Abstract
Salmonella Typhimurium is a causative agent of nontyphoidal salmonellosis, for which there is a lack of a clinically approved vaccine in humans. As an intracellular pathogen, Salmonella impacts many cellular pathways. However, the intercellular communication mechanism facilitated by host-derived small extracellular vesicles (EVs), such as exosomes, is an overlooked aspect of the host responses to this infection. We used a comprehensive proteome-based network analysis of exosomes derived from Salmonella-infected macrophages to identify host molecules that are trafficked via these EVs. This analysis predicted that the host-derived small EVs generated during macrophage infection stimulate macrophages and promote activation of T helper 1 (Th1) cells. We identified that exosomes generated during infection contain Salmonella proteins, including unique antigens previously shown to stimulate protective immune responses against Salmonella in murine studies. Furthermore, we showed that host EVs formed upon infection stimulate a mucosal immune response against Salmonella infection when delivered intranasally to BALB/c mice, a route of antigen administration known to initiate mucosal immunity. Specifically, the administration of these vesicles to animals stimulated the production of anti-Salmonella IgG antibodies, such as anti-OmpA antibodies. Exosomes also stimulated antigen-specific cell-mediated immunity. In particular, splenic mononuclear cells isolated from mice administered with exosomes derived from Salmonella-infected antigen-presenting cells increased CD4+ T cells secreting Th1-type cytokines in response to Salmonella antigens. These results demonstrate that small EVs, formed during infection, contribute to Th1 cell bias in the anti-Salmonella responses. Collectively, this study helps to unravel the role of host-derived small EVs as vehicles transmitting antigens to induce Th1-type immunity against Gram-negative bacteria. Understanding the EV-mediated defense mechanisms will allow the development of future approaches to combat bacterial infections.
Highlights
The high incidence of multidrug-resistant salmonellae and invasive nontyphoidal salmonellae (NTS) highlights the need to develop preventative and therapeutic strategies to control these infections
Our earlier work showed that Salmonella infection leads to the generation of immunogenic small extracellular vesicles (EVs) by macrophages
We confirmed in vivo that mucosal administration of these EVs promotes a mucosal immune response against Salmonella infection in BALB/c mice
Summary
The high incidence of multidrug-resistant salmonellae and invasive nontyphoidal salmonellae (NTS) highlights the need to develop preventative and therapeutic strategies to control these infections. The early endosomes mature into late endosomes, further generating intraluminal vesicles (ILVs) by endosomal membrane invagination These ILVs are liberated into the extracellular milieu as exosomes by the fusion of MVBs with the plasma membrane [19]. Exosomes can serve as decoys to capture bacterial toxins, as shown for Gram-positive pathogen Staphylococcus aureus [24]. These vesicles potentially support both innate and adaptive responses to Exosomes derived from infected cells stimulate pathogen-specific Th1-type responses in vivo pathogens, yet it is unknown whether exosomes affect immune defenses directed towards gram-negative infections by eliciting humoral or T cell-mediated responses against these bacterial pathogens
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