# Typhoid toxin of Salmonella Typhi elicits host antimicrobial response during acute typhoid fever

## TL;DR

The typhoid toxin from Salmonella Typhi triggers DNA damage responses in the host, leading to antimicrobial defenses that reduce blood infections during typhoid fever.

## Contribution

This study reveals a novel mechanism where typhoid toxin-induced DNA damage responses elicit antimicrobial responses to suppress Salmonella bacteraemia.

## Key findings

- Typhoid toxin activates DNA damage responses that increase lysozyme and APOC3 secretion in human plasma.
- Lysozyme inhibits Salmonella infections and ROS-induced DNA damage, reinforcing host protection.
- p53-mediated expression of lysozyme is triggered by mitochondrial oxidative stress from typhoid toxin.

## Abstract

Salmonella Typhi secretes typhoid toxin that activates cellular DNA damage responses (DDR) during acute typhoid fever. Human infection challenge studies revealed that the toxin suppresses bacteraemia via unknown mechanisms. Using quantitative proteomic analysis on the plasma of bacteraemic participants, we demonstrate that wild-type toxigenic Salmonella induced secretion of lysozyme (LYZ) and apolipoprotein C3 (APOC3). Recombinant typhoid toxin or Salmonella infection recapitulated LYZ and APOC3 secretion in cultured cells, which involved ATM/ATR-dependent DDRs and confirmed observations in typhoid fever. LYZ caused spheroplast formation, inhibited the Salmonella type 3 secretion system, and intracellular infections. LYZ expression was regulated by p53 in a cell type-specific manner and driven by mitochondrial oxidative stress that caused nuclear DDRs and p53-mediated senescence responses. Addition of LYZ inhibited oxidative DNA damage and resulting senescence responses caused by typhoid toxin. Our findings may indicate that toxin-induced DDRs elicit antimicrobial responses, which suppress Salmonella bacteraemia during typhoid fever.

DNA damage responses (DDRs) counteract cancer but whether they defend against bacterial infections is unclear. We provide evidence that DDRs by typhoid toxin of Salmonella Typhi elicits an antimicrobial response, which is associated with shorter blood infections in humans with acute typhoid fever.

Quantitative proteomic analysis of plasma from bacteraemic human participants identified increased levels of the antimicrobial lysozyme in response to the typhoid toxin of Salmonella Typhi.Lysozyme expression was triggered by the DNase activity of typhoid toxin that caused mitochondrial oxidative stress resulting in reactive oxygen species (ROS).Mitochondrial ROS induced nuclear DNA damage causing p53 activation that mediated expression of lysozyme.Lysozyme inhibited Salmonella infections and ROS-induced DNA damage reinforcing host protection.

Quantitative proteomic analysis of plasma from bacteraemic human participants identified increased levels of the antimicrobial lysozyme in response to the typhoid toxin of Salmonella Typhi.

Lysozyme expression was triggered by the DNase activity of typhoid toxin that caused mitochondrial oxidative stress resulting in reactive oxygen species (ROS).

Mitochondrial ROS induced nuclear DNA damage causing p53 activation that mediated expression of lysozyme.

Lysozyme inhibited Salmonella infections and ROS-induced DNA damage reinforcing host protection.

DNA damage responses (DDRs) counteract cancer but whether they defend against bacterial infections is unclear. We provide evidence that DDRs by typhoid toxin of Salmonella Typhi elicits an antimicrobial response, which is associated with shorter blood infections in humans with acute typhoid fever.