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 C., Liao, Chia-Te, da Fonseca, Diogo M., Griffiths, James S., Andrews, Robert, Jones, Adam V., Clement, Mathew ORCID: https://orcid.org/0000-0002-9280-5281, Brown, Gordon D., Humphreys, Ian R. ORCID: https://orcid.org/0000-0002-9512-5337, Taylor, Philip R. ORCID: https://orcid.org/0000-0003-0163-1421 and Orr, Selinda J. 2019. The protective effect of inflammatory monocytes during systemic C. albicans infection is dependent on collaboration between C-type lectin-like receptors. PLoS Pathogens 15 (6) , e1007850. 10.1371/journal.ppat.1007850

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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.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Advanced Research Computing @ Cardiff (ARCCA) Dentistry Medicine
Additional Information:	This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium,provided the original author and source are credited.
Publisher:	Public Library of Science
ISSN:	1553-7366
Funders:	Wellcome Trust
Date of First Compliant Deposit:	1 July 2019
Date of Acceptance:	20 May 2019
Last Modified:	11 Oct 2023 20:21
URI:	https://orca.cardiff.ac.uk/id/eprint/123761

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