Aberrant type 1 immunity drives susceptibility to mucosal fungal infections

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 mic...

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Bibliographic Details
Published in:	Science (American Association for the Advancement of Science) Vol. 371; no. 6526
Main Authors:	Break, Timothy J, Oikonomou, Vasileios, Dutzan, Nicolas, Desai, Jigar V, Swidergall, Marc, Freiwald, Tilo, Chauss, Daniel, Harrison, Oliver J, Alejo, Julie, Williams, Drake W, Pittaluga, Stefania, Lee, Chyi-Chia R, Bouladoux, Nicolas, Swamydas, Muthulekha, Hoffman, Kevin W, Greenwell-Wild, Teresa, Bruno, Vincent M, Rosen, Lindsey B, Lwin, Wint, Renteria, Andy, Pontejo, Sergio M, Shannon, John P, Myles, Ian A, Olbrich, Peter, Ferré, Elise M N, Schmitt, Monica, Martin, Daniel, Barber, Daniel L, Solis, Norma V, Notarangelo, Luigi D, Serreze, David V, Matsumoto, Mitsuru, Hickman, Heather D, Murphy, Philip M, Anderson, Mark S, Lim, Jean K, Holland, Steven M, Filler, Scott G, Afzali, Behdad, Belkaid, Yasmine, Moutsopoulos, Niki M, Lionakis, Michail S
Format:	Journal Article
Language:	English
Published:	United States The American Association for the Advancement of Science 15-01-2021
Subjects:	Aberration Adolescent Adult Aged AIRE protein Animals Antigens Antiinfectives and antibacterials Autoantibodies Autoimmune diseases Bacteria Candida albicans Candida albicans - immunology Candidiasis Candidiasis, Chronic Mucocutaneous - genetics Candidiasis, Chronic Mucocutaneous - immunology CD4 antigen CD8 antigen Chronic mucocutaneous candidiasis Cytokines Disease Disease Models, Animal Dystrophy Female Fungal diseases Fungal infections Fungi Fungicides Hereditary diseases Human tissues Humans Immunity Immunity, Mucosal - genetics Immunity, Mucosal - immunology Immunologic Surveillance - genetics Immunologic Surveillance - immunology Immunological tolerance Infections Inhibition Interferon Interferon-gamma - genetics Interleukin 17 Interleukin-22 Interleukins - genetics Janus kinase Janus Kinases - genetics Kinases Lymphocytes Lymphocytes T Male Medical treatment Mice Mice, Inbred BALB C Middle Aged Mouth Mucosa - immunology Mouth Mucosa - pathology Mucosal immunity Mutation Pathogens Patients Pharmacology Phenotypes Polyendocrinopathies, Autoimmune - genetics Polyendocrinopathies, Autoimmune - immunology Receptors, Interleukin-17 - genetics Signal transduction Signaling Signs and symptoms Stat1 protein STAT1 Transcription Factor - genetics Surveillance Susceptibility T-Lymphocytes - immunology Therapeutic applications Tissues Transcription Viruses Yeast Yeasts Young Adult γ-Interferon
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Summary:	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 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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 These authors contributed equally to this work. Author contributions: T.J.B., V.O., and M.S.L. designed the study and experiments; M.S.L. wrote the manuscript; T.J.B. and V.O. performed the experiments and analyzed the data; N.D., J.V.D., Ma.S., J.A., D.W.W., S.P., N.B., Mu.S., K.W.H., T.G.-W., L.B.R., W.L., A.R., J.P.S., I.A.M., P.O., and N.V.S. participated in performing experiments; T.F., D.C., O.J.H., V.M.B., S.G.F., B.A., L.D.N., H.D.H., P.M.M., M.S.A., J.K.L., S.M.H., D.L.B., Y.B., and N.M.M. provided intellectual expertise and helped to analyze and interpret experimental results; the Genomics and Computational Biology Core performed RNA-seq library preparation and sequencing; D.W.W. performed experimental periodontitis experiments and analyzed data; N.B. performed Citrobacter experiments and analyzed data; S.M.P. performed mCMV experiments and analyzed data; J.P.S. performed vaccinia experiments and analyzed data; I.A.M. performed skin staphylococcal experiments and analyzed data; D.M. assisted with RNA-seq studies; C.-C.R.L. performed histological analyses of oral mucosal tissues; D.V.S., M.S.A., and M.M. shared mouse strains; E.M.N.F. and Mo.S. provided clinical care and obtained saliva samples from APECED patients and healthy donors; N.M.M. obtained oral mucosal biopsies from APECED patients and healthy donors. Present address: Benaroya Research Institute at Virginia Mason, 1201 Ninth Avenue, Seattle, WA 98101, USA.
ISSN:	0036-8075 1095-9203
DOI:	10.1126/science.aay5731