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Toll-like receptor 4 and macrophage scavenger receptor 1 crosstalk regulates phagocytosis of a fungal pathogen.

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Peer-reviewed

Repository DOI


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Authors

Onyishi, Chinaemerem U  ORCID logo  https://orcid.org/0000-0001-8292-9873
Desanti, Guillaume E 

Abstract

The opportunistic fungal pathogen Cryptococcus neoformans causes lethal infections in immunocompromised patients. Macrophages are central to the host response to cryptococci; however, it is unclear how C. neoformans is recognised and phagocytosed by macrophages. Here we investigate the role of TLR4 in the non-opsonic phagocytosis of C. neoformans. We find that loss of TLR4 function unexpectedly increases phagocytosis of non-opsonised cryptococci by murine and human macrophages. The increased phagocytosis observed in Tlr4-/- cells was dampened by pre-treatment of macrophages with oxidised-LDL, a known ligand of scavenger receptors. The scavenger receptor, macrophage scavenger receptor 1 (MSR1) (also known as SR-A1 or CD204) was upregulated in Tlr4-/- macrophages. Genetic ablation of MSR1 resulted in a 75% decrease in phagocytosis of non-opsonised cryptococci, strongly suggesting that it is a key non-opsonic receptor for this pathogen. We go on to show that MSR1-mediated uptake likely involves the formation of a multimolecular signalling complex involving FcγR leading to SYK, PI3K, p38 and ERK1/2 activation to drive actin remodelling and phagocytosis. Altogether, our data indicate a hitherto unidentified role for TLR4/MSR1 crosstalk in the non-opsonic phagocytosis of C. neoformans.

Description

Acknowledgements: We thank Maria Makarova for assistance with confocal microscopy, Michael G. Tomlinson for his in-silico analysis of MSR1 and contribution to the discussion, Sean D. Kelly for technical help regarding the establishment of MPI cell lines and Sarah Dimeloe and Nancy Gudgeon for helpful advice on the culture of PBMCs. The MSR1 knockout and MSR1/MARCO double knockout lines were established with the support of NC3Rs Grant NC/V001019/1. Work in C.E.B. lab is supported by grant BB/V000276/1. This work was partly supported by a Royal Society project grant (RGS\R2\202260) to S.M lab. C.U.O is supported by a Ph.D. studentship from the Darwin Trust of Edinburgh. A.L.W. was supported by Ph.D. funding from the Wellcome Trust ‘MIDAS’ doctoral training program. R.C.M. gratefully acknowledges support from the BBSRC and European Research Council Consolidator Award.

Keywords

Animals, Humans, Mice, Cryptococcosis, Cryptococcus neoformans, Macrophages, Phagocytosis, Toll-Like Receptor 4, Scavenger Receptors, Class A

Journal Title

Nat Commun

Conference Name

Journal ISSN

2041-1723
2041-1723

Volume Title

14

Publisher

Springer Science and Business Media LLC
Sponsorship
BBSRC (BB/V000276/1)