Sex-dependent immune response and lethality of COVID-19

Li, Albert Jiarui; Li, Xiajun

COVID-19 has spread to all countries around the world after it was first discovered in Wuhan of China at the end of 2019. It is caused by a novel coronavirus called SARS-CoV-2 with much semblance to SARS-CoV including the sequence homology and disease symptoms. It is reported to be more infectious than SARS-CoV due to higher binding affinities between its spike protein and the ACE2 receptor on cell surface. Despite this, its case fatality rate is much lower compared with that of SARS-CoV although it varies in different countries. However, the case fatality rate increases steadily with age and it is reported to be the highest in aged COVID-19 male patients in almost all countries. Consistent with these, females have higher antiviral immune responses. Males and females are different in inflammatory response and aberrantly hyperactive cytokines are the main lethal causes of COVID-19. Interestingly, the gene encoding the ACE2 receptor protein and some genes encoding the immune regulatory proteins such as TLR7 are located on X chromosome which is subject to X chromosome inactivation and sex hormone regulation. These may account for some sex-dependent immune responses and lethality observed in COVID-19 patients. In general, children are less likely to be infected with SARS-CoV-2 and only less than 1% of pediatric COVID-19 patients may die of COVID-19. However, the most severe pediatric cases become multisystem inflammatory syndrome that is similar to Kawasiki disease with features of viral infection. Since most infected kids were boys in China, there may be sex-dependent immune response in pediatric COVID-19 cases as well.