Fig. 2.

Sexually dimorphic regulation of COVID-19 immune response. SARS-CoV-2 uses ACE2 as the receptor for infection. The spike protein on the envelope of the coronavirus SARS-CoV-2 is first activated after being processed by the transmembrane protease TMPRSS2 before it can bind to the ACE2 receptor attached to the cell membrane. Then the attached virus undergoes endocytosis and the viral RNA is released into the cytoplasm afterwards. After being amplified by RNA-dependent RNA polymerase (RdRP), the viral RNA transcripts are processed and then viral products are generated. These will induce NF-kB and other immune regulatory factors which will cause cytokine storm and ARDS in the infected COVID-19 patients. Male hormones will enhance these immune responses. By contrast, females have higher TLR7 and other immune regulatory proteins which result in higher antiviral response by prevention of binding of the virus to the receptors on the cells or inhibition of uncoating of virus inside the cells. The membrane-bound ACE2 receptor can be cleaved by ADAM17 to become soluble ACE2 which can inhibit the binding of spike proteins on the envelope of the virus to the ACE2 receptor on the cell membrane.