Immune regulation by fungal strain diversity in inflammatory bowel disease

Xin V. Li; Irina  Leonardi; Gregory G.  Putzel; Alexa  Semon; William D.  Fiers; Takato  Kusakabe; Woan-Yu  Lin; Iris H.  Gao; Itai  Doron; Alejandra  Gutierrez-Guerrero; Meghan Bialt  DeCelie; Marissa  Mesko; Yang  Chen; Julian R. Naglik; Bernhard Hube; Ellen J.   Scherl; Iliyan D.  Iliev

doi:10.1038/s41586-022-04502-w

Immune regulation by fungal strain diversity in inflammatory bowel disease

Xin V. Li, Irina Leonardi, Gregory G. Putzel, Alexa Semon, William D. Fiers, Takato Kusakabe, Woan-Yu Lin, Iris H. Gao, Itai Doron, Alejandra Gutierrez-Guerrero, Meghan Bialt DeCelie, Marissa Mesko, Yang Chen, Julian R. Naglik, Bernhard Hube, Ellen J. Scherl, Iliyan D. Iliev

Centre for Host Microbiome Interactions

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Abstract

The fungal microbiota (mycobiota) is an integral part of the complex multikingdom microbial community colonizing the mammalian gastrointestinal tract and has an important role in immune regulation1,2,3,4,5,6. Although aberrant changes in the mycobiota have been linked to several diseases, including inflammatory bowel disease3,4,5,6,7,8,9, it is currently unknown whether fungal species captured by deep sequencing represent living organisms and whether specific fungi have functional consequences for disease development in affected individuals. Here we developed a translational platform for the functional analysis of the mycobiome at the fungal-strain- and patient-specific level. Combining high-resolution mycobiota sequencing, fungal culturomics and genomics, a CRISPR–Cas9-based fungal strain editing system, in vitro functional immunoreactivity assays and in vivo models, this platform enables the examination of host–fungal crosstalk in the human gut. We discovered a rich genetic diversity of opportunistic Candida albicans strains that dominate the colonic mucosa of patients with inflammatory bowel disease. Among these human-gut-derived isolates, strains with high immune-cell-damaging capacity (HD strains) reflect the disease features of individual patients with ulcerative colitis and aggravated intestinal inflammation in vivo through IL-1β-dependent mechanisms. Niche-specific inflammatory immunity and interleukin-17A-producing T helper cell (TH17 cell) antifungal responses by HD strains in the gut were dependent on the C. albicans-secreted peptide toxin candidalysin during the transition from a benign commensal to a pathobiont state. These findings reveal the strain-specific nature of host–fungal interactions in the human gut and highlight new diagnostic and therapeutic targets for diseases of inflammatory origin.

Original language	English
Pages (from-to)	672-678
Number of pages	7
Journal	NATURE
Volume	603
Issue number	7902
Early online date	16 Mar 2022
DOIs	https://doi.org/10.1038/s41586-022-04502-w
Publication status	Published - 24 Mar 2022

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Fungal strain-level diversity_LI_Accepted22October2021_GREEN AAMAccepted author manuscript, 2.08 MB

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Li, X. V., Leonardi, I., Putzel, G. G., Semon, A., Fiers, W. D., Kusakabe, T., Lin, W.-Y., Gao, I. H., Doron, I., Gutierrez-Guerrero, A., DeCelie, M. B., Mesko, M., Chen, Y., Naglik, J. R., Hube, B., Scherl, E. J., & Iliev, I. D. (2022). Immune regulation by fungal strain diversity in inflammatory bowel disease. NATURE, 603(7902), 672-678. https://doi.org/10.1038/s41586-022-04502-w

@article{b6cc3903a6784ec5b9df57dcaa1eda45,

title = "Immune regulation by fungal strain diversity in inflammatory bowel disease",

abstract = "The fungal microbiota (mycobiota) is an integral part of the complex multikingdom microbial community colonizing the mammalian gastrointestinal tract and has an important role in immune regulation1,2,3,4,5,6. Although aberrant changes in the mycobiota have been linked to several diseases, including inflammatory bowel disease3,4,5,6,7,8,9, it is currently unknown whether fungal species captured by deep sequencing represent living organisms and whether specific fungi have functional consequences for disease development in affected individuals. Here we developed a translational platform for the functional analysis of the mycobiome at the fungal-strain- and patient-specific level. Combining high-resolution mycobiota sequencing, fungal culturomics and genomics, a CRISPR–Cas9-based fungal strain editing system, in vitro functional immunoreactivity assays and in vivo models, this platform enables the examination of host–fungal crosstalk in the human gut. We discovered a rich genetic diversity of opportunistic Candida albicans strains that dominate the colonic mucosa of patients with inflammatory bowel disease. Among these human-gut-derived isolates, strains with high immune-cell-damaging capacity (HD strains) reflect the disease features of individual patients with ulcerative colitis and aggravated intestinal inflammation in vivo through IL-1β-dependent mechanisms. Niche-specific inflammatory immunity and interleukin-17A-producing T helper cell (TH17 cell) antifungal responses by HD strains in the gut were dependent on the C. albicans-secreted peptide toxin candidalysin during the transition from a benign commensal to a pathobiont state. These findings reveal the strain-specific nature of host–fungal interactions in the human gut and highlight new diagnostic and therapeutic targets for diseases of inflammatory origin.",

author = "Li, {Xin V.} and Irina Leonardi and Putzel, {Gregory G.} and Alexa Semon and Fiers, {William D.} and Takato Kusakabe and Woan-Yu Lin and Gao, {Iris H.} and Itai Doron and Alejandra Gutierrez-Guerrero and DeCelie, {Meghan Bialt} and Marissa Mesko and Yang Chen and Naglik, {Julian R.} and Bernhard Hube and Scherl, {Ellen J.} and Iliev, {Iliyan D.}",

note = "Funding Information: We thank the members of the Iliev laboratory for suggestions relating to the manuscript; W. Jin and C. Guo, who shared cloning reagents and equipment; G. Fink, V. K. Vyas and D. A. Bernstein for providing plasmids and protocols and all contributing members of the JRI IBD Live Cell Bank Consortium; and the staff at the Microbiome Core Laboratory of Weill Cornell Medicine. Support for sample acquisition through the JRI IBD Live Cell Bank is provided by the JRI, Jill Roberts Center for IBD, Cure for IBD, the Rosanne H. Silbermann Foundation and Weill Cornell Medicine Division of Pediatric Gastroenterology and Nutrition. X.V.L. is supported by fellowship from the Charles H. Revson Foundation. I.L. is supported by fellowships from the Crohn?s and Colitis Foundation (568319). W.D.F. is supported by a fellowship from the NIH (F32DK120228). J.R.N is supported by the Wellcome Trust (214229_Z_18_Z), NIH (R37-DE022550) and IS-BRC-1215-20006. B.H. is supported by the German Research Foundation (Deutsche Forschungsgemeinschaft, DFG) within the Cluster of Excellence ?Balance of the Microverse?, under Germany?s Excellence Strategy, EXC 2051, Project-ID 390713860. Research in the Iliev laboratory is supported by US National Institutes of Health (R01DK113136, R01DK121977, R21AI146957 and R01AI163007), the Irma T. Hirschl Career Scientist Award, the Kenneth Rainin Foundation, the Crohn?s and Colitis Foundation, the Leona M. and Harry B. Helmsley Charitable Trust and the?Burroughs Wellcome Fund Investigators in the Pathogenesis of Infectious Disease (PATH) Award. Funding Information: We thank the members of the Iliev laboratory for suggestions relating to the manuscript; W. Jin and C. Guo, who shared cloning reagents and equipment; G. Fink, V. K. Vyas and D. A. Bernstein for providing plasmids and protocols and all contributing members of the JRI IBD Live Cell Bank Consortium; and the staff at the Microbiome Core Laboratory of Weill Cornell Medicine. Support for sample acquisition through the JRI IBD Live Cell Bank is provided by the JRI, Jill Roberts Center for IBD, Cure for IBD, the Rosanne H. Silbermann Foundation and Weill Cornell Medicine Division of Pediatric Gastroenterology and Nutrition. X.V.L. is supported by fellowship from the Charles H. Revson Foundation. I.L. is supported by fellowships from the Crohn{\textquoteright}s and Colitis Foundation (568319). W.D.F. is supported by a fellowship from the NIH (F32DK120228). J.R.N is supported by the Wellcome Trust (214229_Z_18_Z), NIH (R37-DE022550) and IS-BRC-1215-20006. B.H. is supported by the German Research Foundation (Deutsche Forschungsgemeinschaft, DFG) within the Cluster of Excellence {\textquoteleft}Balance of the Microverse{\textquoteright}, under Germany{\textquoteright}s Excellence Strategy, EXC 2051, Project-ID 390713860. Research in the Iliev laboratory is supported by US National Institutes of Health (R01DK113136, R01DK121977, R21AI146957 and R01AI163007), the Irma T. Hirschl Career Scientist Award, the Kenneth Rainin Foundation, the Crohn{\textquoteright}s and Colitis Foundation, the Leona M. and Harry B. Helmsley Charitable Trust and the Burroughs Wellcome Fund Investigators in the Pathogenesis of Infectious Disease (PATH) Award. Publisher Copyright: {\textcopyright} 2022, The Author(s), under exclusive licence to Springer Nature Limited.",

year = "2022",

month = mar,

day = "24",

doi = "10.1038/s41586-022-04502-w",

language = "English",

volume = "603",

pages = "672--678",

journal = "NATURE",

issn = "0028-0836",

publisher = "Nature Publishing Group",

number = "7902",

}

TY - JOUR

T1 - Immune regulation by fungal strain diversity in inflammatory bowel disease

AU - Li, Xin V.

AU - Leonardi, Irina

AU - Putzel, Gregory G.

AU - Semon, Alexa

AU - Fiers, William D.

AU - Kusakabe, Takato

AU - Lin, Woan-Yu

AU - Gao, Iris H.

AU - Doron, Itai

AU - Gutierrez-Guerrero, Alejandra

AU - DeCelie, Meghan Bialt

AU - Mesko, Marissa

AU - Chen, Yang

AU - Naglik, Julian R.

AU - Hube, Bernhard

AU - Scherl, Ellen J.

AU - Iliev, Iliyan D.

N1 - Funding Information: We thank the members of the Iliev laboratory for suggestions relating to the manuscript; W. Jin and C. Guo, who shared cloning reagents and equipment; G. Fink, V. K. Vyas and D. A. Bernstein for providing plasmids and protocols and all contributing members of the JRI IBD Live Cell Bank Consortium; and the staff at the Microbiome Core Laboratory of Weill Cornell Medicine. Support for sample acquisition through the JRI IBD Live Cell Bank is provided by the JRI, Jill Roberts Center for IBD, Cure for IBD, the Rosanne H. Silbermann Foundation and Weill Cornell Medicine Division of Pediatric Gastroenterology and Nutrition. X.V.L. is supported by fellowship from the Charles H. Revson Foundation. I.L. is supported by fellowships from the Crohn?s and Colitis Foundation (568319). W.D.F. is supported by a fellowship from the NIH (F32DK120228). J.R.N is supported by the Wellcome Trust (214229_Z_18_Z), NIH (R37-DE022550) and IS-BRC-1215-20006. B.H. is supported by the German Research Foundation (Deutsche Forschungsgemeinschaft, DFG) within the Cluster of Excellence ?Balance of the Microverse?, under Germany?s Excellence Strategy, EXC 2051, Project-ID 390713860. Research in the Iliev laboratory is supported by US National Institutes of Health (R01DK113136, R01DK121977, R21AI146957 and R01AI163007), the Irma T. Hirschl Career Scientist Award, the Kenneth Rainin Foundation, the Crohn?s and Colitis Foundation, the Leona M. and Harry B. Helmsley Charitable Trust and the?Burroughs Wellcome Fund Investigators in the Pathogenesis of Infectious Disease (PATH) Award. Funding Information: We thank the members of the Iliev laboratory for suggestions relating to the manuscript; W. Jin and C. Guo, who shared cloning reagents and equipment; G. Fink, V. K. Vyas and D. A. Bernstein for providing plasmids and protocols and all contributing members of the JRI IBD Live Cell Bank Consortium; and the staff at the Microbiome Core Laboratory of Weill Cornell Medicine. Support for sample acquisition through the JRI IBD Live Cell Bank is provided by the JRI, Jill Roberts Center for IBD, Cure for IBD, the Rosanne H. Silbermann Foundation and Weill Cornell Medicine Division of Pediatric Gastroenterology and Nutrition. X.V.L. is supported by fellowship from the Charles H. Revson Foundation. I.L. is supported by fellowships from the Crohn’s and Colitis Foundation (568319). W.D.F. is supported by a fellowship from the NIH (F32DK120228). J.R.N is supported by the Wellcome Trust (214229_Z_18_Z), NIH (R37-DE022550) and IS-BRC-1215-20006. B.H. is supported by the German Research Foundation (Deutsche Forschungsgemeinschaft, DFG) within the Cluster of Excellence ‘Balance of the Microverse’, under Germany’s Excellence Strategy, EXC 2051, Project-ID 390713860. Research in the Iliev laboratory is supported by US National Institutes of Health (R01DK113136, R01DK121977, R21AI146957 and R01AI163007), the Irma T. Hirschl Career Scientist Award, the Kenneth Rainin Foundation, the Crohn’s and Colitis Foundation, the Leona M. and Harry B. Helmsley Charitable Trust and the Burroughs Wellcome Fund Investigators in the Pathogenesis of Infectious Disease (PATH) Award. Publisher Copyright: © 2022, The Author(s), under exclusive licence to Springer Nature Limited.

PY - 2022/3/24

Y1 - 2022/3/24

N2 - The fungal microbiota (mycobiota) is an integral part of the complex multikingdom microbial community colonizing the mammalian gastrointestinal tract and has an important role in immune regulation1,2,3,4,5,6. Although aberrant changes in the mycobiota have been linked to several diseases, including inflammatory bowel disease3,4,5,6,7,8,9, it is currently unknown whether fungal species captured by deep sequencing represent living organisms and whether specific fungi have functional consequences for disease development in affected individuals. Here we developed a translational platform for the functional analysis of the mycobiome at the fungal-strain- and patient-specific level. Combining high-resolution mycobiota sequencing, fungal culturomics and genomics, a CRISPR–Cas9-based fungal strain editing system, in vitro functional immunoreactivity assays and in vivo models, this platform enables the examination of host–fungal crosstalk in the human gut. We discovered a rich genetic diversity of opportunistic Candida albicans strains that dominate the colonic mucosa of patients with inflammatory bowel disease. Among these human-gut-derived isolates, strains with high immune-cell-damaging capacity (HD strains) reflect the disease features of individual patients with ulcerative colitis and aggravated intestinal inflammation in vivo through IL-1β-dependent mechanisms. Niche-specific inflammatory immunity and interleukin-17A-producing T helper cell (TH17 cell) antifungal responses by HD strains in the gut were dependent on the C. albicans-secreted peptide toxin candidalysin during the transition from a benign commensal to a pathobiont state. These findings reveal the strain-specific nature of host–fungal interactions in the human gut and highlight new diagnostic and therapeutic targets for diseases of inflammatory origin.

AB - The fungal microbiota (mycobiota) is an integral part of the complex multikingdom microbial community colonizing the mammalian gastrointestinal tract and has an important role in immune regulation1,2,3,4,5,6. Although aberrant changes in the mycobiota have been linked to several diseases, including inflammatory bowel disease3,4,5,6,7,8,9, it is currently unknown whether fungal species captured by deep sequencing represent living organisms and whether specific fungi have functional consequences for disease development in affected individuals. Here we developed a translational platform for the functional analysis of the mycobiome at the fungal-strain- and patient-specific level. Combining high-resolution mycobiota sequencing, fungal culturomics and genomics, a CRISPR–Cas9-based fungal strain editing system, in vitro functional immunoreactivity assays and in vivo models, this platform enables the examination of host–fungal crosstalk in the human gut. We discovered a rich genetic diversity of opportunistic Candida albicans strains that dominate the colonic mucosa of patients with inflammatory bowel disease. Among these human-gut-derived isolates, strains with high immune-cell-damaging capacity (HD strains) reflect the disease features of individual patients with ulcerative colitis and aggravated intestinal inflammation in vivo through IL-1β-dependent mechanisms. Niche-specific inflammatory immunity and interleukin-17A-producing T helper cell (TH17 cell) antifungal responses by HD strains in the gut were dependent on the C. albicans-secreted peptide toxin candidalysin during the transition from a benign commensal to a pathobiont state. These findings reveal the strain-specific nature of host–fungal interactions in the human gut and highlight new diagnostic and therapeutic targets for diseases of inflammatory origin.

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U2 - 10.1038/s41586-022-04502-w

DO - 10.1038/s41586-022-04502-w

M3 - Article

AN - SCOPUS:85126355141

SN - 0028-0836

VL - 603

SP - 672

EP - 678

JO - NATURE

JF - NATURE

IS - 7902

ER -

Immune regulation by fungal strain diversity in inflammatory bowel disease

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