Pathogenic salmonellae are one of the leading causes of enteric infections in the USA. According to WHO, these pathogens account for the majority of cases of infectious diarrhea worldwide, leading to an estimated 2,000,000 deaths annually, including nearly 525,000 children under the age of five. Unfortunately, infectious diarrhoeal diseases are still the second leading cause of death in children under five years old. One of the reasons behind the high incidence of these infections is the lack of effective vaccines providing lasting protection against non-typhoidal (NTS) Salmonella infections. Stimulation of humoral immunity by vaccination leads to the production of antibodies, which in case of NTS infection predominantly include non-protective anti- bodies. The mechanism behind aspects of the antibody response is unknown, particularly as some of these Salmonella antigens are not well accessible on the cell surface. In this proposal, we will evaluate the contribu- tion of exosomes to the antibody response against salmonellosis and detect antigens in exosomes formed dur- ing infection. Our long-term goal is to facilitate the discovery of preventative measures against Salmonella infection by improving our knowledge of the host-pathogen interactions. The objective of our proposal is to identify the contribution of exosomes in expanding the repertoire of antigens for antigen-presenting cells and stimulating protective responses. Our central hypothesis is that Salmonella induces production of M?s- derived exosomes containing Salmonella Ags. The exosome-enclosed Ags are predicted to provide protection against Salmonella. The rationale is that once the studies in this proposal are completed, we will answer if exosomes can elicit protective responses against salmonellosis and set foundations for future re- search centered around therapeutic applications. The outcomes of this study will be: (1) evaluation if exo- somes produced during infection with Salmonella contribute to protective responses, and (2) identification whether ubiquitin modification is required for antigen trafficking into exosomes. In summary, our proposed pro- ject will improve our understanding of the function of exosomes in adaptive immunity, thereby uncovering a novel host response mechanism to Salmonella infection. The innovation of this proposal lies in addressing the novel mechanism for expanding antigen repertoire and stimulating immune responses. This study is signifi- cant because we will advance knowledge on host responses to infection by secretory vesicles.
This proposed project is relevant to public health because the characterization of the protective functions of exosomes in Salmonella infection will help understand how the immune system?s signaling is modulated via the host?s secretory pathways. This proposal is relevant to the NIAID?s mission to support fundamental and mechanistic research investigating regulatory aspects of immune signaling.