Identification of potential key genetic factors in the long-term success of Shigella as pathogens

Abstract

Bacterial of the genus Shigella are a major contributor to the global diarrhoea burden causing 100,000 deaths per annum globally. Further to this, increasing antibiotic resistance in Shigella and the lack of a licenced vaccine has led WHO to recognise Shigella as a priority organism for the development of new antibiotics. Understanding what drives the long-term persistence and success of this pathogen will thus aid the global management of shigellosis and may identify targets relevant to other enteric bacteria. To identify key genetic drivers of Shigella evolution over the past 100 years, we have used the historical Murray collection; comprising several hundred pre-antibiotic era (1917 – 1954) Enterobacteriaceae from diverse geographical locations. We employed genome-wide association studies to sequences from over 100 Shigella isolates from the Murray collection alongsidemore modern (i.e. 1950s – 2018) isolates to identify genetic factors (SNPs and genes) significantly associated with time as a continuous variable. GWAS hits (e.g. a putative resistance protein) then underwent variation, functional and phenotypic analysis to examine the plausibility of their role in shaping Shigella populations and as potential targets for managing this pathogen.