The Molecular Basis Of The Sex-linked Functional Differences In B Cells

B 细胞性别相关功能差异的分子基础

• 批准号: BB/W010747/1
• 负责人: Sara Buonomo
• 金额: $ 13.36万
• 依托单位: University of Edinburgh
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2021
• 资助国家: 英国
• 起止时间: 2021 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FW010747%2F1
• 关键词: Molecular; Basis; Sex; linked; Functional

The risk of mortality from Covid-19 is up to two-fold higher in men versus women, especially in themiddle-age category, across different cultures and social structures. However, the biologicalreasons behind this difference is unknown. Recent research has highlighted significant divergencesin the immune system response between the two sexes. This observation has been paralleled bythe discovery of tissue-specific euchromatinisation of the inactive X chromosome in both B and Tcells, accompanied by the identification of immune-related genes that specifically escape Xinactivation in B cells. One of these escapees, TLR7, is a receptor for ssRNA viruses such as SARSCoV-2. Its increased dosage caused by bi-allelic expression in women, has been shown to beadvantageous for B cells response upon stimulation of TLR7. Moreover, recent studies have shownhypomorphic alleles of TLR7 lead to severe Covid-19 in young men. We hypothesised that,following escape from X inactivation, double-dosage of one or more X-encoded genes involved in Bcell activation could be at the basis of the sex-linked differential mortality from Covid-19. Toidentify the X-encoded B-cell specific proteins that are present in higher dosage in women, wepropose an unbiased approach, employing quantitative mass spectrometry from B cells fromhealthy, middle-aged men and women. We thus aim at identifying relevant proteins which couldrepresent potential pharmaceutical targets to improve the prognosis of SARS-CoV-2.

在不同的文化和社会结构中，男性死于Covid-19的风险比女性高出两倍，尤其是在中年人群中。然而，这种差异背后的生物学原因尚不清楚。最近的研究强调了两性在免疫系统反应上的显著差异。这一发现与B细胞和t细胞中失活X染色体的组织特异性常染色化的发现相一致，同时还发现了B细胞中特异性逃避新激活的免疫相关基因。其中一种逃逸物TLR7是SARSCoV-2等ssRNA病毒的受体。在女性中，双等位基因表达导致其剂量增加，已被证明有利于B细胞对TLR7刺激的反应。此外，最近的研究表明，TLR7的亚型等位基因会导致年轻男性患上严重的Covid-19。我们假设，在逃离X失活后，参与b细胞活化的一个或多个X编码基因的双倍剂量可能是Covid-19性别相关死亡率差异的基础。为了鉴定女性中较高剂量的x编码B细胞特异性蛋白，我们提出了一种无偏倚的方法，使用来自健康中年男性和女性的B细胞的定量质谱法。因此，我们旨在鉴定可能代表潜在药物靶点的相关蛋白，以改善SARS-CoV-2的预后。