Molecular Epidemiology and Evolution of Corynebacterium diphtheriae and Vibrio cholerae Robert C. Will

The infectious diseases diphtheria and cholera affect thousands of people around the world every year, and are caused by the bacterial species Corynebacterium diphtheriae and Vibrio cholerae respectively. While the two pathogens appear quite different biologically, diphtheria and cholera do share key similarities, including the fact that both diseases are intrinsically linked with poverty, outbreaking rapidly in areas of social turmoil, and during both natural and man-made disasters. Both are also highly treatable and survivable with the right resources available, including antibiotics and antitoxins. Vaccines are also available against both causative agents, although the diphtheria toxoid vaccine is in much wider use than cholera vaccine. In this thesis I have used genomics to investigate the epidemiology and evolution of both pathogens in global and national settings. For C. diphtheriae, we assembled a large collection of sequenced genomes to investigate the evolutionary and population dynamics of the pathogen across the globe. We added a focus on India as the country with the highest number of reported cases in recent years. We identified multiple large phylogenetic clades of the species circulating across geography and time concurrently. Using this collection, we also identified the presence of antimicrobial resistance determinant genes in recently isolated C. diphtheriae. In addition, we categorised a series of variants of the diphtheria toxin gene tox from isolates around the world, several of which were non-synonymous and estimated to have an impact on the 3D structure of the toxin protein.

In V. cholerae, we investigated the intriguing population and evolutionary dynamics of cholera in Ghana, presenting a picture of time-separated clades circulating around neighbouring countries in West Africa. We also highlight the increasing presence of AMR in West African V. cholerae, in line with other reports from the ongoing 7th Pandemic. Finally, we present preliminary analysis of a large V. cholerae O139 collection and highlight how rapid AMR development may have caused O139 to so effectively outcompete the existing O1 serogroup, before disappearing almost as quickly due to subsequent loss of AMR.

Taken together, these results highlight how much there is still left to understand about both of diseases, which in many parts of the world are believed to be a problem of the past. This dearth of knowledge applies both to the vastly under-researched diphtheria and the more widely researched cholera.