Several investigations have shown that COVID-19 is more infectious in males than in women, and men are more likely to develop severe illness. While some have proposed that behavioral differences may account for higher transmission to men, this does not account for the more morbid prognosis.
To find the cause, a team of scientists from the University of Catania analyzed potential genes and pathways that could help explain this difference.
The findings were published in the journal Scientific Reports.
To do their research, the team included genes, from freely available human protein atlas program, involved with inflammatory processes such as chemokines, cytokines, metalloproteinase, bone marrow stromal antigen 2, tetherin, ANPEP, ENPEP, forkhead box P3 (FOXP3), GATA Binding Protein 1 (GATA1), High Mobility Group1 (HMGB1), Interferon Regulatory Factor (IRF1 and 2), and Serine/Cysteine Proteinase Inhibitor Clade G Member 1 (SERPING1), integrating these with the list of the HPA program and filtering on selective expression in gender-specific tissue, such as the ovary and testes.
Androgen and estrogen receptors were also included.
Further study was carried out using the Cytoscape software, which allowed the visualization of protein-protein interactions, and the researchers were able to establish a network of gene-gene interactions. They concentrated their attention again on the interactions between proteins that interacted with SARS-CoV-2, inflammation-related genes, and androgen/estrogen receptors, as well as other factors.
The scientists were able to identify overrepresented biological processes using gene ontology functional enrichment analysis and rectify them using Benjami and Hochburg false discovery rate adjustment.
The researchers discovered that a number of SARS-CoV-2 interaction proteins expressed specifically in gonadal tissues differed significantly across sexes, with 386 genes in the testes and 268 in the ovaries.
The scientists discovered co-expression, followed by physical relationships, but they also discovered co-localization, genetic interactions, pathway interconnections, shared protein domains, and projected protein interactions.
The ovary-related network had 223 proteins and 3,726 connections. These relationships followed a similar trend to the male network, albeit with physical interactions accounting for a greater share of total contacts.
When the researchers concentrated on androgen and estrogen receptor genes, the networks consisted of 49 proteins with 318 interactions (testis-related network) and 82 proteins with 634 interactions (ovary-related network).
The networks were then analyzed using Cytoscape for GO enrichment, with the most overrepresented terms linked with cell/leukocyte activation, immunological response, and peptide transport. Topological network analysis revealed four hub genes that were shared by both networks, with radixin (RDX) having the most connectivity in both networks, followed by HMGB1, RAB5C, and IRF2. SERPING1, CC chemokine receptor-5, TMPRSS2, and ADAM2 were also high degree nodes in the testis network. The high degree nodes in the ovary-related network included BST2, GATA1, ENPEP, TLR4, TLR7, IRF1, and IRF2.
Angiotensin-converting enzyme 2 (ACE-2) is the major receptor for SARS-CoV-2. In order to allow viral cell entry, the S1 subunit of the SARS-CoV-2 spike protein features a receptor-binding domain that interacts with ACE2.
The researchers point out that high amounts of ACE2 mRNA and SARS-CoV-2 interacting protein expression allow the SARS-CoV-2 virus to infect cells more easily, with various male sex hormones likely supporting. TMPRSS2 can promote access to host cells, and androgen receptor stimulation raises TMPRSS2 levels. TMPRSS2 is also considerably more active in male lungs than female lungs, which may explain why men have a higher risk of transmission and severe illness. Because ACE2 is likewise regulated by the androgen receptor, it might potentially contribute to the condition in the same way.
Previous research in mice has shown that estrogen can protect against lung harm, according to scientists. It is hypothesized that this is due to a decrease in ACE2 and an increase in an interferon response.
The evidence collected here could clarify the differences in infection and transmission between men and women, as well as guide drug makers and researchers as they create new anti-covid treatments.
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