Yet to be determined are (1) how binding of ALRs and DDX41 to STING activates it; (2) how endosomal PRRs recognize viral PAMPs during natural infection; (3) why mice have an expanded ALR locus and whether pathogens like retroviruses, or endogenous retroviruses contributed to this expansion; and (4) given the persistence of these retroviruses in mice for millions of years, whether there are as-of-yet undiscovered viral proteins that block sensor recognition? Here, STING1 is linked to infection.