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Human monogenic disorders have revealed the critical contribution of type 17 responses in mucosal fungal surveillance. We unexpectedly found that in certain settings, enhanced type 1 immunity rather than defective type 17 responses can promote mucosal fungal infection susceptibility. Notably, in mice and humans with AIRE deficiency, an autoimmune disease characterized by selective susceptibility to mucosal but not systemic fungal infection, mucosal type 17 responses are intact while type 1 responses are exacerbated. These responses promote aberrant interferon-γ (IFN-γ)- and signal transducer and activator of transcription 1 (STAT1)-dependent epithelial barrier defects as well as mucosal fungal infection susceptibility. Concordantly, genetic and pharmacologic inhibition of IFN-γ or Janus kinase (JAK)-STAT signaling ameliorates mucosal fungal disease. Thus, we identify aberrant T cell-dependent, type 1 mucosal inflammation as a critical tissue-specific pathogenic mechanism that promotes mucosal fungal infection susceptibility in mice and humans. Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.


Timothy J Break, Vasileios Oikonomou, Nicolas Dutzan, Jigar V Desai, Marc Swidergall, Tilo Freiwald, Daniel Chauss, Oliver J Harrison, Julie Alejo, Drake W Williams, Stefania Pittaluga, Chyi-Chia R Lee, Nicolas Bouladoux, Muthulekha Swamydas, Kevin W Hoffman, Teresa Greenwell-Wild, Vincent M Bruno, Lindsey B Rosen, Wint Lwin, Andy Renteria, Sergio M Pontejo, John P Shannon, Ian A Myles, Peter Olbrich, Elise M N Ferré, Monica Schmitt, Daniel Martin, Genomics and Computational Biology Core, Daniel L Barber, Norma V Solis, Luigi D Notarangelo, David V Serreze, Mitsuru Matsumoto, Heather D Hickman, Philip M Murphy, Mark S Anderson, Jean K Lim, Steven M Holland, Scott G Filler, Behdad Afzali, Yasmine Belkaid, Niki M Moutsopoulos, Michail S Lionakis. Aberrant type 1 immunity drives susceptibility to mucosal fungal infections. Science (New York, N.Y.). 2021 Jan 15;371(6526)

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PMID: 33446526

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