Investigating host and pathogen factors that modulate the phagocytosis of Cryptococcus neoformans by macrophages.

Onyishi, Chinaemerem U. ORCID: 0000-0001-8292-9873 (2023). Investigating host and pathogen factors that modulate the phagocytosis of Cryptococcus neoformans by macrophages. University of Birmingham. Ph.D.

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Abstract

Infection with the opportunist fungal pathogen, Cryptococcus neoformans, is thought to begin with the inhalation of spores or desiccated yeast into the lungs, where phagocytes of the innate immune system serve as the first line of defence against infection. However, for a long time, very little was understood about the mechanism by which C. neoformans is detected and phagocytosed by macrophages. Therefore, my PhD research sought to investigate the role of pattern recognition receptors (PRR) such as TLR4 and scavenger receptors in the non-opsonic phagocytosis of C. neoformans. I also investigated broader aspects of phagocyte-Cryptococcus interactions, including how pathogen factors such as extracellular vesicle (EV) production impact the host and how resistance to amoebal phagocytosis may relate to the mammalian immune response.
I found that TLR4 was not directly involved in the uptake of C. neoformans. Instead TLR4 deficiency led to increased non-opsonic uptake via increased expression of the scavenger receptor, MSR1. MSR1 knock out and immunofluorescence imaging identified MSR1 as a key receptor for the non-opsonic phagocytosis of C. neoformans. Therefore, I identify TLR4/MSR1 crosstalk in modulating C. neoformans uptake.
In parallel, I found that the scavenger receptor MARCO is only involved in uptake in certain contexts but has a hitherto unrecognised role as a broadly relevant modulator of non-lytic expulsion. Finally, in collaborative projects with other groups, I discovered that loss of EV production led to decreased phagocytosis of cryptococci and that resistance to amoebal uptake was not a predictor of cryptococcus virulence to macrophages as measured by phagocytosis rate and intracellular proliferation. Taken together, my work highlights the importance of C. neoformans interactions with macrophages as a possible predictor of disease outcome, suggesting that strategies to manipulate non-opsonic uptake of cryptococci may serve as useful therapeutic targets in the future.

Type of Work:

Thesis (Doctorates > Ph.D.)

Award Type:

Doctorates > Ph.D.

Supervisor(s):