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

影响女性健康的最常见的酵母感染之一是生殖器鹅口疮，它是由白色念珠菌引起的。每年，75%的女性会经历一次生殖器鹅口疮发作，其中高达15%的女性会继续发展为反复感染，其定义是在12个月内出现三次或三次以上的感染。最近的估计表明，每年有超过1.38亿例反复感染。在怀孕期间自然发生的、或由于使用口服避孕药和激素替代疗法而导致的高循环雌激素水平的妇女，患生殖器鹅口疮的风险更高。虽然不会危及生命，但这些感染是痛苦的，可能会导致怀孕期间的并发症，并对妇女的福祉产生重大影响。因此，了解为什么雌激素水平较高的女性感染风险增加是至关重要的。人类免疫系统的主要功能是将外来颗粒识别为“非我”，并将其从人体中移除。清除酵母菌的关键是白念珠菌是吞噬和摧毁微生物的白血球。这些白细胞与体液中的蛋白质一起工作，这种蛋白质被称为补体。补体蛋白附着在白色念珠菌等外来颗粒的表面，并以它们为目标被吞噬细胞破坏。然而，在生殖器鹅口疮期间，这种免疫保护被破坏，天然免疫系统不再清除雌性生殖道中的酵母。最近，我们已经证明，如果酵母暴露在雌激素中，吞噬细胞吞噬和摧毁白色念珠菌的能力较弱。这种免疫反应的降低是由于一种名为Gpd2的酵母蛋白表达增加所致。这种酵母蛋白的功能是结合将酵母伪装成“自我”的人类蛋白，从而防止补体蛋白粘在酵母细胞表面。因此，酵母不再被认为是“非我的”，因此，不能被导致感染的先天免疫系统从体内清除。去除这种单一的酵母蛋白可以恢复补体蛋白附着在酵母细胞表面的能力，并确保吞噬细胞有效地去除酵母。因此，我们现在想知道雌激素的存在是如何增加这种蛋白质的水平的，这种蛋白质是如何到达酵母细胞表面的，以及这种蛋白质在感染中所起的作用。解决这些重要问题将确定新的酵母菌靶标，我们可以针对这些靶标设计新药，作为预防或治疗感染的一种方式，并将提供关键信息来改善妇女的健康和福祉。

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 a result, 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.