Semen Proteomics of COVID-19 Convalescent Men Reveals Disruption of Key Biological Pathways Relevant to Male Reproductive Function

[Image: see text] A considerable section of males suffered from COVID-19, with many experiencing long-term repercussions. Recovered males have been documented to have compromised fertility, albeit the mechanisms remain unclear. We investigated the impact of COVID-19 on semen proteome following complete clinical recovery using mass spectrometry. A label-free quantitative proteomics study involved 10 healthy fertile subjects and 17 COVID-19-recovered men. With 1% false discovery rate and >1 unique peptide stringency, MaxQuant analysis found 1099 proteins and 8503 peptides. Of the 48 differentially expressed proteins between the healthy and COVID-19-recovered groups, 21 proteins were downregulated and 27 were upregulated in COVID-19-recovered males. The major pathways involved in reproductive functions, such as sperm–oocyte recognition, testosterone response, cell motility regulation, adhesion regulation, extracellular matrix adhesion, and endopeptidase activity, were downregulated in COVID-19-recovered patients according to bioinformatics analysis. Furthermore, the targeted approach revealed significant downregulation of semenogelin 1 and prosaposin, two proteins related to male fertility. Therefore, we demonstrate the alteration of semen proteome in response to COVID-19, thus disrupting the male reproductive function despite the patient’s clinical remission. Hence, to understand fertility-related biological processes triggered by this infection, a protracted evaluation of the consequences of COVID-19 in recovered men is warranted.