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

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

Swansea University Author: Luke Davies Orcid Logo

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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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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 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.
College: Faculty of Medicine, Health and Life Sciences
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.
Issue: 6
Start Page: e1007850

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