Abstract
Outer membrane vesicles (OMVs) isolated from Salmonella Typhimurium are potentially useful for developing subunit vaccines because of high immunogenicity and protective efficacy. However, flagella might remain in OMV pellets following OMV purification, resulting in non-essential immune responses and counteraction of bacterial protective immune responses when developing a vaccine against infection of multiple serotypes Salmonella. In this study, a flagellin-deficient S. Typhimurium mutant was constructed. Lipopolysaccharide profiles, protein profiles and cryo-electron microscopy revealed that there were no significant differences between the wild-type and mutant OMVs, with the exception of a large amount of flagellin in the wild-type OMVs. Neither the wild-type OMVs nor the non-flagellin OMVs were toxic to macrophages. Mice immunized with the non-flagellin OMVs produced high concentrations of IgG. The non-flagellin OMVs elicited strong mucosal antibody responses in mice when administered via the intranasal route in addition to provoking higher cross-reactive immune responses against OMPs isolated from S. Choleraesuis and S. Enteritidis. Both intranasal and intraperitoneal immunization with the non-flagellin OMVs provided efficient protection against heterologous S. Choleraesuis and S. Enteritidis challenge. Our results indicate that the flagellin-deficient OMVs may represent a new vaccine platform that could be exploited to facilitate the production of a broadly protective vaccine.
Highlights
Flagellin is often used as an adjuvant in vaccines, in which the corresponding flagellin is engineered to display a foreign peptide on the surface, fused with foreign proteins, or chemically linked to bacterial polysaccharides[20,21,22]
Flagellin acts as a good protective antigen because it is capable of providing protection against bacterial infection[23,24]
Compared to live attenuated vaccine candidates, OMVs provide several potential advantages, including a lack of replication, better safety, higher immunogenicity and intrinsic adjuvant effects that are provided by LPS, outer membrane proteins (OMPs) and other immune-stimulating molecules[11,38]
Summary
OMVs from Gram-negative bacteria have a structure with a spherical bilayer membrane that contains biologically active components, such as membrane proteins and lipopolysaccharide (LPS). LPS and outer membrane proteins (OMPs) contained in the OMVs may serve as adjuvants of immunestimulating molecules to potently stimulate professional antigen-presenting cells (APCs) and thereby enhance immune responses[7]. The structural protein contained in bacterial flagella, is common in pathogenic and commensal bacteria such as Salmonella and E. coli[16,17]. The presence of large amounts of flagellin in OMVs may interfere with the immunogenicity of other antigens or induce excessive pro-inflammatory responses as a result of the characteristics of the immune-stimulating molecule[16,25]. We demonstrated that the non-flagellin OMVs induced strong mucosal and systemic responses and provided effective protection against challenge with diverse Salmonella serovars
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