The protective effect of inflammatory monocytes during systemic C. albicans infection is dependent on collaboration between C-type lectin-like receptors

Thompson, Aiysha; Davies, Luke; Liao, Chia-Te; da, Diogo M.; Griffiths, James S.; Andrews, Robert; Jones, Adam V.; Clement, Mathew; Brown, Gordon D.; Humphreys, Ian R.; Taylor, Philip R.; Orr, Selinda J.

doi:10.1371/journal.ppat.1007850

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The protective effect of inflammatory monocytes during systemic C. albicans infection is dependent on collaboration between C-type lectin-like receptors

Aiysha Thompson

, Luke Davies

, Chia-Te Liao

, Diogo M. da Fonseca

, James S. Griffiths, Robert Andrews

, Adam V. Jones, Mathew Clement

, Gordon D. Brown, Ian R. Humphreys

, Philip R. Taylor, Selinda J. Orr

PLOS Pathogens, Volume: 15, Issue: 6, Start page: e1007850

Swansea University Author: Luke Davies

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DOI (Published version): 10.1371/journal.ppat.1007850

Abstract

Invasive candidiasis, mainly caused by Candida albicans, is a serious healthcare problem with high mortality rates, particularly in immunocompromised patients. Innate immune cells express pathogen recognition receptors (PRRs) including C-type lectin-like receptors (CLRs) that bind C. albicans to ini...

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Published in:	PLOS Pathogens
ISSN:	1553-7374
Published:	Public Library of Science (PLoS) 2019
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URI:	https://cronfa.swan.ac.uk/Record/cronfa61698
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Multiple CLRs including Dectin-1, Dectin-2 and Mincle have been proposed individually to contribute to the immune response to C. albicans. However how these receptors collaborate to clear a fungal infection is unknown. Herein, we used novel multi-CLR knockout (KO) mice to decipher the individual, collaborative and collective roles of Dectin-1, Dectin-2 and Mincle during systemic C. albicans infection. These studies revealed an unappreciated and profound role for CLR co-operation in anti-fungal immunity. The protective effect of multiple CLRs was markedly greater than any single receptor, and was mediated through inflammatory monocytes via recognition and phagocytosis of C. albicans, and production of C. albicans-induced cytokines and chemokines. These CLRs were dispensable for mediating similar responses from neutrophils, likely due to lower expression of these CLRs on neutrophils compared to inflammatory monocytes. Concurrent deletion of Dectin-1 and Dectin-2, or all three CLRs, resulted in dramatically increased susceptibility to systemic C. albicans infection compared to mice lacking a single CLR. Multi-CLR KO mice were unable to control fungal growth due to an inadequate early inflammatory monocyte-mediated response. In response to excessive fungal growth, the multi-CLR KO mice mounted a hyper-inflammatory response, likely leading to multiple organ failure. Thus, these data reveal a critical role for CLR co-operation in the effective control of C. albicans and maintenance of organ function during infection.</abstract><type>Journal Article</type><journal>PLOS Pathogens</journal><volume>15</volume><journalNumber>6</journalNumber><paginationStart>e1007850</paginationStart><paginationEnd/><publisher>Public Library of Science (PLoS)</publisher><placeOfPublication/><isbnPrint/><isbnElectronic/><issnPrint/><issnElectronic>1553-7374</issnElectronic><keywords/><publishedDay>26</publishedDay><publishedMonth>6</publishedMonth><publishedYear>2019</publishedYear><publishedDate>2019-06-26</publishedDate><doi>10.1371/journal.ppat.1007850</doi><url/><notes/><college>COLLEGE NANME</college><department>Biomedical Sciences</department><CollegeCode>COLLEGE CODE</CollegeCode><DepartmentCode>BMS</DepartmentCode><institution>Swansea University</institution><apcterm/><funders>SJO was funded by a Sir Henry Dale Fellowship jointly funded by the Wellcome Trust and the Royal Society (Grant Number 099953/Z/ 12/Z) and by a Wellcome Trust ISSF Cross Disciplinary Award. LCD is supported by a Henry Wellcome Trust Postdoctoral Fellowship (103973/ Z/14/Z). CL is supported by a Kidney Research UK/ MedImmune Joint Fellowship Award (PDF_006_20151127). GDB is funded by a Wellcome Trust Investigator Award (102705) and the MRC Centre for Medical Mycology and the University of Aberdeen (MR/N006364/1). IRH is supported by a Wellcome Trust Senior Research Fellowship (207503/Z/17/Z). PRT is supported by a Wellcome Trust Investigator Award (107964/Z/15/ Z) and the UK Dementia Research Institute. Funding URLs: https://wellcome.ac.uk/ https:// royalsociety.org/ https://www.kidneyresearchuk. org/ https://mrc.ukri.org/ https://ukdri.ac.uk/ The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.</funders><projectreference/><lastEdited>2022-11-07T13:49:21.5517219</lastEdited><Created>2022-10-31T12:38:14.3088010</Created><path><level id="1">Faculty of Medicine, Health and Life Sciences</level><level id="2">Swansea University Medical School - Medicine</level></path><authors><author><firstname>Aiysha</firstname><surname>Thompson</surname><orcid>0000-0002-6729-2015</orcid><order>1</order></author><author><firstname>Luke</firstname><surname>Davies</surname><orcid>0000-0001-7767-4060</orcid><order>2</order></author><author><firstname>Chia-Te</firstname><surname>Liao</surname><orcid>0000-0001-7036-9565</orcid><order>3</order></author><author><firstname>Diogo M. da</firstname><surname>Fonseca</surname><orcid>0000-0002-2796-6572</orcid><order>4</order></author><author><firstname>James S.</firstname><surname>Griffiths</surname><order>5</order></author><author><firstname>Robert</firstname><surname>Andrews</surname><orcid>0000-0002-3491-2361</orcid><order>6</order></author><author><firstname>Adam V.</firstname><surname>Jones</surname><order>7</order></author><author><firstname>Mathew</firstname><surname>Clement</surname><orcid>0000-0002-9280-5281</orcid><order>8</order></author><author><firstname>Gordon D.</firstname><surname>Brown</surname><order>9</order></author><author><firstname>Ian R.</firstname><surname>Humphreys</surname><orcid>0000-0002-9512-5337</orcid><order>10</order></author><author><firstname>Philip R.</firstname><surname>Taylor</surname><order>11</order></author><author><firstname>Selinda J.</firstname><surname>Orr</surname><orcid>0000-0001-8539-7825</orcid><order>12</order></author></authors><documents><document><filename>61698__25670__535ba63448cb4675ab50382b0370f321.pdf</filename><originalFilename>61698.pdf</originalFilename><uploaded>2022-11-07T13:47:34.4146329</uploaded><type>Output</type><contentLength>4250248</contentLength><contentType>application/pdf</contentType><version>Version of Record</version><cronfaStatus>true</cronfaStatus><documentNotes>© 2019 Thompson et al. 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spelling	2022-11-07T13:49:21.5517219 v2 61698 2022-10-31 The protective effect of inflammatory monocytes during systemic C. albicans infection is dependent on collaboration between C-type lectin-like receptors ff080296775381560053d5e3a6e81745 0000-0001-7767-4060 Luke Davies Luke Davies true false 2022-10-31 BMS Invasive candidiasis, mainly caused by Candida albicans, is a serious healthcare problem with high mortality rates, particularly in immunocompromised patients. Innate immune cells express pathogen recognition receptors (PRRs) including C-type lectin-like receptors (CLRs) that bind C. albicans to initiate an immune response. Multiple CLRs including Dectin-1, Dectin-2 and Mincle have been proposed individually to contribute to the immune response to C. albicans. However how these receptors collaborate to clear a fungal infection is unknown. Herein, we used novel multi-CLR knockout (KO) mice to decipher the individual, collaborative and collective roles of Dectin-1, Dectin-2 and Mincle during systemic C. albicans infection. These studies revealed an unappreciated and profound role for CLR co-operation in anti-fungal immunity. The protective effect of multiple CLRs was markedly greater than any single receptor, and was mediated through inflammatory monocytes via recognition and phagocytosis of C. albicans, and production of C. albicans-induced cytokines and chemokines. These CLRs were dispensable for mediating similar responses from neutrophils, likely due to lower expression of these CLRs on neutrophils compared to inflammatory monocytes. Concurrent deletion of Dectin-1 and Dectin-2, or all three CLRs, resulted in dramatically increased susceptibility to systemic C. albicans infection compared to mice lacking a single CLR. Multi-CLR KO mice were unable to control fungal growth due to an inadequate early inflammatory monocyte-mediated response. In response to excessive fungal growth, the multi-CLR KO mice mounted a hyper-inflammatory response, likely leading to multiple organ failure. Thus, these data reveal a critical role for CLR co-operation in the effective control of C. albicans and maintenance of organ function during infection. Journal Article PLOS Pathogens 15 6 e1007850 Public Library of Science (PLoS) 1553-7374 26 6 2019 2019-06-26 10.1371/journal.ppat.1007850 COLLEGE NANME Biomedical Sciences COLLEGE CODE BMS Swansea University SJO was funded by a Sir Henry Dale Fellowship jointly funded by the Wellcome Trust and the Royal Society (Grant Number 099953/Z/ 12/Z) and by a Wellcome Trust ISSF Cross Disciplinary Award. LCD is supported by a Henry Wellcome Trust Postdoctoral Fellowship (103973/ Z/14/Z). CL is supported by a Kidney Research UK/ MedImmune Joint Fellowship Award (PDF_006_20151127). GDB is funded by a Wellcome Trust Investigator Award (102705) and the MRC Centre for Medical Mycology and the University of Aberdeen (MR/N006364/1). IRH is supported by a Wellcome Trust Senior Research Fellowship (207503/Z/17/Z). PRT is supported by a Wellcome Trust Investigator Award (107964/Z/15/ Z) and the UK Dementia Research Institute. Funding URLs: https://wellcome.ac.uk/ https:// royalsociety.org/ https://www.kidneyresearchuk. org/ https://mrc.ukri.org/ https://ukdri.ac.uk/ The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. 2022-11-07T13:49:21.5517219 2022-10-31T12:38:14.3088010 Faculty of Medicine, Health and Life Sciences Swansea University Medical School - Medicine Aiysha Thompson 0000-0002-6729-2015 1 Luke Davies 0000-0001-7767-4060 2 Chia-Te Liao 0000-0001-7036-9565 3 Diogo M. da Fonseca 0000-0002-2796-6572 4 James S. Griffiths 5 Robert Andrews 0000-0002-3491-2361 6 Adam V. Jones 7 Mathew Clement 0000-0002-9280-5281 8 Gordon D. Brown 9 Ian R. Humphreys 0000-0002-9512-5337 10 Philip R. Taylor 11 Selinda J. Orr 0000-0001-8539-7825 12 61698__25670__535ba63448cb4675ab50382b0370f321.pdf 61698.pdf 2022-11-07T13:47:34.4146329 Output 4250248 application/pdf Version of Record true © 2019 Thompson et al. This is an open access article distributed under the terms of the Creative Commons Attribution License true eng http://creativecommons.org/licenses/by/4.0/
title	The protective effect of inflammatory monocytes during systemic C. albicans infection is dependent on collaboration between C-type lectin-like receptors
spellingShingle	The protective effect of inflammatory monocytes during systemic C. albicans infection is dependent on collaboration between C-type lectin-like receptors Luke Davies
title_short	The protective effect of inflammatory monocytes during systemic C. albicans infection is dependent on collaboration between C-type lectin-like receptors
title_full	The protective effect of inflammatory monocytes during systemic C. albicans infection is dependent on collaboration between C-type lectin-like receptors
title_fullStr	The protective effect of inflammatory monocytes during systemic C. albicans infection is dependent on collaboration between C-type lectin-like receptors
title_full_unstemmed	The protective effect of inflammatory monocytes during systemic C. albicans infection is dependent on collaboration between C-type lectin-like receptors
title_sort	The protective effect of inflammatory monocytes during systemic C. albicans infection is dependent on collaboration between C-type lectin-like receptors
author_id_str_mv	ff080296775381560053d5e3a6e81745
author_id_fullname_str_mv	ff080296775381560053d5e3a6e81745_***_Luke Davies
author	Luke Davies
author2	Aiysha Thompson Luke Davies Chia-Te Liao Diogo M. da Fonseca James S. Griffiths Robert Andrews Adam V. Jones Mathew Clement Gordon D. Brown Ian R. Humphreys Philip R. Taylor Selinda J. Orr
format	Journal article
container_title	PLOS Pathogens
container_volume	15
container_issue	6
container_start_page	e1007850
publishDate	2019
institution	Swansea University
issn	1553-7374
doi_str_mv	10.1371/journal.ppat.1007850
publisher	Public Library of Science (PLoS)
college_str	Faculty of Medicine, Health and Life Sciences
hierarchytype
hierarchy_top_id	facultyofmedicinehealthandlifesciences
hierarchy_top_title	Faculty of Medicine, Health and Life Sciences
hierarchy_parent_id	facultyofmedicinehealthandlifesciences
hierarchy_parent_title	Faculty of Medicine, Health and Life Sciences
department_str	Swansea University Medical School - Medicine{{{_:::_}}}Faculty of Medicine, Health and Life Sciences{{{_:::_}}}Swansea University Medical School - Medicine
document_store_str	1
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description	Invasive candidiasis, mainly caused by Candida albicans, is a serious healthcare problem with high mortality rates, particularly in immunocompromised patients. Innate immune cells express pathogen recognition receptors (PRRs) including C-type lectin-like receptors (CLRs) that bind C. albicans to initiate an immune response. Multiple CLRs including Dectin-1, Dectin-2 and Mincle have been proposed individually to contribute to the immune response to C. albicans. However how these receptors collaborate to clear a fungal infection is unknown. Herein, we used novel multi-CLR knockout (KO) mice to decipher the individual, collaborative and collective roles of Dectin-1, Dectin-2 and Mincle during systemic C. albicans infection. These studies revealed an unappreciated and profound role for CLR co-operation in anti-fungal immunity. The protective effect of multiple CLRs was markedly greater than any single receptor, and was mediated through inflammatory monocytes via recognition and phagocytosis of C. albicans, and production of C. albicans-induced cytokines and chemokines. These CLRs were dispensable for mediating similar responses from neutrophils, likely due to lower expression of these CLRs on neutrophils compared to inflammatory monocytes. Concurrent deletion of Dectin-1 and Dectin-2, or all three CLRs, resulted in dramatically increased susceptibility to systemic C. albicans infection compared to mice lacking a single CLR. Multi-CLR KO mice were unable to control fungal growth due to an inadequate early inflammatory monocyte-mediated response. In response to excessive fungal growth, the multi-CLR KO mice mounted a hyper-inflammatory response, likely leading to multiple organ failure. Thus, these data reveal a critical role for CLR co-operation in the effective control of C. albicans and maintenance of organ function during infection.
published_date	2019-06-26T04:20:42Z
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score	10.999161

The protective effect of inflammatory monocytes during systemic C. albicans infection is dependent on collaboration between C-type lectin-like receptors

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