The role of inflammation in the formation of multi-drug resistant lineages of E. coli

Connor, Christopher ORCID: 0000-0002-1761-2412 (2022). The role of inflammation in the formation of multi-drug resistant lineages of E. coli. University of Birmingham. Ph.D.

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Abstract

E. coli exists as a commensal in the gastrointestinal tract of humans and other animals but can also cause severe disease in humans. Pathogenic E. coli that infect sites outside of the intestine are called extra-intestinal pathogenic E. coli (ExPEC) and are the most common cause of urinary tract infections (UTI). ExPEC can also cause soft tissue infections, blood stream infections and meningitis all of which can be severe life threatening diseases. ExPEC infections are further complicated by antimicrobial resistance (AMR) with ExPEC infections increasingly presenting as multi-drug resistant (MDR) limiting the number of effective therapies. Curiously AMR in ExPEC is not uniform, instead specific clones are responsible for the majority of resistant infections. For example the spread of the AMR gene CTX-M has been attributed to a single ExPEC clone called ST131 which frequently causes UTI in humans. These MDR clones are adept at colonising healthy individuals with international travellers frequently importing MDR E. coli upon their return, resulting in onward trans- mission within households. Understanding why AMR is concentrated in specific clones and how these clones transmit between healthy individuals can help combat the spread of MDR pathogens. Previous pangenomic analysis has identified that genes involved in anaerobic metabolism exhibit increased variation in ST131 compared to other ExPEC lineages. Expanding on this previous analysis we identify a significant link between metabolism and carriage of AMR genes, specifically MDR lineages of E. coli display an increased abundance of genes associated with core energy metabolism and carbohydrate utilisation. Invading pathogenic bacteria are known to compete with resident gut commensals for limited nutrients and so have evolved mechanisms to out-compete commensals. The host inflammatory response can inadvertently provide a novel set of compounds which enteric pathogens have adapted to exploit. We hypothesise that our observed metabolic signature in MDR ExPEC is evidence that they are also using compounds derived from the host inflammatory response. Testing this hypothesis we demonstrate that an MDR ST131 strain out-competes a commensal strain, isolated from a healthy human, in nutrient limited media under in vitro conditions. We further demonstrate that an MDR ST131 strain is able to out-compete a commensal strain when introduced into a germ-free mouse. The MDR ST131 is not only able to out-compete a commensal but also displace a resident commensal in a pre-colonised mouse. Displacement of the resident commensal occurs within 48 hours when mice are co-housed, with the ST131 strain becoming the dominant strain in all mice. Lastly, mice that are colonised by ST131 have elevated levels of pro-inflammatory cytokines in their caecum compared to commensally colonised mice. This thesis highlights the importance of metabolism in the evolution of MDR lineages of E. coli and contributes towards a greater understanding of how these pathogens spread.

Type of Work:

Thesis (Doctorates > Ph.D.)

Award Type:

Doctorates > Ph.D.

Supervisor(s):