Award details

Mooning the immune system: Elucidating the role of the moonlighting protein Gpd2 in the pathogenicity of Candida albicans

Reference	BB/W014866/1
Principal Investigator / Supervisor	Dr Rebecca hall
Co-Investigators / Co-Supervisors	Dr Donna MacCallum, Professor Carol Munro
Institution	University of Kent
Department	Sch of Biosciences
Funding type	Research
Value (£)	589,353
Status	Current
Type	Research Grant
Start date	02/12/2022
End date	01/12/2025
Duration	36 months

Abstract

Vulvovaginal candidiasis (VVC) affects 75% of the female population, and is caused by the fungus Candida albicans. Women with higher circulatory oestrogen levels, as a result of pregnancy, or the use of oral contraceptives and hormone replacement therapy are at an increased risk of developing infection. Our preliminary data confirm that oestrogen promotes the virulence of C. albicans. This increase in virulence was attributed to the reduced ability of human macrophages and neutrophils to effectively phagocytose and kill the pathogen. Key to this novel innate immune evasion strategy is the fungal moonlighting protein (a protein that exhibits more than one physiological function) Gpd2. Upon oestrogen stimulation, GPD2 is upregulated and functions to inhibit the actions of the alternative complement system. Gpd2 is involved in glycerol metabolism, but proteomic studies have identified Gpd2 at the cell surface in response to specific environmental stimuli. We hypothesise that oestrogen induces the expression and post-translational modification of Gpd2, resulting in its trafficking to the cell wall where it functions to promote innate immune evasion through inhibition of the alternative complement system. We will test this hypothesis by focusing on the molecular mechanism that targets Gpd2 to the cell surface. Initially, using reverse genetic approaches combined with chromatin immunoprecipitation, we will define key transcriptional regulators of GPD2. Then using transmission electron microscopy in combination with live cell imaging we will deduce where Gpd2 is located, and how Gpd2 is trafficked to the cell wall. Finally, using in vivo infections models we will ascertain the role Gpd2 plays in fungal virulence in both VVC and systemic infection. The impact of this work will be the identification of a novel secretion pathway, essential for the delivery of fungal virulence factors to the cell surface, that will provide new antifungal and anti-virulence targets.

Summary

One of the most common yeast infections affecting women's health is genital thrush, which is caused by Candida albicans. Each year, 75% of women will experience an episode of genital thrush, with up to 15% of these women going on to develop recurrent infection which is defined as three or more episodes within a 12-month period. Recent estimates suggest that there are over 138 million cases of recurrent infection each year. Women with high circulatory levels of the hormone oestrogen, that occur naturally during pregnancy, or result from the use of oral contraceptives and hormone replacement therapy are at increased risk of developing genital thrush. Although not life-threatening, these infections are painful, can lead to complications during pregnancy, and have a significant effect on the wellbeing of women. Therefore, understanding why women with higher oestrogen levels are at an increased risk of infection is paramount. The main function of the human immune system is to recognised foreign particles as "non-self" and to remove them from the human body. Key to the clearance of the yeast C. albicans are white blood cells (also known as phagocytes) that engulf and destroy microbes. These white blood cells work together with proteins located in body fluids known as complement. Complement proteins stick to the surface of foreign particles like C. albicans and target them for destruction by the phagocytes. However, during genital thrush there is a breakdown in this immune protection and the innate immune system no longer clears the yeast from the female genital tract. Recently, we have shown that phagocytes are less able to engulf and destroy C. albicans, if the yeast has been exposed to oestrogen. This reduced immune response is due to the increased expression of a yeast protein called Gpd2. This yeast protein functions to bind human proteins which disguise the yeast as "self" and subsequently prevent complement proteins sticking to the yeast cell surface. As aresult, the yeast is no longer recognised as "non-self" and is, therefore, not cleared from the body by the innate immune system resulting in infection. Removing this single yeast protein restores the ability of complement proteins to stick to the yeast cell surface and ensures effective removal of the yeast by the phagocytes. Therefore, we now want to know how the level of this protein is increased by the presence of oestrogen, how the protein gets to the yeast cell surface, and the role this protein plays in infection. Addressing these important questions will identify novel yeast targets to which we can design new drugs to, as a way to either prevent or treat infections, and will provide critical information to improve women's health and wellbeing.

Committee	Research Committee B (Plants, microbes, food & sustainability)
Research Topics	X – not assigned to a current Research Topic
Research Priority	X – Research Priority information not available
Research Initiative	X - not in an Initiative
Funding Scheme	X – not Funded via a specific Funding Scheme

I accept the terms and conditions of use (opens in new window)

export PDF file

back to list new search