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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| Veröffentlicht in: | Science (American Association for the Advancement of Science) 2021-01, Vol.371 (6526) |
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| creator | 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 |
| description | 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. |
| doi_str_mv | 10.1126/science.aay5731 |
| format | Article |
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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.</description><identifier>ISSN: 0036-8075</identifier><identifier>EISSN: 1095-9203</identifier><identifier>DOI: 10.1126/science.aay5731</identifier><identifier>PMID: 33446526</identifier><language>eng</language><publisher>United States: The American Association for the Advancement of Science</publisher><subject>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</subject><ispartof>Science (American Association for the Advancement of Science), 2021-01, Vol.371 (6526)</ispartof><rights>Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.</rights><rights>Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c487t-a095b1288efc9ccea93249faa4eb1d584f74ca6f98133aac2b8b14944b6118473</citedby><cites>FETCH-LOGICAL-c487t-a095b1288efc9ccea93249faa4eb1d584f74ca6f98133aac2b8b14944b6118473</cites><orcidid>0000-0003-2968-1156 ; 0000-0002-6978-1349 ; 0000-0002-3285-7768 ; 0000-0002-8665-7016 ; 0000-0003-1515-9586 ; 0000-0002-8880-9087 ; 0000-0001-7278-3700 ; 0000-0003-4168-4894 ; 0000-0002-5306-7781 ; 0000-0001-5894-3878 ; 0000-0001-7614-5925 ; 0000-0002-5261-6267 ; 0000-0002-4572-6417 ; 0000-0002-8722-2209 ; 0000-0002-3093-4758 ; 0000-0003-1593-671X ; 0000-0001-8343-0214 ; 0000-0002-7718-2098 ; 0000-0001-9853-7903 ; 0000-0003-0344-9447 ; 0000-0002-4759-717X ; 0000-0002-8823-0796 ; 0000-0002-7756-9831 ; 0000-0002-1080-8201 ; 0000-0003-3207-5464 ; 0000-0002-7553-0159 ; 0000-0003-1683-2015 ; 0000-0002-8335-0262 ; 0000-0001-9316-3703 ; 0000-0001-5987-7817 ; 0000-0002-7365-6735 ; 0000-0003-4284-4108 ; 0000-0001-9962-3571 ; 0000-0003-4994-9500 ; 0000-0001-7688-1439</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,776,780,881,2871,2872,27901,27902</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/33446526$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Break, Timothy J</creatorcontrib><creatorcontrib>Oikonomou, Vasileios</creatorcontrib><creatorcontrib>Dutzan, Nicolas</creatorcontrib><creatorcontrib>Desai, Jigar V</creatorcontrib><creatorcontrib>Swidergall, Marc</creatorcontrib><creatorcontrib>Freiwald, Tilo</creatorcontrib><creatorcontrib>Chauss, Daniel</creatorcontrib><creatorcontrib>Harrison, Oliver J</creatorcontrib><creatorcontrib>Alejo, Julie</creatorcontrib><creatorcontrib>Williams, Drake W</creatorcontrib><creatorcontrib>Pittaluga, Stefania</creatorcontrib><creatorcontrib>Lee, Chyi-Chia R</creatorcontrib><creatorcontrib>Bouladoux, Nicolas</creatorcontrib><creatorcontrib>Swamydas, Muthulekha</creatorcontrib><creatorcontrib>Hoffman, Kevin W</creatorcontrib><creatorcontrib>Greenwell-Wild, Teresa</creatorcontrib><creatorcontrib>Bruno, Vincent M</creatorcontrib><creatorcontrib>Rosen, Lindsey B</creatorcontrib><creatorcontrib>Lwin, Wint</creatorcontrib><creatorcontrib>Renteria, Andy</creatorcontrib><creatorcontrib>Pontejo, Sergio M</creatorcontrib><creatorcontrib>Shannon, John P</creatorcontrib><creatorcontrib>Myles, Ian A</creatorcontrib><creatorcontrib>Olbrich, Peter</creatorcontrib><creatorcontrib>Ferré, Elise M N</creatorcontrib><creatorcontrib>Schmitt, Monica</creatorcontrib><creatorcontrib>Martin, Daniel</creatorcontrib><creatorcontrib>Barber, Daniel L</creatorcontrib><creatorcontrib>Solis, Norma V</creatorcontrib><creatorcontrib>Notarangelo, Luigi D</creatorcontrib><creatorcontrib>Serreze, David V</creatorcontrib><creatorcontrib>Matsumoto, Mitsuru</creatorcontrib><creatorcontrib>Hickman, Heather D</creatorcontrib><creatorcontrib>Murphy, Philip M</creatorcontrib><creatorcontrib>Anderson, Mark S</creatorcontrib><creatorcontrib>Lim, Jean K</creatorcontrib><creatorcontrib>Holland, Steven M</creatorcontrib><creatorcontrib>Filler, Scott G</creatorcontrib><creatorcontrib>Afzali, Behdad</creatorcontrib><creatorcontrib>Belkaid, Yasmine</creatorcontrib><creatorcontrib>Moutsopoulos, Niki M</creatorcontrib><creatorcontrib>Lionakis, Michail S</creatorcontrib><creatorcontrib>Genomics and Computational Biology Core</creatorcontrib><title>Aberrant type 1 immunity drives susceptibility to mucosal fungal infections</title><title>Science (American Association for the Advancement of Science)</title><addtitle>Science</addtitle><description>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.</description><subject>Aberration</subject><subject>Adolescent</subject><subject>Adult</subject><subject>Aged</subject><subject>AIRE protein</subject><subject>Animals</subject><subject>Antigens</subject><subject>Antiinfectives and antibacterials</subject><subject>Autoantibodies</subject><subject>Autoimmune diseases</subject><subject>Bacteria</subject><subject>Candida albicans</subject><subject>Candida albicans - immunology</subject><subject>Candidiasis</subject><subject>Candidiasis, Chronic Mucocutaneous - genetics</subject><subject>Candidiasis, Chronic Mucocutaneous - immunology</subject><subject>CD4 antigen</subject><subject>CD8 antigen</subject><subject>Chronic mucocutaneous candidiasis</subject><subject>Cytokines</subject><subject>Disease</subject><subject>Disease Models, Animal</subject><subject>Dystrophy</subject><subject>Female</subject><subject>Fungal diseases</subject><subject>Fungal infections</subject><subject>Fungi</subject><subject>Fungicides</subject><subject>Hereditary diseases</subject><subject>Human tissues</subject><subject>Humans</subject><subject>Immunity</subject><subject>Immunity, Mucosal - genetics</subject><subject>Immunity, Mucosal - immunology</subject><subject>Immunologic Surveillance - genetics</subject><subject>Immunologic Surveillance - immunology</subject><subject>Immunological tolerance</subject><subject>Infections</subject><subject>Inhibition</subject><subject>Interferon</subject><subject>Interferon-gamma - genetics</subject><subject>Interleukin 17</subject><subject>Interleukin-22</subject><subject>Interleukins - genetics</subject><subject>Janus kinase</subject><subject>Janus Kinases - genetics</subject><subject>Kinases</subject><subject>Lymphocytes</subject><subject>Lymphocytes T</subject><subject>Male</subject><subject>Medical treatment</subject><subject>Mice</subject><subject>Mice, Inbred BALB C</subject><subject>Middle Aged</subject><subject>Mouth Mucosa - immunology</subject><subject>Mouth Mucosa - pathology</subject><subject>Mucosal immunity</subject><subject>Mutation</subject><subject>Pathogens</subject><subject>Patients</subject><subject>Pharmacology</subject><subject>Phenotypes</subject><subject>Polyendocrinopathies, Autoimmune - genetics</subject><subject>Polyendocrinopathies, Autoimmune - immunology</subject><subject>Receptors, Interleukin-17 - genetics</subject><subject>Signal transduction</subject><subject>Signaling</subject><subject>Signs and symptoms</subject><subject>Stat1 protein</subject><subject>STAT1 Transcription Factor - genetics</subject><subject>Surveillance</subject><subject>Susceptibility</subject><subject>T-Lymphocytes - immunology</subject><subject>Therapeutic applications</subject><subject>Tissues</subject><subject>Transcription</subject><subject>Viruses</subject><subject>Yeast</subject><subject>Yeasts</subject><subject>Young Adult</subject><subject>γ-Interferon</subject><issn>0036-8075</issn><issn>1095-9203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2021</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpdkUtLAzEUhYMotlbX7mTAjZtp85qZZCOU4gsLbnQdMmmmpswkNckU-u9NbRV1deHe7x7O4QBwieAYIVxOgjLaKj2WcltUBB2BIYK8yDmG5BgMISRlzmBVDMBZCCsI042TUzAghNKywOUQPE9r7b20MYvbtc5QZrqutyZus4U3Gx2y0Ael19HUpt1to8u6Xrkg26zp7TINYxutonE2nIOTRrZBXxzmCLzd373OHvP5y8PTbDrPFWVVzGVyUSPMmG4UV0pLTjDljZRU12hRMNpUVMmy4QwRIqXCNasR5ZTWJUKMVmQEbve6677u9EJpG71sxdqbTvqtcNKIvxdr3sXSbQQjuKwoSQI3BwHvPnodouhMStm20mrXB4FpxZIPVMCEXv9DV673NsX7oiCnkOJETfaU8i4Er5sfMwiKXVHiUJQ4FJU-rn5n-OG_myGfsgmS1Q</recordid><startdate>20210115</startdate><enddate>20210115</enddate><creator>Break, Timothy J</creator><creator>Oikonomou, 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type 1 immunity drives susceptibility to mucosal fungal infections</title><author>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</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c487t-a095b1288efc9ccea93249faa4eb1d584f74ca6f98133aac2b8b14944b6118473</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2021</creationdate><topic>Aberration</topic><topic>Adolescent</topic><topic>Adult</topic><topic>Aged</topic><topic>AIRE protein</topic><topic>Animals</topic><topic>Antigens</topic><topic>Antiinfectives and antibacterials</topic><topic>Autoantibodies</topic><topic>Autoimmune diseases</topic><topic>Bacteria</topic><topic>Candida albicans</topic><topic>Candida albicans - immunology</topic><topic>Candidiasis</topic><topic>Candidiasis, Chronic Mucocutaneous - genetics</topic><topic>Candidiasis, Chronic Mucocutaneous - immunology</topic><topic>CD4 antigen</topic><topic>CD8 antigen</topic><topic>Chronic mucocutaneous candidiasis</topic><topic>Cytokines</topic><topic>Disease</topic><topic>Disease Models, Animal</topic><topic>Dystrophy</topic><topic>Female</topic><topic>Fungal diseases</topic><topic>Fungal infections</topic><topic>Fungi</topic><topic>Fungicides</topic><topic>Hereditary diseases</topic><topic>Human tissues</topic><topic>Humans</topic><topic>Immunity</topic><topic>Immunity, Mucosal - genetics</topic><topic>Immunity, Mucosal - immunology</topic><topic>Immunologic Surveillance - genetics</topic><topic>Immunologic Surveillance - immunology</topic><topic>Immunological tolerance</topic><topic>Infections</topic><topic>Inhibition</topic><topic>Interferon</topic><topic>Interferon-gamma - genetics</topic><topic>Interleukin 17</topic><topic>Interleukin-22</topic><topic>Interleukins - genetics</topic><topic>Janus kinase</topic><topic>Janus Kinases - genetics</topic><topic>Kinases</topic><topic>Lymphocytes</topic><topic>Lymphocytes T</topic><topic>Male</topic><topic>Medical treatment</topic><topic>Mice</topic><topic>Mice, Inbred BALB C</topic><topic>Middle Aged</topic><topic>Mouth Mucosa - immunology</topic><topic>Mouth Mucosa - pathology</topic><topic>Mucosal immunity</topic><topic>Mutation</topic><topic>Pathogens</topic><topic>Patients</topic><topic>Pharmacology</topic><topic>Phenotypes</topic><topic>Polyendocrinopathies, Autoimmune - genetics</topic><topic>Polyendocrinopathies, Autoimmune - immunology</topic><topic>Receptors, Interleukin-17 - genetics</topic><topic>Signal transduction</topic><topic>Signaling</topic><topic>Signs and symptoms</topic><topic>Stat1 protein</topic><topic>STAT1 Transcription Factor - genetics</topic><topic>Surveillance</topic><topic>Susceptibility</topic><topic>T-Lymphocytes - immunology</topic><topic>Therapeutic applications</topic><topic>Tissues</topic><topic>Transcription</topic><topic>Viruses</topic><topic>Yeast</topic><topic>Yeasts</topic><topic>Young Adult</topic><topic>γ-Interferon</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Break, Timothy J</creatorcontrib><creatorcontrib>Oikonomou, Vasileios</creatorcontrib><creatorcontrib>Dutzan, Nicolas</creatorcontrib><creatorcontrib>Desai, Jigar V</creatorcontrib><creatorcontrib>Swidergall, Marc</creatorcontrib><creatorcontrib>Freiwald, Tilo</creatorcontrib><creatorcontrib>Chauss, Daniel</creatorcontrib><creatorcontrib>Harrison, Oliver J</creatorcontrib><creatorcontrib>Alejo, Julie</creatorcontrib><creatorcontrib>Williams, Drake W</creatorcontrib><creatorcontrib>Pittaluga, Stefania</creatorcontrib><creatorcontrib>Lee, Chyi-Chia R</creatorcontrib><creatorcontrib>Bouladoux, Nicolas</creatorcontrib><creatorcontrib>Swamydas, Muthulekha</creatorcontrib><creatorcontrib>Hoffman, Kevin W</creatorcontrib><creatorcontrib>Greenwell-Wild, Teresa</creatorcontrib><creatorcontrib>Bruno, Vincent M</creatorcontrib><creatorcontrib>Rosen, Lindsey B</creatorcontrib><creatorcontrib>Lwin, Wint</creatorcontrib><creatorcontrib>Renteria, Andy</creatorcontrib><creatorcontrib>Pontejo, Sergio M</creatorcontrib><creatorcontrib>Shannon, John P</creatorcontrib><creatorcontrib>Myles, Ian A</creatorcontrib><creatorcontrib>Olbrich, Peter</creatorcontrib><creatorcontrib>Ferré, Elise M N</creatorcontrib><creatorcontrib>Schmitt, Monica</creatorcontrib><creatorcontrib>Martin, Daniel</creatorcontrib><creatorcontrib>Barber, Daniel L</creatorcontrib><creatorcontrib>Solis, Norma V</creatorcontrib><creatorcontrib>Notarangelo, Luigi D</creatorcontrib><creatorcontrib>Serreze, David V</creatorcontrib><creatorcontrib>Matsumoto, Mitsuru</creatorcontrib><creatorcontrib>Hickman, Heather D</creatorcontrib><creatorcontrib>Murphy, Philip M</creatorcontrib><creatorcontrib>Anderson, Mark S</creatorcontrib><creatorcontrib>Lim, Jean K</creatorcontrib><creatorcontrib>Holland, Steven M</creatorcontrib><creatorcontrib>Filler, Scott G</creatorcontrib><creatorcontrib>Afzali, Behdad</creatorcontrib><creatorcontrib>Belkaid, Yasmine</creatorcontrib><creatorcontrib>Moutsopoulos, Niki M</creatorcontrib><creatorcontrib>Lionakis, Michail S</creatorcontrib><creatorcontrib>Genomics and Computational Biology Core</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Aluminium Industry Abstracts</collection><collection>Animal Behavior Abstracts</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Ceramic Abstracts</collection><collection>Chemoreception Abstracts</collection><collection>Computer and Information Systems Abstracts</collection><collection>Corrosion Abstracts</collection><collection>Ecology Abstracts</collection><collection>Electronics & Communications Abstracts</collection><collection>Engineered Materials Abstracts</collection><collection>Entomology Abstracts (Full archive)</collection><collection>Industrial and Applied Microbiology Abstracts (Microbiology A)</collection><collection>Materials Business File</collection><collection>Mechanical & Transportation Engineering Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Solid State and Superconductivity Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>METADEX</collection><collection>Technology Research Database</collection><collection>Environmental Sciences and Pollution Management</collection><collection>ANTE: Abstracts in New Technology & Engineering</collection><collection>Engineering Research Database</collection><collection>Aerospace Database</collection><collection>Copper Technical Reference Library</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>Materials Research Database</collection><collection>ProQuest Computer Science Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Civil Engineering Abstracts</collection><collection>Advanced Technologies Database with Aerospace</collection><collection>Computer and Information Systems Abstracts Academic</collection><collection>Computer and Information Systems Abstracts Professional</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Science (American Association for the Advancement of Science)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Break, Timothy J</au><au>Oikonomou, Vasileios</au><au>Dutzan, Nicolas</au><au>Desai, Jigar V</au><au>Swidergall, Marc</au><au>Freiwald, Tilo</au><au>Chauss, Daniel</au><au>Harrison, Oliver J</au><au>Alejo, Julie</au><au>Williams, Drake W</au><au>Pittaluga, Stefania</au><au>Lee, Chyi-Chia R</au><au>Bouladoux, Nicolas</au><au>Swamydas, Muthulekha</au><au>Hoffman, Kevin W</au><au>Greenwell-Wild, Teresa</au><au>Bruno, Vincent M</au><au>Rosen, Lindsey B</au><au>Lwin, Wint</au><au>Renteria, Andy</au><au>Pontejo, Sergio M</au><au>Shannon, John P</au><au>Myles, Ian A</au><au>Olbrich, Peter</au><au>Ferré, Elise M N</au><au>Schmitt, Monica</au><au>Martin, Daniel</au><au>Barber, Daniel L</au><au>Solis, Norma V</au><au>Notarangelo, Luigi D</au><au>Serreze, David V</au><au>Matsumoto, Mitsuru</au><au>Hickman, Heather D</au><au>Murphy, Philip M</au><au>Anderson, Mark S</au><au>Lim, Jean K</au><au>Holland, Steven M</au><au>Filler, Scott G</au><au>Afzali, Behdad</au><au>Belkaid, Yasmine</au><au>Moutsopoulos, Niki M</au><au>Lionakis, Michail S</au><aucorp>Genomics and Computational Biology Core</aucorp><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Aberrant type 1 immunity drives susceptibility to mucosal fungal infections</atitle><jtitle>Science (American Association for the Advancement of Science)</jtitle><addtitle>Science</addtitle><date>2021-01-15</date><risdate>2021</risdate><volume>371</volume><issue>6526</issue><issn>0036-8075</issn><eissn>1095-9203</eissn><abstract>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.</abstract><cop>United States</cop><pub>The American Association for the Advancement of Science</pub><pmid>33446526</pmid><doi>10.1126/science.aay5731</doi><orcidid>https://orcid.org/0000-0003-2968-1156</orcidid><orcidid>https://orcid.org/0000-0002-6978-1349</orcidid><orcidid>https://orcid.org/0000-0002-3285-7768</orcidid><orcidid>https://orcid.org/0000-0002-8665-7016</orcidid><orcidid>https://orcid.org/0000-0003-1515-9586</orcidid><orcidid>https://orcid.org/0000-0002-8880-9087</orcidid><orcidid>https://orcid.org/0000-0001-7278-3700</orcidid><orcidid>https://orcid.org/0000-0003-4168-4894</orcidid><orcidid>https://orcid.org/0000-0002-5306-7781</orcidid><orcidid>https://orcid.org/0000-0001-5894-3878</orcidid><orcidid>https://orcid.org/0000-0001-7614-5925</orcidid><orcidid>https://orcid.org/0000-0002-5261-6267</orcidid><orcidid>https://orcid.org/0000-0002-4572-6417</orcidid><orcidid>https://orcid.org/0000-0002-8722-2209</orcidid><orcidid>https://orcid.org/0000-0002-3093-4758</orcidid><orcidid>https://orcid.org/0000-0003-1593-671X</orcidid><orcidid>https://orcid.org/0000-0001-8343-0214</orcidid><orcidid>https://orcid.org/0000-0002-7718-2098</orcidid><orcidid>https://orcid.org/0000-0001-9853-7903</orcidid><orcidid>https://orcid.org/0000-0003-0344-9447</orcidid><orcidid>https://orcid.org/0000-0002-4759-717X</orcidid><orcidid>https://orcid.org/0000-0002-8823-0796</orcidid><orcidid>https://orcid.org/0000-0002-7756-9831</orcidid><orcidid>https://orcid.org/0000-0002-1080-8201</orcidid><orcidid>https://orcid.org/0000-0003-3207-5464</orcidid><orcidid>https://orcid.org/0000-0002-7553-0159</orcidid><orcidid>https://orcid.org/0000-0003-1683-2015</orcidid><orcidid>https://orcid.org/0000-0002-8335-0262</orcidid><orcidid>https://orcid.org/0000-0001-9316-3703</orcidid><orcidid>https://orcid.org/0000-0001-5987-7817</orcidid><orcidid>https://orcid.org/0000-0002-7365-6735</orcidid><orcidid>https://orcid.org/0000-0003-4284-4108</orcidid><orcidid>https://orcid.org/0000-0001-9962-3571</orcidid><orcidid>https://orcid.org/0000-0003-4994-9500</orcidid><orcidid>https://orcid.org/0000-0001-7688-1439</orcidid><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0036-8075 |
| ispartof | Science (American Association for the Advancement of Science), 2021-01, Vol.371 (6526) |
| issn | 0036-8075 1095-9203 |
| language | eng |
| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_8326743 |
| source | American Association for the Advancement of Science; MEDLINE |
| 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 |
| title | Aberrant type 1 immunity drives susceptibility to mucosal fungal infections |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-21T20%3A32%3A35IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Aberrant%20type%201%20immunity%20drives%20susceptibility%20to%20mucosal%20fungal%20infections&rft.jtitle=Science%20(American%20Association%20for%20the%20Advancement%20of%20Science)&rft.au=Break,%20Timothy%20J&rft.aucorp=Genomics%20and%20Computational%20Biology%20Core&rft.date=2021-01-15&rft.volume=371&rft.issue=6526&rft.issn=0036-8075&rft.eissn=1095-9203&rft_id=info:doi/10.1126/science.aay5731&rft_dat=%3Cproquest_pubme%3E2478584150%3C/proquest_pubme%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2478094042&rft_id=info:pmid/33446526&rfr_iscdi=true |