Gut Microbe-Derived Outer Membrane Vesicles: A Potential Platform to Control Cecal Load of Campylobacter jejuni

Abstract

Acute diarrheal illness and gastroenteritis caused by Campylobacter jejuni infection remain significant public health risks in developing countries with substantial mortality and morbidity in humans, particularly in children under the age of five. Genetic diversities among Campylobacter jejuni and limited understanding of immunological correlations of host protection remain primary impediments for developing an effective measure to controlCampylobacter infection. Moreover, the lack of a reliable in vivo model to mimic natural infection against Campylobacter jejuni has substantially delayed the vaccine-development process. Given the role of bacterial outer membrane associated proteins in intestinal adherence and invasion as well as modulating dynamic interplay between host and pathogens, bacterial outer-membrane vesicles have emerged as a potential vaccine target against a number of gut pathogens, including Campylobacter jejuni. Here, we describe a mucosal vaccine strategy using chitosan-coated outer-membrane vesicles to induce specific immune responses against Campylobacter jejuni in mice. To overcome the challenges of mucosal delivery of outer membrane vesicles in terms of exposure to variable pH and risk of enzymatic degradation, we preferentially used chitosan as a nontoxic, mucoadhesive polymer. We show that intragastric delivery of chitosan-coated outer-membrane vesicles imparts significant immune protection against Campylobacter jejuni with high level local and systemic antibody production. Further, immunization with the outer membrane vesicles resulted in potent cellular responses with an increased CD4 + and CD8 + T cell population. Moreover, significant upregulation of IFN-γ and IL-6 gene expression suggests that mucosal delivery of outer membrane vesicles promotes a Th1/Th2 mixed-type immune response. Together, as an acellular and nonreplicating canonical end product of bacterial secretion, mucosal delivery of outer membrane vesicles may represent a promising platform for developing an effective vaccine against Campylobacter jejuni.

Extracellular Vesicles—Oral Therapeutics of the Future

“…Bacterial-derived EVs appear to be candidates for mucosal vaccines causing immune protection against specific pathogens [ 47 , 48 , 49 ]. Accordingly, massive production of both intestinal sIgA as well as serum IgG antibodies against EV-transmitted antigens was noted in mice that were orally immunized with three doses of chitosan-coated Campylobacter jejuni -derived EVs together with the induction of a specific cell-mediated immune response.…”

“…Accordingly, massive production of both intestinal sIgA as well as serum IgG antibodies against EV-transmitted antigens was noted in mice that were orally immunized with three doses of chitosan-coated Campylobacter jejuni -derived EVs together with the induction of a specific cell-mediated immune response. Furthermore, after a subsequent intragastric challenge with C. jejuni , a significant reduction in the bacterial load and only slight histological changes in the cecal tissue was observed in immunized animals [ 47 ]. Similarly, four intragastric administrations of H. pylori -derived EVs with a cholera toxin as an adjuvant protected mice from H. pylori infection by activating the production of antibodies specific for EVs’ outer membrane protein [ 49 ].…”

Multi-Omics Approach Reveals the Potential Core Vaccine Targets for the Emerging Foodborne Pathogen Campylobacter jejuni

“…Consequently, the estimation of the core VF proteins for subcellular location revealed that 47 proteins were cytoplasmic, 19 were located in the cytoplasmic membrane, one was in the outer membrane, three were unknown, and four were periplasmic ( Figure 3C ). It is known that outer membrane vesicles (OMVs) are a molecular complex consisting of lipopolysaccharides (LPS), outer membrane proteins, periplasmic proteins, lipids, and even cytoplasmic proteins, which are important vehicles for the simultaneous delivery of many effector molecules to host cells ( Cai et al, 2018 ; Singh et al, 2021 ). Exposed proteins are often attractive targets for vaccine design, but sometimes not all proteins must be exposed to the surface, including some periplasmic proteins present in OMV preparations, which may also elicit an immunogenic response ( Awanye et al, 2019 ).…”

“…Exposed proteins are often attractive targets for vaccine design, but sometimes not all proteins must be exposed to the surface, including some periplasmic proteins present in OMV preparations, which may also elicit an immunogenic response ( Awanye et al, 2019 ). Due to the role of OMVs in intestinal adhesion and invasion, and in regulating the dynamic interaction between host and pathogens, OMVs have become potential vaccine targets for a variety of intestinal pathogens ( Singh et al, 2021 ). Therefore, the bacterial cell surface and secreted proteins, usually located in the extracellular, periplasmic, and outer membranes, could be more effective as vaccine candidates or diagnostic targets.…”

Cell membrane-coated nanoparticles: An emerging antibacterial platform for pathogens of food animals

“…The chitosan-nanoparticles were coated with outer-membrane vesicles and then evaluated in mouse model for induction of specific immune response against C. jejuni . The results indicated that intragastric delivery of chitosan-coated outer-membrane vesicles impart significant immune protection ( 166 ).…”