airway epithelial cells","volume":"28","author":"Li","year":"2010","journal-title":"Cell Biochem. Funct."},{"key":"ref_42","first-page":"1257","article-title":"Acute plastic bronchitis","volume":"41","author":"Vijayasekaran","year":"2004","journal-title":"Indian Pediatr."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"301","DOI":"10.1160\/TH08-03-0179","article-title":"Functional Toll-like receptor 4 mutations modulate the response to fibrinogen","volume":"100","author":"Hodgkinson","year":"2008","journal-title":"Thromb. Haemost."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"19502","DOI":"10.1074\/jbc.M109.098186","article-title":"Molecular mechanism that induces activation of Spatzle, the ligand for the Drosophila Toll receptor","volume":"285","author":"Arnot","year":"2010","journal-title":"J. Biol. Chem."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"8834","DOI":"10.1074\/jbc.RA118.006724","article-title":"Selective cleavage of fibrinogen by diverse proteinases initiates innate allergic and antifungal immunity through CD11b","volume":"294","author":"Landers","year":"2019","journal-title":"J. Biol. Chem."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1596","DOI":"10.1172\/JCI20741","article-title":"Leukocyte engagement of fibrin(ogen) via the integrin receptor alphaMbeta2\/Mac-1 is critical for host inflammatory response in vivo","volume":"113","author":"Flick","year":"2004","journal-title":"J. Clin. Investig."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"90","DOI":"10.1056\/NEJM199307083290204","article-title":"Preventing bronchoconstriction in exercise-induced asthma with inhaled heparin","volume":"329","author":"Ahmed","year":"1993","journal-title":"N. Engl. J. Med."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1009","DOI":"10.1378\/chest.107.4.1009","article-title":"Effect of inhaled heparin on methacholine-induced bronchial hyperreactivity","volume":"107","author":"Ceyhan","year":"1995","journal-title":"Chest"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1645","DOI":"10.1084\/jem.20021340","article-title":"Lipopolysaccharide-enhanced, toll-like receptor 4-dependent T helper cell type 2 responses to inhaled antigen","volume":"196","author":"Eisenbarth","year":"2002","journal-title":"J. Exp. Med."},{"key":"ref_50","first-page":"7849","article-title":"A toll-like receptor 4 (TLR4) variant is associated with asthma severity","volume":"8","author":"Zhang","year":"2015","journal-title":"Int. J. Clin. Exp. Med."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"3591","DOI":"10.12659\/MSM.895380","article-title":"Association of TLR4 (896A\/G and 1196C\/T) Gene Polymorphisms with Asthma Risk: A Meta-Analysis","volume":"21","author":"Li","year":"2015","journal-title":"Med. Sci. Monit."}],"container-title":["Journal of Fungi"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2309-608X\/6\/2\/74\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T09:33:47Z","timestamp":1760175227000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2309-608X\/6\/2\/74"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,5,29]]},"references-count":51,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2020,6]]}},"alternative-id":["jof6020074"],"URL":"https:\/\/doi.org\/10.3390\/jof6020074","relation":{},"ISSN":["2309-608X"],"issn-type":[{"value":"2309-608X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,5,29]]}}}