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

## TL;DR

This study reveals how Rickettsia bacteria use toxin-antitoxin systems to survive and cause disease in their host by manipulating RNA and evading oxidative stress.

## Contribution

This is the first study to elucidate the function of toxin-antitoxin modules in an obligatory intracellular bacterium.

## Key findings

- The vapBC1 module induces bacterial dormancy by cleaving tRNAfMet in response to host reactive oxidative species.
- The vapBC2 module contributes to virulence by degrading host ribosomal RNAs.
- Disrupting VapC toxins could be a viable anti-infection therapy for host-associated bacteria.

## Abstract

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.

Vascular endothelial cells employ ROS as a common and efficient defense against pathogen infections. However, little is known about how those obligatory intracellular bacteria combat the oxidative attack that develops inside their host. Here, we demonstrated how the obligate intracellular bacterium Rickettsia’s vapBC1 TA module induces bacterial persisters in response to their host ROS threat, promoting rickettsial survival and, eventually, making infection establishment in mice easier. Notably, unspecific degradation of host ribosomal RNAs by free VapC toxin exposed to the host cytosol may alter host metabolism and promote bacterial survival. To the best of our knowledge, this is the first study to elucidate TA function in an obligatory intracellular bacterium. Moreover, for all host-associated bacteria that possess vapBC TA modules, disrupting the impact of VapC toxins may be a viable anti-infection therapy.