Bacterial diseases are a grave threat for humankind causing approximately six million deaths per year. Antimicrobial resistance is on the increase and better vaccines are needed.
The prevention and treatment of bacterial infections must be underpinned by an in-depth knowledge of the biology and pathogenesis of the microbes and their interactions with the immune system.
Using invasive invasive Salmonella diseases as a broadly representative model, we have integrated multidisciplinary approaches in mammalian hosts to understand how the location, growth, spread of pathogens impacts of the efficacy of vaccines and antibiotics. We have also used advanced mathematical modelling, molecularly tagged bacteria and global genomic approaches to study the in vivo interactions between bacterial and host genes and to determine the qualitative aspects and functional requirements of protective immune responses as well as the impact of immune-deficiencies on disease and vaccination.
We have established that Salmonella has a pathogenesis that is both extracellular and intracellular, with systemic spread in multiple body tissues and with heterogeneous behaviour of different bacterial subpopulations within the same host. Salmonellae are vulnerable to antibodies and complement that lyse the bacteria and/or target them to phagocytes, increasing the antimicrobial functions of host cells. We have identified phagocyte receptors, intracellular killing mechanisms and bacterial evasion strategies that affect phagocyte- and antibody-mediated killing. We have determined the relative potency of different IgG subclasses in murine and human preclinical models, thus generating essential information on the requirements of the protective response. We have also determined the interactions between pathogen behavior and the efficacy of antibiotic therapy. This work lays a foundation for the development of better vaccines and antibiotic treatments for Salmonella infections and establishes principles applicable to other bacterial diseases in a range of host species.