Development and Application of Escherichia coli and Streptococcus Agalactiae Murine Colonisation Models to Study Bacterial Pathogenesis in the Female Urogenital Tract

Abstract

Urinary tract infection (UTI) is one of the most common infections and costs millions of dollar each year to the health care industry. Escherichia coli is the causative agent responsible for over 80% of UTIs. However, other pathogens such as Group B streptococcus (GBS), a Grampositive bacterium, also cause UTI. In addition, GBS is an important commensal microbe in the female genital tract. Researchers have used various murine models to study mechanisms of disease pathogenesis for UTI and microbe colonisation of the genital tract. However, there is a lack of understanding of the pathogenic mechanisms and microbe virulence factors involved in UTI and genital tract colonisation due to both E. coli and GBS. This thesis reports on a series of experiments using murine models to better understand the pathogenesis of E. coli and GBS infection in the urogenital tract. It explores the use of several murine models to better understand host responses to these infections. In one series of experiments on both E. coli and GBS, murine models were utilised to define the global host immune response to these bacteria in UTI on a genome-wide scale with the aid of microarrays. Another series of experiments used a murine model of E. coli UTI to study the virulence factor α-hemolysin and how this factor influences host responses. The thesis also describes the development of a novel GBS long-term genital tract colonisation model in mice that was used to define the nature of GBS colonisation and survival in this infection. Thus, a series of novel murine models are described in the thesis that were applied in various host response studies and virulence assays to better understand how E. coli and GBS survive and cause infection in the urogenital tract in vivo. The application of murine models to study urogenital tract infection as described in this thesis provides researchers with a solid platform to examine the effects of virulence factors, and host responses in more detail in future studies. One particular area for future research relates to the specific series of experiments in which a murine UTI model was used to test the efficacy of prophylactic use of a novel E. coli 83972 ‘probi otic strain’ expressing a P fimbriae oligosaccharide receptor mimic to prevent acute infection. In this way, the data described in this thesis also provides vital new insight into how murine models can be used to test possible novel treatment strategies for preventing UTI.