ORCID
- Fejer, Gyorgy: 0000-0001-6761-0506
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.
DOI
10.1038/s41467-023-40635-w
Publication Date
2023-08-14
Publication Title
Nature Communications
Volume
14
Issue
1
ISSN
2041-1723
Embargo Period
2023-11-24
Organisational Unit
School of Biomedical Sciences
Recommended Citation
Onyishi, C. U., Desanti, G., Wilkinson, A., Lara-Reyna, S., Frickel, E., Fejer, G., Christophe, O., Bryant, C., Mukhopadhyay, S., Gordon, S., & May, R. (2023) 'Toll-like receptor 4 and macrophage scavenger receptor 1 crosstalk regulates phagocytosis of a fungal pathogen', Nature Communications, 14(1). Available at: https://doi.org/10.1038/s41467-023-40635-w
