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

The risk of mortality from Covid-19 is up to two-fold higher in men versus women, especially in the middle-age category, across different cultures and social structures. However, the biological reasons behind this difference is unknown. Recent research has highlighted significant divergences in the immune system response between the two sexes. This observation has been paralleled by the discovery of tissue-specific euchromatinisation of the inactive X chromosome in both B and T cells, accompanied by the identification of immune-related genes that specifically escape X inactivation 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 be advantageous for B cells response upon stimulation of TLR7. Moreover, recent studies have shown hypomorphic 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 B cell activation could be at the basis of the sex-linked differential mortality from Covid-19. To identify the X-encoded B-cell specific proteins that are present in higher dosage in women, we propose an unbiased approach, employing quantitative mass spectrometry from B cells from healthy, middle-aged men and women. We thus aim at identifying relevant proteins which could represent potential pharmaceutical targets to improve the prognosis of SARS-CoV-2.