There is no licensed vaccine for humans against potentially life-threatening paratyphoid and nontyphoidal
septicemia caused by the Salmonella enterica. This intracellular pathogen evades sophisticated host immune
defenses. The host immune system is controlled by regulatory mechanisms, such as intercellular communication
between infected and uninfected cells, which can also be accomplished via small extracellular vesicles (EVs),
exosomes. Exosomes are vesicles that originate in the endosomal pathway and transport cargo to other cells.
We found that exosomes carry bacterial antigens (Ags) from S. Typhimurium-infected macrophages (
MF
s) and
stimulate naïve antigen-presenting cells involved in T cell recruitment, and an intranasal administration of these
exosomes leads to the production of anti-S. Typhimurium antibodies (Abs) and stimulation of Th 1 response
critical for engulfing and killing intracellular bacteria. These adaptive responses are Ags-dependent, but the Ags
responsible for this humoral response or the mechanisms responsible for Ag trafficking to EVs are unknown. We
will address the contribution of exosomes to adaptive immune responses against intracellular pathogens as there
is a critical need to determine new mechanisms of protective immune responses, such as exosome-modulated
immunity. Our long-term goal is to advance the development of mechanism-based preventative measures for
bacterial infections. Our overall objective is to elucidate the mechanisms whereby bacterial Ags are trafficked to
exosomes and identify the capability of exosomes to generate protective cellular and humoral immunity against
intracellular Salmonella. Our central hypothesis is that Salmonella Ags are trafficked to endosomal
compartments of infected MFs and released via exosomes to stimulate innate responses and Ag-specific
Th1
cell responses
. The rationale is that determining the mechanisms via which Salmonella Ags are trafficked to
exosomes and generate adaptive immunity against Salmonella, we will assign a novel role of EVs in host
defense, important for the design of preventative approaches. In Aim 1, we will identify mechanisms whereby
Salmonella Ags are trafficked into EVs. In Aim 2, we will determine the mechanisms by which EVs produced by
Salmonella-infected
determine how EVs
MF
s regulate the activation and function of DCs in mucosal tissues. In Aim 3, we will
derived from Salmonella-infected
MF
s drive adaptive immunity. The expected outcomes
are that we will have established a mechanism responsible for the trafficking of Ags into EVs, and characterize
novel roles of EVs in innate immunity and Th1 adaptive immunity. This study will have a positive impact as it will
provide a conceptual framework for the future development of targets for vaccine design and significantly
advance knowledge of how Salmonella disrupts host immunity, which is vital for the development of preventative
and therapeutic approaches against this pathogen. The innovation lies in addressing the function of EVs
produced by host cells in rendering protection against salmonellosis. This study is significant since we will
advance knowledge on the function of host exosomes in altering the immune response to Salmonella infection.