Targeting Salmonella subversion of cellular senescence to combat antimicrobial-resistant typhoid fever

Antimicrobial-resistant typhoid fever The world faces epidemics of antimicrobial-resistant (AMR) typhoid fever caused by Salmonella Typhi that underlies 12 million cases / 129 000 deaths each year. For example, AMR typhoid increased from 7% of cases in 2010 to 97% by 2015 in Malawi, Southeastern Africa, where typhoid is

endemic and is the predominant cause of bloodstream infections among adults and children. Developing 'strategies to identify and treat' S.Typhi-infected individuals is a WHO research priority. Understanding how infection develops and identifying effective control strategies is vital to typhoid elimination efforts.

Typhoid toxin damages human cells causing an ageing-like process called senescence A major virulence factor implicated in typhoid is the typhoid toxin of S.Typhi. We discovered that the toxin induces DNA damage responses in human cells that accelerates an ageing-like process called senescence ( Ibler et al 2019, Nature Communications) . Senescence is an innate defence against

cancer in early life but deregulation of senescence underlies age-related diseases. Human cells undergoing toxin-induced senescence released a stress secretome, which established a senescence- associated secretory phenotype (SASP) in bystander cells that were rendered more susceptible to infection (ElGhazaly et al 2023, Cell Reports) . This makes sense as infections are harder to combat as

we age but whether pathogens hijack host senescence to cause disease is unclear.