Institute: University of Sheffield
Biography
Infections by multi-drug resistant bacterial pathogens have devastating consequences to human health and represent major poverty drivers. This is exemplified by the human bacterial pathogen Salmonella Typhi that causes typhoid fever underlying ~12 million cases and ~128,000 deaths each year in low- and middle-income countries. In addition to typhoid fever, disease transmission is driven by chronic Salmonella carriage. Humans are the only known reservoir for S. Typhi and chronic carriers, like the infamous Typhoid Mary, are an intractable population who retain and transmit S. Typhi in the community by contaminating the food chain.
To combat S.Typhi, we must resolve the disease mechanisms. Experiments in animal models indicate that typhoid and the establishment of chronic carriage are attributed to S.Typhi’s typhoid toxin, which activates the human cell DNA damage response. Cellular function depends on DNA integrity, yet our DNA is damaged on a daily basis often generating double strand breaks. The aberrant DNA structures are flagged and targeted for repair by a coordinated DNA damage response and malfunction results in many pathologies. Unsurprisingly given its importance, many bacterial pathogens target the DDR to establish infections yet how DNA damage induced by the typhoid toxin of Salmonella Typhi promotes disease is not understood.
A recent human infection challenge study with wild-type Salmonella Typhi and a mutant strain deficient in the typhoid toxin (Gibani et al 2019), provides a golden opportunity to investigate the toxin in extraordinary new detail. We propose to resolve the identity of proteins released into the plasma of human participants during infection with Salmonella Typhi or the toxin-deficient strain. This will provide insight into how the typhoid toxin manipulates host immunological responses during Salmonella Typhi infections and help us understand the role of the toxin in disease.
Key Publications
A list of publications can be found here.
Web Links of Interest