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 da Fonseca, James Griffiths, Robert Andrews, Adam Jones, Mathew Clement, Gordon Brown, Ian Humphreys, Philip Taylor, Selinda Orr

Research output: Contribution to journalArticle

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.

LanguageEnglish
Pagese1007850
JournalPLoS Pathogens
Volume15
Issue number6
DOIs
Publication statusPublished - 26 Jun 2019

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C-Type Lectins
Monocytes
Infection
Candida albicans
Knockout Mice
Neutrophils
Invasive Candidiasis
Multiple Organ Failure
Mycoses
Immunocompromised Host
Growth
Phagocytosis
Chemokines
Immunity

Cite this

Thompson, Aiysha ; Davies, Luke ; Liao, Chia-Te ; da Fonseca, Diogo ; Griffiths, James ; Andrews, Robert ; Jones, Adam ; Clement, Mathew ; Brown, Gordon ; Humphreys, Ian ; Taylor, Philip ; Orr, Selinda. / The protective effect of inflammatory monocytes during systemic C. albicans infection is dependent on collaboration between C-type lectin-like receptors. In: PLoS Pathogens. 2019 ; Vol. 15, No. 6. pp. e1007850.
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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.",
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Thompson, A, Davies, L, Liao, C-T, da Fonseca, D, Griffiths, J, Andrews, R, Jones, A, Clement, M, Brown, G, Humphreys, I, Taylor, P & Orr, S 2019, 'The protective effect of inflammatory monocytes during systemic C. albicans infection is dependent on collaboration between C-type lectin-like receptors', PLoS Pathogens, vol. 15, no. 6, pp. e1007850. https://doi.org/10.1371/journal.ppat.1007850

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 Fonseca, Diogo; Griffiths, James; Andrews, Robert ; Jones, Adam; Clement, Mathew; Brown, Gordon; Humphreys, Ian ; Taylor, Philip; Orr, Selinda.

In: PLoS Pathogens, Vol. 15, No. 6, 26.06.2019, p. e1007850.

Research output: Contribution to journalArticle

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T1 - The protective effect of inflammatory monocytes during systemic C. albicans infection is dependent on collaboration between C-type lectin-like receptors

AU - Thompson, Aiysha

AU - Davies, Luke

AU - Liao, Chia-Te

AU - da Fonseca, Diogo

AU - Griffiths, James

AU - Andrews, Robert

AU - Jones, Adam

AU - Clement, Mathew

AU - Brown, Gordon

AU - Humphreys, Ian

AU - Taylor, Philip

AU - Orr, Selinda

PY - 2019/6/26

Y1 - 2019/6/26

N2 - 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.

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DO - 10.1371/journal.ppat.1007850

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