Candida Albicans Elicits Protective Allergic Responses Via Platelet Mediated T helper 2 and T helper 17 Cell Polarization

Yifan Wu; Zhimin  Zeng; Yubiao  Guo; Lizhen  Song; Jill E.  Weatherhead; Xinyan Huang; Yuying  Zeng; Lynn  Bimler; Cheng-yen  Chang; John M. Knight; Christian  Valladolid; Hua  Sun; Miguel A. Cruz; Bernhard Hube; Julian R. Naglik; Amber U. Luong; Farrah Kheradmand; David B.  Corry

doi:10.1016/j.immuni.2021.08.009

Candida Albicans Elicits Protective Allergic Responses Via Platelet Mediated T helper 2 and T helper 17 Cell Polarization

Yifan Wu, Zhimin Zeng, Yubiao Guo, Lizhen Song, Jill E. Weatherhead, Xinyan Huang, Yuying Zeng, Lynn Bimler, Cheng-yen Chang, John M. Knight, Christian Valladolid, Hua Sun, Miguel A. Cruz, Bernhard Hube, Julian R. Naglik, Amber U. Luong, Farrah Kheradmand, David B. Corry

Centre for Host Microbiome Interactions

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Abstract

Fungal airway infection (airway mycosis) is an important cause of allergic airway diseases such as asthma, but the mechanisms by which fungi trigger asthmatic reactions are poorly understood. Here, we leverage wild-type and mutant Candida albicans to determine how this common fungus elicits characteristic Th2 and Th17 cell-dependent allergic airway disease in mice. We demonstrate that rather than proteinases that are essential virulence factors for molds, C. albicans instead promoted allergic airway disease through the peptide toxin candidalysin. Candidalysin activated platelets through the Von Willebrand factor (VWF) receptor GP1bα to release the Wnt antagonist Dickkopf-1 (Dkk-1) to drive Th2 and Th17 cell responses that correlated with reduced lung fungal burdens. Platelets simultaneously precluded lethal pulmonary hemorrhage resulting from fungal lung invasion. Thus, in addition to hemostasis, platelets promoted protection against C. albicans airway mycosis through an antifungal pathway involving candidalysin, GP1bα, and Dkk-1 that promotes Th2 and Th17 responses.

Original language	English
Pages (from-to)	2595-2610.e7
Journal	Immunity
Volume	54
Issue number	11
Early online date	9 Sept 2021
DOIs	https://doi.org/10.1016/j.immuni.2021.08.009
Publication status	Published - 9 Nov 2021

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10.1016/j.immuni.2021.08.009

Candida Albicans Elicits Protective_WU_Accepted2021_GREEN AAMAccepted author manuscript, 16.9 MB

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Wu, Y., Zeng, Z., Guo, Y., Song, L., Weatherhead, J. E., Huang, X., Zeng, Y., Bimler, L., Chang, C., Knight, J. M., Valladolid, C., Sun, H., Cruz, M. A., Hube, B., Naglik, J. R., Luong, A. U., Kheradmand, F., & Corry, D. B. (2021). Candida Albicans Elicits Protective Allergic Responses Via Platelet Mediated T helper 2 and T helper 17 Cell Polarization. Immunity, 54(11), 2595-2610.e7. https://doi.org/10.1016/j.immuni.2021.08.009

@article{0c1f33231ee74481a95d56309a54d3eb,

title = "Candida Albicans Elicits Protective Allergic Responses Via Platelet Mediated T helper 2 and T helper 17 Cell Polarization",

abstract = "Fungal airway infection (airway mycosis) is an important cause of allergic airway diseases such as asthma, but the mechanisms by which fungi trigger asthmatic reactions are poorly understood. Here, we leverage wild-type and mutant Candida albicans to determine how this common fungus elicits characteristic Th2 and Th17 cell-dependent allergic airway disease in mice. We demonstrate that rather than proteinases that are essential virulence factors for molds, C. albicans instead promoted allergic airway disease through the peptide toxin candidalysin. Candidalysin activated platelets through the Von Willebrand factor (VWF) receptor GP1bα to release the Wnt antagonist Dickkopf-1 (Dkk-1) to drive Th2 and Th17 cell responses that correlated with reduced lung fungal burdens. Platelets simultaneously precluded lethal pulmonary hemorrhage resulting from fungal lung invasion. Thus, in addition to hemostasis, platelets promoted protection against C. albicans airway mycosis through an antifungal pathway involving candidalysin, GP1bα, and Dkk-1 that promotes Th2 and Th17 responses.",

author = "Yifan Wu and Zhimin Zeng and Yubiao Guo and Lizhen Song and Weatherhead, {Jill E.} and Xinyan Huang and Yuying Zeng and Lynn Bimler and Cheng-yen Chang and Knight, {John M.} and Christian Valladolid and Hua Sun and Cruz, {Miguel A.} and Bernhard Hube and Naglik, {Julian R.} and Luong, {Amber U.} and Farrah Kheradmand and Corry, {David B.}",

note = "Funding Information: The content is solely the responsibility of the authors and does not necessarily represent the official views of the United States National Institutes of Health or the Veterans Administration Office of Research and Development. The authors thank Katherine Polsky for technical assistance. This work was supported by US National Institutes of Health grants T32AI053831 , R01HL117181 , HL140398 , R01AI135803 , and R41AI124997 ; VA Office of Research and Development grant I01BX004828 ; the National Natural Science Foundation of China grant 81770024 ; and the Project of Department of Finance of Guangdong Province grant 20160907 . This project was further supported by the Cytometry and Cell Sorting Core at Baylor College of Medicine with funding from the CPRIT Core Facility Support Award ( CPRIT-RP180672 ), the NIH ( CA125123 and RR024574 ), and the assistance of Joel M. Sederstrom . J.R.N was supported by grants from the Wellcome Trust ( 214229_Z_18_Z ), National Institutes of Health ( R37-DE022550 ), the NIH Research at Guys and St. Thomas{\textquoteright}s NHS Foundation Trust, and the King{\textquoteright}s College London Biomedical Research Centre ( IS-BRC-1215-20006 ). B.H. was supported by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germany{\textquoteright}s Excellence Strategy (Balance of the Microverse Cluster – EXC 2051 – Project-ID 390713860 ) and the Collaborative Research Centre CRC/TR 124 FungiNet project C1 . All illustrative figures were generated at biorender.com . Funding Information: The content is solely the responsibility of the authors and does not necessarily represent the official views of the United States National Institutes of Health or the Veterans Administration Office of Research and Development. The authors thank Katherine Polsky for technical assistance. This work was supported by US National Institutes of Health grants T32AI053831, R01HL117181, HL140398, R01AI135803, and R41AI124997; VA Office of Research and Development grant I01BX004828; the National Natural Science Foundation of China grant 81770024; and the Project of Department of Finance of Guangdong Province grant 20160907. This project was further supported by the Cytometry and Cell Sorting Core at Baylor College of Medicine with funding from the CPRIT Core Facility Support Award (CPRIT-RP180672), the NIH (CA125123 and RR024574), and the assistance of Joel M. Sederstrom. J.R.N was supported by grants from the Wellcome Trust (214229_Z_18_Z), National Institutes of Health (R37-DE022550), the NIH Research at Guys and St. Thomas's NHS Foundation Trust, and the King's College London Biomedical Research Centre (IS-BRC-1215-20006). B.H. was supported by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germany's Excellence Strategy (Balance of the Microverse Cluster ? EXC 2051 ? Project-ID 390713860) and the Collaborative Research Centre CRC/TR 124 FungiNet project C1. All illustrative figures were generated at biorender.com. D.B.C. and F.K. conceived, designed, and supervised the project. Y.W. and Z.Z. performed essential experiments, analyzed data, and wrote initial manuscript draft. L.S. J.E.W. X.H. Y.Z. L.B. C.-Y.C. and J.M.K. performed essential experiments. C.V. M.A.C. B.H. A.U.L. and J.R.N. provided essential reagents and technical advice. All authors edited the manuscript. D.B.C is a scientific consultant to Atrapos Therapeutics, LLC and Pulmocide, LLC. We worked to ensure gender balance in the recruitment of human subjects. We worked to ensure ethnic or other types of diversity in the recruitment of human subjects. We worked to ensure sex balance in the selection of non-human subjects. One or more of the authors of this paper self-identifies as an underrepresented ethnic minority in science. The author list of this paper includes contributors from the location where the research was conducted who participated in the data collection, design, analysis, and/or interpretation of the work. Publisher Copyright: {\textcopyright} 2021 Elsevier Inc.",

year = "2021",

month = nov,

day = "9",

doi = "10.1016/j.immuni.2021.08.009",

language = "English",

volume = "54",

pages = "2595--2610.e7",

journal = "Immunity",

issn = "1074-7613",

publisher = "Cell Press",

number = "11",

}

Wu, Y, Zeng, Z, Guo, Y, Song, L, Weatherhead, JE, Huang, X, Zeng, Y, Bimler, L, Chang, C, Knight, JM, Valladolid, C, Sun, H, Cruz, MA, Hube, B, Naglik, JR, Luong, AU, Kheradmand, F & Corry, DB 2021, 'Candida Albicans Elicits Protective Allergic Responses Via Platelet Mediated T helper 2 and T helper 17 Cell Polarization', Immunity, vol. 54, no. 11, pp. 2595-2610.e7. https://doi.org/10.1016/j.immuni.2021.08.009

TY - JOUR

T1 - Candida Albicans Elicits Protective Allergic Responses Via Platelet Mediated T helper 2 and T helper 17 Cell Polarization

AU - Wu, Yifan

AU - Zeng, Zhimin

AU - Guo, Yubiao

AU - Song, Lizhen

AU - Weatherhead, Jill E.

AU - Huang, Xinyan

AU - Zeng, Yuying

AU - Bimler, Lynn

AU - Chang, Cheng-yen

AU - Knight, John M.

AU - Valladolid, Christian

AU - Sun, Hua

AU - Cruz, Miguel A.

AU - Hube, Bernhard

AU - Naglik, Julian R.

AU - Luong, Amber U.

AU - Kheradmand, Farrah

AU - Corry, David B.

N1 - Funding Information: The content is solely the responsibility of the authors and does not necessarily represent the official views of the United States National Institutes of Health or the Veterans Administration Office of Research and Development. The authors thank Katherine Polsky for technical assistance. This work was supported by US National Institutes of Health grants T32AI053831 , R01HL117181 , HL140398 , R01AI135803 , and R41AI124997 ; VA Office of Research and Development grant I01BX004828 ; the National Natural Science Foundation of China grant 81770024 ; and the Project of Department of Finance of Guangdong Province grant 20160907 . This project was further supported by the Cytometry and Cell Sorting Core at Baylor College of Medicine with funding from the CPRIT Core Facility Support Award ( CPRIT-RP180672 ), the NIH ( CA125123 and RR024574 ), and the assistance of Joel M. Sederstrom . J.R.N was supported by grants from the Wellcome Trust ( 214229_Z_18_Z ), National Institutes of Health ( R37-DE022550 ), the NIH Research at Guys and St. Thomas’s NHS Foundation Trust, and the King’s College London Biomedical Research Centre ( IS-BRC-1215-20006 ). B.H. was supported by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germany’s Excellence Strategy (Balance of the Microverse Cluster – EXC 2051 – Project-ID 390713860 ) and the Collaborative Research Centre CRC/TR 124 FungiNet project C1 . All illustrative figures were generated at biorender.com . Funding Information: The content is solely the responsibility of the authors and does not necessarily represent the official views of the United States National Institutes of Health or the Veterans Administration Office of Research and Development. The authors thank Katherine Polsky for technical assistance. This work was supported by US National Institutes of Health grants T32AI053831, R01HL117181, HL140398, R01AI135803, and R41AI124997; VA Office of Research and Development grant I01BX004828; the National Natural Science Foundation of China grant 81770024; and the Project of Department of Finance of Guangdong Province grant 20160907. This project was further supported by the Cytometry and Cell Sorting Core at Baylor College of Medicine with funding from the CPRIT Core Facility Support Award (CPRIT-RP180672), the NIH (CA125123 and RR024574), and the assistance of Joel M. Sederstrom. J.R.N was supported by grants from the Wellcome Trust (214229_Z_18_Z), National Institutes of Health (R37-DE022550), the NIH Research at Guys and St. Thomas's NHS Foundation Trust, and the King's College London Biomedical Research Centre (IS-BRC-1215-20006). B.H. was supported by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germany's Excellence Strategy (Balance of the Microverse Cluster ? EXC 2051 ? Project-ID 390713860) and the Collaborative Research Centre CRC/TR 124 FungiNet project C1. All illustrative figures were generated at biorender.com. D.B.C. and F.K. conceived, designed, and supervised the project. Y.W. and Z.Z. performed essential experiments, analyzed data, and wrote initial manuscript draft. L.S. J.E.W. X.H. Y.Z. L.B. C.-Y.C. and J.M.K. performed essential experiments. C.V. M.A.C. B.H. A.U.L. and J.R.N. provided essential reagents and technical advice. All authors edited the manuscript. D.B.C is a scientific consultant to Atrapos Therapeutics, LLC and Pulmocide, LLC. We worked to ensure gender balance in the recruitment of human subjects. We worked to ensure ethnic or other types of diversity in the recruitment of human subjects. We worked to ensure sex balance in the selection of non-human subjects. One or more of the authors of this paper self-identifies as an underrepresented ethnic minority in science. The author list of this paper includes contributors from the location where the research was conducted who participated in the data collection, design, analysis, and/or interpretation of the work. Publisher Copyright: © 2021 Elsevier Inc.

PY - 2021/11/9

Y1 - 2021/11/9

N2 - Fungal airway infection (airway mycosis) is an important cause of allergic airway diseases such as asthma, but the mechanisms by which fungi trigger asthmatic reactions are poorly understood. Here, we leverage wild-type and mutant Candida albicans to determine how this common fungus elicits characteristic Th2 and Th17 cell-dependent allergic airway disease in mice. We demonstrate that rather than proteinases that are essential virulence factors for molds, C. albicans instead promoted allergic airway disease through the peptide toxin candidalysin. Candidalysin activated platelets through the Von Willebrand factor (VWF) receptor GP1bα to release the Wnt antagonist Dickkopf-1 (Dkk-1) to drive Th2 and Th17 cell responses that correlated with reduced lung fungal burdens. Platelets simultaneously precluded lethal pulmonary hemorrhage resulting from fungal lung invasion. Thus, in addition to hemostasis, platelets promoted protection against C. albicans airway mycosis through an antifungal pathway involving candidalysin, GP1bα, and Dkk-1 that promotes Th2 and Th17 responses.

AB - Fungal airway infection (airway mycosis) is an important cause of allergic airway diseases such as asthma, but the mechanisms by which fungi trigger asthmatic reactions are poorly understood. Here, we leverage wild-type and mutant Candida albicans to determine how this common fungus elicits characteristic Th2 and Th17 cell-dependent allergic airway disease in mice. We demonstrate that rather than proteinases that are essential virulence factors for molds, C. albicans instead promoted allergic airway disease through the peptide toxin candidalysin. Candidalysin activated platelets through the Von Willebrand factor (VWF) receptor GP1bα to release the Wnt antagonist Dickkopf-1 (Dkk-1) to drive Th2 and Th17 cell responses that correlated with reduced lung fungal burdens. Platelets simultaneously precluded lethal pulmonary hemorrhage resulting from fungal lung invasion. Thus, in addition to hemostasis, platelets promoted protection against C. albicans airway mycosis through an antifungal pathway involving candidalysin, GP1bα, and Dkk-1 that promotes Th2 and Th17 responses.

UR - http://www.scopus.com/inward/record.url?scp=85118530497&partnerID=8YFLogxK

U2 - 10.1016/j.immuni.2021.08.009

DO - 10.1016/j.immuni.2021.08.009

M3 - Article

SN - 1074-7613

VL - 54

SP - 2595-2610.e7

JO - Immunity

JF - Immunity

IS - 11

ER -

Candida Albicans Elicits Protective Allergic Responses Via Platelet Mediated T helper 2 and T helper 17 Cell Polarization

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