Temporal changes to cellular bioenergetics, cholesterol metabolism, innate immune responses and microbiota during infection

Bacterial infections are major cause of morbidity and mortality in children under 5 years of age, especially in Low and Middle Income Countries (LMIC). In industrial countries, bacterial infections mainly affect the elderly (both in the community and in hospitals) and the immunocompromised (e.g. patients undergoing chemotherapy or infected with HIV). While the ability to treat bacterial infections with antibiotics is arguably the most important achievement of modern medicine, the extensive misuse and overuse of antibiotics in human medicine and livestock has contributed to the rise and spread of antimicrobial resistance (AMR). The threat of antibiotic resistance is well reported, being sighted in many newspaper articles, high-level government reports and campaigns in recent years. Already responsible for 700,000 deaths per year, antibiotic-resistant bacteria are predicted to cause a staggering 10 million deaths by 2050. Whilst there has been a dramatic rise in the spread of multi-drug resistant bacteria, the discovery rate of new antibiotics has tumbled over the past decades, with only a few new approved drugs reaching the clinic. This highlights the urgent need to complement traditional drug discovery routes with new approaches to treat bacterial infections. Importantly, unintended targets of antibiotics include the normal, beneficial, gut bacteria (microbiota). Accordingly, we need to employ innovative approaches to treat bacterial infections, which minimise both selective pressure-promoting emergence of resistance and impact on the microbiota. The development of effective and novel control measures requires a systematic understanding of the biology of the disease, particularly the complex interactions between bacterial pathogens and their hosts in the context of the gut microbiota. By definition, this type of research relies on utilisation of robust and physiologically relevant animal models. Citrobacter rodentium is mouse specific extracellular pathogen, which shares an infection strategy with human pathogenic E. coli strains (for example E. coli O157). Being a natural mouse pathogen, C. rodentium provides an ideal model to study infections with gut pathogens in the natural host and in the context of the gut microbiota. C. rodentium causes a self-limiting infection and triggers robust immune responses, proliferation of epithelial cells and displacement of the normal gut bacteria which mimic the characteristics observed during human infection with pathogenic E. coli. Recently, by applying state-of-the-art molecular methods to study the interaction of C. rodentium with cells that line the gut we found that the infection causes drastic changes to energy production and central metabolism in the host cells, in what seems to be an attempt to dampen inflammation. While previously the focus has been on immune cells, it is only now that we are starting to realise that controlling metabolism in epithelial cells is another key frontier in host-pathogen interactions. In this project we aim to obtain an unprecedented molecular resolution of host-pathogen interactions over the duration of infection, in the context of a whole organism. Our proof-of-concept studies have already shown deregulation in the production and release of cholesterol during C. rodentium infection. In this project we will use wild type and mutant C. rodentium strains as well as wild type mice and mice deficient in a key controllers of cholesterol metabolism. We will study changes in metabolism over time, from infection to recovery, and match these changes to the presence of specific gut microbiota. The use of selected mutants, both bacterial and host, will allow us to unravel the molecular processes involved. We believe our pioneering approach would lead to conceptual shifts in understanding of host-bacterial infections and thus open new avenues for the development of novel treatment strategies for bacterial infection.