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

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Summary: 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 infection with toxigenic Salmonella recapitulate LYZ and APOC3 secretion in cultured cells, which involved ATM/ATR-dependent DDRs and confirmed observations in typhoid fever. LYZ alone inhibited secretion of virulence effector proteins SipB and SopE. LYZ caused loss of Salmonella morphology characterised by spheroplast formation. Spheroplast formation was mediated by LYZ and enhanced by lactoferrin, which was identified by proteomics in participants with typhoid fever. Our findings may indicate that toxin-induced DDRs elicit antimicrobial responses, which suppress Salmonella bacteraemia during typhoid fever.
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