Typhoid Toxin of Salmonella enterica Induces ISG15 Responses Mediating Host Cell Survival and Counteracting Intracellular Infection

ABSTRACT The typhoid toxin is a secreted virulence factor of typhoidal serovars of the bacterial pathogen Salmonella enterica implicated in typhoid fever and chronic infections. The toxin causes a DNA damage response in human cells, characterised by cell‐cycle arrest and cellular distension, resulting in cellular senescence and increased bacterial burden. To better understand host responses to typhoid toxin, we performed a transcriptomic analysis of intoxicated host cells and found that the toxin induced expression of genes relating to the type‐I interferon response, including the ubiquitin‐like protein ISG15. ISG15 was upregulated in a STING‐dependent manner, reduced bacterial burden, and was found to be critical to host cell survival in response to the typhoid toxin and interferon. This highlights ISG15 as an important component of the host cell defence to the typhoid toxin.