A male sex bias has emerged in the COVID-19 pandemic, fitting to the sex-biased pattern in other viral infections. Males are 2.84 times more often admitted to the ICU and mortality is 1.39 times higher as a result of COVID-19. Various factors play a role in this, and novel studies suggest that the gene-dose of Toll-Like Receptor (TLR) 7 could contribute to the sex-skewed severity. TLR7 is one of the crucial pattern recognition receptors for SARS-CoV-2 ssRNA and the gene-dose effect is caused by X chromosome inactivation (XCI) escape. Female immune cells with TLR7 XCI escape have biallelic TLR7 expression and produce more type 1 interferon (IFN) upon TLR7 stimulation. In COVID-19, TLR7 in plasmacytoid dendritic cells is one of the pattern recognition receptors responsible for IFN production and a delayed IFN response has been associated with immunopathogenesis and mortality. Here, we provide a hypothesis that females may be protected to some extend against severe COVID-19, due to the biallelic TLR7 expression, allowing them to mount a stronger and more protective IFN response early after infection. Studies exploring COVID-19 treatment via the TLR7-mediated IFN pathway should consider this sex difference. Various factors such as age, sex hormones and escape modulation remain to be investigated concerning the TLR7 gene-dose effect.
【저자키워드】 COVID-19, TLR7, interferon, sex differences, X chromosome inactivation escape, gene-dose effect, 【초록키워드】 Treatment, SARS-CoV-2, Mortality, severe COVID-19, COVID-19 pandemic, severity, Infection, TLR7, interferon, Sex hormones, viral infections, Toll-like receptor, dendritic cells, ICU, COVID-19 treatment, Pattern recognition, Viral, inactivation, Immunopathogenesis, female, plasmacytoid dendritic cells, IFN, immune cells, age, Pattern recognition receptors, Sex difference, expression, X chromosome, Protective, Hypothesis, Immune cell, Male sex, IFN response, pattern recognition receptor, sex hormone, Factor, modulation, ssRNA, TLR7 gene, TLR, type 1 interferon, IFN pathway, responsible, caused, investigated, contribute, concerning, biallelic, plasmacytoid dendritic cell, 【제목키워드】 Effect,