Host DNA damage responses to the typhoid toxin of Salmonella enterica

The typhoid toxin is a virulence factor of the bacterial pathogen Salmonella enterica, which causes typhoid fever. The toxin has been shown to cause a DNA damage response in intoxicated human cells and to promote infection (Ibler et al., 2019). DNA damage responses have been shown to activate innate immune pathways via leakage of self-DNA into the cytosol and activation of the cGAS-STING pathway (Wolf et al., 2016). This thesis shows that purified typhoid toxin upregulates a type-I interferon-like response, including the antiviral ubiquitin-like interferon-stimulated gene 15 (ISG15), in a STING-dependent manner. ISG15 was upregulated in response to toxigenic Salmonella infection and overexpression of ISG15 reduced Salmonella burden, suggesting a role in host defence. Chronic Salmonella infection has been linked to gallbladder cancer (Di Domenico et al., 2017), and ISG15 has been implicated as a regulator of P53 and thus tumour suppression in response to DNA damage (Park et al., 2016). The toxin induces cell death in wild-type MEFs, whereas ISG15 KO MEFs survive and proliferate despite hallmarks of genomic instability such as micronuclei. This suggests that ISG15 may protect the host from pathogen-induced genomic instability. Taken together, this thesis provides new insights into host responses to the typhoid toxin, and the findings may be applicable to other bacterial genotoxins.