Infectious diseases are among the leading causes of morbidity and mortality in the developed and developing world. Bacterial pathogens are highly adaptable and horizontal transfer of DNA between isolates allows rapid acquisition of new traits, particularly those under acute selective pressure like antibiotic resistance and pathogenesis in new hosts (e.g.: zoonoses).
Figure left: Regulatory RNA network interactions from the human pathogen Enterohaemorhaggic E. coli O157:H7 (Waters et al 2017 EMBO J). Yellow nodes represent regulatory small RNAs and blue nodes represent mRNA targets.
A major focus in the lab is enterohaemorhaggic E. coli (EHEC), a pathogenic cousin of the harmless, commensal E. coli species in our normal floral. EHEC causes sporadic outbreaks of disease when it enters the food chain, often through contaminated meat or vegetables. Infection is associated with diarrhea disease, but can progress to potential fatal haemolytic uremic syndrome (kidney damage from Shiga toxins). Genome sequencing has demonstrated that EHEC has horizontally acquired an extra ~1.5Mb of DNA when compared with its commensal E. coli cousin. This extra DNA includes about 24 cryptic and active prophage elements (bacterial viruses integrated into the genome), that carry the lion’s share of virulence genes.
Much like new computer hardware requires new software to operate effectively, we are interested in how bacterial pathogens control “newly acquired” virulence genes.
To this end, the lab has is exploring an exciting new area of bacterial gene regulation, termed regulatory non-coding RNAs. In essence, these are short (50-500nt), untranslated RNAs that control gene expression post-transcriptionally (after an mRNA is made from the gene). Using high-throughput techniques to study RNA-protein interactions and RNA-RNA interactions, we have shown that the extra ~1.5Mb of DNA in EHEC is rich in regulatory non-coding RNAs. We have also developed a technique for studying their functions within the cell. Using these tools we are dissecting the regulatory software that is “installed” into this important human pathogen and are understanding how it is rewired for pathogenesis.
Figure left: The type 3 secretion system of EHEC is controlled by an RNA-based “toggle switch” that allows transient expression of needle filaments (Wang et al 2018 NAR).