Understanding how mutability facilitates survival of alternating selection and bottlenecks by the major food-borne pathogen Campylobacter jejuni

Campylobacter jejuni is a leading cause of gastroenterious in humans, particularly in the developing world through the consumption of contaminated meat. The C. jejuni genome contains many phase variable genes, a phasome, these hypermutability loci can switch expression states of a gene heritably, stochastically and with high frequency and can be driven by various molecular mechanisms. Botlenecks occur through selective or non-selective mechanisms, both act to reduce the population size. This thesis aims to understand the role of botlenecks during infection, colonisation, and persistence by C. jejuni and the role of phase variation in adaptation.

An investigation into the distribution of phase variable genes across C. jejuni clonal complexes, to understand adaptive effect of phase variable genes, reveals a strong association between the phasome and the evolutionary niche adaptation of the clonal complexes. The identified phase variable genes also drove diversifying selection, further adapting C. jejuni towards environmental stressors. The results presented highlight the important role of phase variation in niche adaptation.

Improving on current modelling techniques, an in-silico model combining selective and non-selective botleneck effects was developed allowing complex scenarios to be simulated and botleneck events predicted. This led to the generation of machine learning models to predict selection coefficients and non-selective botleneck widths, culminating in accurate predictions, which can enhance our understanding of selection in vitro and in vivo.

The effects of persistent selection on phase variable genes and survival was tested through the development of a passage assay using bacteriophage F336. Infection is controlled by a phase variable switch in C. jejuni. Serial passages revealed the survival of both the bacteria and bacteriophage despite increasing resistance in the C. jejuni population. The resistance profile shown in vitro confirmed in-silico modelling and suggested counter selection against the bacteriophage which leads to enhanced resistance during colonisation and infection.