The effects of vaccination and immunity on bacterial infection dynamics in vivo: a systems biology analysis

Salmonella enterica causes severe diseases such as typhoid fever, gastroenteritis and septicaemia in humans and in many animal species world-wide. Fatal disease in domestic animals results in severe economic losses; the bacteria can also persist undetected in food animals causing very serious problems to the food industry due to the high incidence of food poisoning. So far it has been difficult to control Salmonella infections using hygiene and biosecurity measures and an increasing number of salmonellae are becoming resistant to numerous drugs. Some of the currently used vaccines against S. enterica, that have been generated mainly though empirical research, confer a moderate, albeit suboptimal, level of protection against colonisation and/or disease. Recent advances in immunology and bacterial genetics offer the possibility to improve vaccine design and delivery, and this process would be empowered by a thorough understanding of how the infection process develops in the presence of different types of immunological pressure. We propose a novel multidisciplinary approach to analyse, in vivo, how different classes of vaccines and types of immune response affect bacterial growth, death, spread and distribution (population dynamics) in the host. The work will develop through different levels of complexity spanning from the analysis of the effects of vaccines and immunity on the direct interactions between individual bacteria and host cells (focal dynamics) to the analysis of how individual molecularly tagged populations of bacteria spread and grow into and between different organs (global dynamics). The interactions between bacteria and cells at the level of individual infection foci (focal dynamics) will be captured by advanced microscopy techniques that allow the observation of fluorescent S. enterica in cells and tissues. The global dynamics of the infection will be studied by monitoring the numerical and spatial fluctuations of distinct bacterial subpopulations each carrying individual DNA tags ('molecular labels') in their genome. This biological research will be integrated with the predictive and resolving power of mathematical models in a series of iterative processes whereby biology and mathematics will synergise and inform each other for a truly advanced understanding of the infection process. The novelty of the biological and mathematical approaches that we shall use is in the unraveling of the infection scenarios across different scales (systems biology research). This will lead to the analysis and reconstruction of the infection processes from their individual biological elements and to the creation of a new paradigm for the study of within-host dynamics of infection that will be extendable to a broad range of pathogens in many animal species and in humans.

Salmonella infections are a serious medical and veterinary problem worldwide and a significant issue for the food industry. Control of Salmonella infections using hygiene and biosecurity measures is difficult; many antibiotics are failing due to the emergence of multi-drug resistant isolates. Current vaccines are far from optimal; design and testing of new preparations is performed empirically often based on reductionist research. The aim of the proposed research is to use a coherent systems biology approach, that evolves from our recent work, to understand how immunity and vaccines affect bacterial infection dynamics in vivo. We will use multidisciplinary research approaches to study the infection process at different levels of complexity in vivo, from the direct interaction between bacteria and host cells to the analysis of global heterogeneous traits of bacterial population dynamics in the host. Using multicolour fluorescence microscopy techniques and quantitation of molecularly tagged bacterial subpopulations we will unravel how the bacteria grow, spread, distribute and persist in the face of different types of vaccine and immune responses. Iterative feedbacks between biological work in vivo and a range of mathematical models will allow synthesis across different scales and reconstruction of the system from its individual biological elements. This work, that will be extendable to a range of pathogens and animal species, will strongly impact on human and animal health through improved understanding of the priniciples underlying vaccine design and will allow academia and industry to capitalise on the increasingly large amount of information available on the genetics of bacterial virulence and on the possibility to modulate the immune system towards specific types of response using appropriate adjuvants or vaccine delivery systems.

Who will benefit from the research? The research will have an immediate impact on the broad academic scientific community and those sectors of industry currently engaged in research on host pathogen relationships, vaccine development, immuno-evasion, immunity to bacterial infection and in vivo mathematical modelling and systems biology of infection processes. Scientists will rapidly benefit from the availability of knowledge and approaches that will be developed and validated during the programme of work and that can be extended to a large number of animal and microbial species. The research will be of benefit for the general public and will impact on human and animal health due to its high impact on future trends of rational vaccine development and testing. The food industry will be another significant beneficiary of the proposed research due to the need for improved vaccines to prevent colonisation of food animals with Salmonella strains that can be transmitted to humans through contaminated meat or eggs. How will they benefit from this research? The research has the potential to impact on human and animal health worldwide given the high and widespread incidence of Salmonella infections. The proposed work will represent a leap forward towards a multi-scale understanding of the strengths and pitfalls of vaccines in the light of the dynamics of the infection process. Therefore, a major impact of the proposed research is its contribution to the replacement of empirical vaccine design and testing. The work will also contribute to a safer use of currently available vaccines. In fact, conditions that predispose to infection can, in selected cases, pose danger to the use of particular classes of vaccine. By understanding precisely the spatiotemporal requirements of immune protection, and by using iterative combinations of mathematical modeling and immunological/epidemiological observations, it will be possible to predict how a specific weakness in a component of the immune response can impact on the safety and efficacy of a particular vaccine in humans and domestic animals.