VapC toxins promote the pathogenesis of Rickettsia heilongjiangensis by cleaving essential RNAs from both Rickettsia and its host.

Toxin-antitoxin (TA) modules enable bacteria to persist under stressful environments. However, they are typically absent from host-associated prokaryotes due to their potential host toxicity. Here, the obligate intracellular bacterium spotted fever group (SFG) rickettsiae, which causes mild to severe human illness, was shown to harbor two vapBC TA modules. One of the vapBC modules (vapBC1) is crucial for Rickettsia to withstand accumulated host reactive oxidative species (ROS), via induction of bacterial dormancy through cleavage on the anti-codon loop of tRNAfMet, thereby facilitating intracellular survival and infection in a mouse model. Another vapBC module (vapBC2) was found to be activated and toxin exposed to host cytoplasm, contributing to Rickettsia's virulence and adaptability in its human host by non-specifically degrading host rRNAs rather than regulating rickettsial growth. Recognition of these rickettsial effectors contributes to understanding the intracellular adaptability and pathogenicity of all host-associated pathogens that harbor TA modules.