Development and prospects of enterohemorrhagic Escherichia coli vaccine
[Background]Enteric infections caused by various pathogenic strains of bacteria are a significant global public health concern.Shiga toxin-producing Escherichia coli(STEC)stands out as a major contributor to severe infections.The enterohemorrhagic E.coli(EHEC)O157:H7 serotype,initially identified during the 1983 gastrointestinal disease outbreak in Oregon and Michigan,represents the most virulent strain of STEC and currently lacks an effective treatment.The development of safe and efficacious vaccines emerges as a crucial strategy to provide immune protection against EHEC infections.Several vaccine types are currently in development,including attenuated vaccines,recombinant protein vaccines,DNA vaccines,and vaccines targeting outer membrane vesicles(OMVs).Among these,OMVs,naturally produced by the bacteria,exhibit exceptional autoimmunity and antigen-carrying capabilities.They hold promising potential as a vaccine development platform for EHEC infections.In the progression of EHEC OMVs vaccine development,researchers can strategically choose suitable antigens and employ molecular cloning techniques to construct OMVs vaccines featuring specific antigens.Through modifications such as vesicular lipopolysaccharide adjustments and antigen loading,personalized OMVs vaccines tailored to specific immunogenic conditions can be engineered.[Progress]Vaccine development strategies for EHEC generally fall into two primary categories.One approach aims to bind and neutralize the systemic response to Shiga toxin(Stx),thereby mitigating its harmful effects on target tissues.The other focuses on inhibiting EHEC attachment and gastrointestinal colonization by activating mucosal immune defenses.Currently,research on EHEC vaccines has assessed diverse immunization strategies in animal models,including Stx mono-or chimeric antibody-based treatments,type Ⅲsecretion system(T3SS)-secreted protein vaccines,recombinant protein vaccines,plant-based vaccines,DNA vaccines,polysaccharide vaccines,epitope vesicle vaccines,and bacterial attenuated vaccines.The current emphasis is on recombinant protein vaccines.Citrobacter rodentium(CR)serves as a model bacterium commonly employed to simulate EHEC A/E injury in mice.It can be introduced into intestinal epithelial cells through a T3SS effector,establishing infection in the mouse intestine.Studies have aimed to develop Stx-secreting CR strains.To facilitate efficient colonization observation,some researchers have inserted the LuxABCDE manipulator into the CR DBS100 genome,creating a strain capable of bioluminescence in mice.OMVs,naturally immunostimulatory and carrying a diverse set of antigens,have been identified as carriers of various EHEC virulence factors into host cells.These factors include Stx2a,CdtV,EHEC hemolysin,and flagellin.Recently,the presence of T3SS-associated transporter proteins,EspB,EspD,and effector Tir,has been demonstrated in EHEC OMVs.Thus,OMVs hold the potential to serve as a platform for bacterial vaccines,addressing a variety of pathogenic microbial infections.[Perspective]EHEC exerts a significant impact on global public health and poses a serious threat,particularly to children's well-being.The mode of EHEC infection and the mechanism of action of OMVs remain partially understood,and effective therapeutic interventions are currently lacking.The development of EHEC vaccines is primarily at the preclinical stage,with existing vaccines predominantly targeting specific serotypes,which limits their broad applicability.There is an urgent need to assess the potential immunogenic consequences of antigenic polymorphisms and variants in in vivo immunization.This study aims to contribute to the establishment of an EHEC vaccine platform for OMVs by providing a comprehensive overview of the potential for OMVs vaccine development.Notably,recent research has identified the presence of transport proteins corresponding to T3SS in EHEC OMVs.This discovery may challenge the existing T3SS injection model,suggesting that OMVs could serve as an alternative pathway for T3SS-associated protein transport.Exploring the manipulation of T3SS protein transport through the use of OMVs,a virulence system prevalent in these bacteria,may be of interest in the future development of EHEC OMVs.
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