The HigB-like SehA toxin promotes non-replicating Salmonella inside macrophages by inhibiting ribonuclease III-dependent rRNA maturation

Many bacteria are often resistant to antibiotic treatment because they can slow down their growth rate, thereby attenuating the drug’s effectiveness. A similar growth slowdown is observed in pathogens that persist inside their hosts. The bacterial toxin–antitoxin systems serve as tunable phenotypic switches by slowing down growth through the expression of a toxin component, though its biological target has been largely unknown. Here, we investigate the biological target of SehA, a HigB-like type II toxin from the intracellular pathogen Salmonella Typhimurium. Contrary to its predicted endoribonuclease function, it does not exhibit endoribonuclease activity. Instead, it inhibits ribonuclease III that mediates the initial cleavage for ribosomal RNA processing. The toxin binds to the dsRNA-binding domain of RNase III, thereby decreasing ribosome assembly and bacterial growth. Given that the SehA toxin induces persister formation within macrophages in an RNase III-dependent manner, inhibition of RNase III represents a newly identified biological target for pathogen persistence within hosts.