TMPRSS2 and infection: Specifically, viruses have evolved a three-pronged strategy to manipulate this system: (i) targeted exploitation of tissue- or cell-specifically expressed protease isoforms [e.g., TMPRSS2 is highly expressed in the respiratory epithelium (37)]; (ii) induction of aberrant protease expression or activation in the infection microenvironment[(e.g., furin cleaves influenza virus HA0 (38, 39)]; (iii) evolution of specific cleavage motifs in viral proteins that are recognized by host proteases [e.g., HIV gp120 contains an REKR cleavage motif (40)].