Abstract
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.
Highlights
In the pandemic, male sex was identified as a risk factor for hospitalization and mortality after SARS-CoV-2 infection [1]
Despite the observed prevalence in young males, the penetrance of deleterious Toll-Like Receptor 7 (TLR7) mutations may be worse in older patients, as both the plasmacytoid dendritic cells (pDCs) number and functional IFN secretion decreases with age, which was associated with a reduced number of pDCs expressing TLR7 [28]
Males are significantly more likely than females to experience severe disease and TLR7 X chromosome inactivation (XCI) escape in females may be partly responsible for this
Summary
Male sex was identified as a risk factor for hospitalization and mortality after SARS-CoV-2 infection [1]. An X chromosomal gene of interest is TLR7, identified as a pattern recognition receptor (PRR), recognizing ssRNA viruses such as SARS-CoV-2. It is one of the PRRs involved in type 1 interferon (IFN) production in COVID-19 [10, 11]. Type 1 IFNs have essential functions: activating an antiviral state in infected cells to limit the viral spread, restraining innate immunity, controlling pro-inflammatory pathways, and activating adaptive immunity. Despite the observed prevalence in young males, the penetrance of deleterious TLR7 mutations may be worse in older patients, as both the pDC number and functional IFN secretion decreases with age, which was associated with a reduced number of pDCs expressing TLR7 [28]
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