Mechanisms of Induction and Maintenance of Systemic and Gut Mucosal T Cell Immunity to Salmonella and Shigella Following Infection and Vaccination in Children and Adults

RP1 PROJECT SUMMARY/ABSTRACT Enteric diseases caused by Salmonella (typhoidal and non-typhoidal -NTS-) and Shigella (multiple serotypes) remain a major health problem worldwide especially in developing nations. Invasive NTS (iNTS) has emerged in sub-Saharan Africa where it is causing devastating morbidity and mortality among young adults and children. While the development of effective vaccines with durable and broad-spectrum protection against these pathogens has become a priority, their development is limited by the lack of knowledge of systemic and local gut immunity including immunological correlates of protection (CoP), particularly in children. No vaccines are available for iNTS and Shigella. Despite considerable progress in our understanding of Salmonella and Shigella T cell mediated immunity (T-CMI), crucial gaps exist in our knowledge of the mechanisms associated with the induction and persistence of local and systemic antigen-specific T cells following vaccination and/or challenge in adults and children. Thus, we propose to address these gaps in knowledge and to uncover the mechanisms (e.g., epigenetics) of induction and persistence of Salmonella specific T-CMI responses to further our understanding of mechanisms of protective immunity using unique specimens from clinical studies (Core 1). Our overarching goal is to evaluate the mechanisms of induction and persistence of S. Typhi, iNTS and Shigella specific T-CMI responses in key T cell subsets, including effector/memory (TEM), stem cell like memory (TSCM), follicular helper (TFH) and regulatory cells (TREG) observed at baseline and soon and long-term after immunization and/or challenge with wt S. Typhi or Shigella and determine their association with protection. Importantly, we will study the mechanisms of induction and persistence in children (the primary population affected by S. Typhi and iNTS) vaccinated with the live oral attenuated typhoid vaccine Ty21a. We will also determine the mechanistic differences between adults challenged with wt S. Typhi or immunized with oral (Ty21a) or a parenteral Trivalent Salmonella conjugate Vaccine (TSCV). Additional studies will involve adults challenged with wt Shigella or following immunization with the candidate attenuated Shigella CVD1208S-122 strain. Finally, we will evaluate the mechanisms of induction and persistence of S. Typhi responsive T cells operating in the local mucosa by using terminal ileum and duodenal biopsies obtained from Ty21a immunized adult volunteers. Throughout these studies, we make use of advanced technologies (e.g., mass-cytometry, EpiTOF, ATAC-seq, RNA-seq, scRNA-seq and imaging mass cytometry (Core 3). All the data will be analyzed by using a sophisticated system biology approach (Core 2) in concert with data provided by other projects (RP2 and RP3). These studies will uncover critical information on the induction and durability of local and systemic antigen specific T-CMI revealing epigenetic and transcriptomic signatures that might lead to the identification of molecular correlates of protection that may inform future vaccine design for adults and children.