Mechanisms of Mucosal and Systemic Immunity to Vaccination and Infection with Enteric Pathogens in Children and Adults

Overall - Abstract Enteric bacterial infections are a significant global health concern, particularly in developing nations, where they disproportionately affect children. These diseases include typhoid fever (caused by Salmonella enterica serovar Typhi -S. Typhi-), invasive non-typhoidal Salmonella (iNTS; e.g., S. Enteritidis, S. Typhimurium), and shigellosis (caused by multiple Shigella serotypes). Limited knowledge of systemic and local gut immunity, including immunological correlates of protection, for human-restricted enteric pathogens (e.g., Salmonella and Shigella) continues to hamper vaccine development. Importantly, very limited information is available regarding immune responses to these enteric pathogens in children. To address these major shortcomings, it is imperative that studies involving human-restricted infectious agents are performed in children and adults. Thus, we are proposing under the central theme of “Mechanisms of Mucosal and Systemic Immunity to Vaccination and Infection with Enteric Pathogens in Children and Adults” to further our understanding of the protective immunological mechanisms that can be elicited systemically and in the gut microenvironment by using exclusively human based models with major human-restricted pathogens, i.e., Salmonella (S. Typhi, S. Typhimurium S. Enteritidis) and Shigella flexneri 2a. These studies will use unique specimens from clinical studies (Core 1) in which participants are immunized, or not, with parenteral or oral candidate vaccines against these major enteric bacterial pathogens, and, in some cases, followed by challenge with wild type organisms (Research projects -RP- 1-2). This will allow us to examine the mechanisms (e.g., epigenetic modifications) involved in the induction and maintenance of human adaptive immunity associated with protection. Furthermore, because of the critical importance of innate immunity elicited in the gut, we will use explant tissues and advanced in vitro models of the human gut mucosa (e.g., enteroids) to study the early crosstalk between epithelial cells and innate immunity and the epigenetic mechanisms at play in the gut microenvironment following exposure to Salmonella and Shigella (RP3). The mechanisms underlying immune responses will be studied using advanced technologies e.g., suspension mass cytometry, imaging mass cytometry (Core 3), EpiTOF, ATAC-seq, transcriptomics (RNA-seq), phosphoflow, and single-cell RNA-seq (RP1-3). Mechanistic studies using unique human specimens, gut organoids and explants will employ common methods of analysis and tools and the same wild type and attenuated bacterial strains. A world-class team of systems biologists (Core 2) will integrate immunological and omics data. The proposed strategy involves synergistic interactions among all RP’s and Cores supported by an interdisciplinary team of renowned scientists in immunology, clinical studies, genomics, epigenetics, bioinformatics, modeling, biostatistics and adjuvants. The long-term goal of this “Enteric CCHI” is to advance our knowledge of systemic and gut human immunity to accelerate the development of novel and better vaccines for enteric bacterial pathogens.