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

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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.