Sex-Specific Plasma Proteomic Alterations Underpin Distinct COVID-19 Progression and Post-COVID-19 Condition

Abstract Sex differences in COVID-19 and its sequelae remain poorly understood, which hinders targeted therapies. We performed plasma proteomic analyses of 69 hospitalized patients with COVID-19 and 30 healthy controls from a prospective Chinese cohort. The UK Biobank and Mount Sinai Biobank were employed for validation and provided insights into the progression mechanisms. Biological and tissue enrichment analyses characterized sex-specific pathways and tissue-enriched proteins. We identified ANXA11, a molecular tether that physically links RNA granules to lysosomal membranes to enable their long-distance transport and local translation, as a protein associated with male-specific susceptibility to SARS-CoV-2 infection. Decreased ANXA11 protein levels were linked to higher risk of infection in males, replicated in the UK Biobank. Sex-specific proteomic alterations revealed distinct biological responses, including glycosylation-related pathways in females and cell adhesion, platelet-leukocyte interactions, and inflammatory responses in males. Sex-specific protein changes were also associated with distinct post-COVID-19 symptom profiles. ANXA11 was identified as a novel protein associated with the male-specific susceptibility to SARS-CoV-2 infection. Sex-specific protein changes revealed distinct mechanistic differences between male and female patients in COVID-19 progression and may explain sex differences in post-COVID-19 conditions.