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1. (CSDB ID: 11884) | report error |
| /Variants 0/-+ | /Variants 1/-+ | | | a-Abep2Ac-(1-3)-+ | | | | | -2)-a-D-Manp-(1-4)-a-L-Rhap-(1-3)-a-D-Galp-(1- /Variants 0/ is: a-D-Glcp-(1-6)- OR (exclusively) a-D-Glcp-(1-4)- /Variants 1/ is: Ac-3)- OR (exclusively) Ac-2)- | Show graphically |
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Salmonella enterica sv. Typhimurium O4,5
(later renamed to: Salmonella enterica ssp. enterica sv. Typhimurium O4,5)
(Ancestor NCBI TaxID 90371,
species name lookup)
, ICD11: XN0QE ]; malaria [ICD11: XN5FW ]; infection due to Salmonella enterica [ICD11: XN5VC ]
gsk.comInvasive nontyphoidal Salmonella disease (iNTS) is a leading cause of death and morbidity in Africa. The most common pathogens are Salmonella enterica serovars Typhimurium and Enteritidis. The O-antigen portion of their lipopolysaccharide is a target of protective immunity and vaccines targeting O-antigen are currently in development. Here we investigate the use of Generalized Modules for Membrane Antigens (GMMA) as delivery system for S. Typhimurium and S. Enteritidis O-antigen. Gram-negative bacteria naturally shed outer membrane in a blebbing process. By deletion of the tolR gene, the level of shedding was greatly enhanced. Further genetic modifications were introduced into the GMMA-producing strains in order to reduce reactogenicity, by detoxifying the lipid A moiety of lipopolysaccharide. We found that genetic mutations can impact on expression of O-antigen chains. All S. Enteritidis GMMA characterized had an O-antigen to protein w/w ratio higher than 0.6, while the ratio was 0.7 for S. Typhimurium ∆tolR GMMA, but decreased to less than 0.1 when further mutations for lipid A detoxification were introduced. Changes were also observed in O-antigen chain length and level and/or position of O-acetylation. When tested in mice, the GMMA induced high levels of anti-O-antigen-specific IgG functional antibodies, despite variation in density and O-antigen structural modifications. In conclusion, simplicity of manufacturing process and low costs of production, coupled with encouraging immunogenicity data, make GMMA an attractive strategy to further investigate for the development of a vaccine against iNTS.
O-antigen, Salmonella typhimurium, vaccine, Salmonella enteritidis, GMMA, Outer membrane vesicles
Structure type: polymer chemical repeating unit|
2. (CSDB ID: 12076) | report error |
| a-Tyvp-(1-3)-+ a-D-Glcp-(1-4)-+ | | -2)-b-D-Manp-(1-4)-a-L-Rhap-(1-3)-a-D-Galp-(1- | Show graphically |
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Salmonella enterica sv. Enteritidis O9
(later renamed to: Salmonella enterica ssp. enterica sv. Enteritidis O9)
(Ancestor NCBI TaxID 149539,
species name lookup)
, ICD11: XN0QE ]; malaria [ICD11: XN5FW ]; infection due to Salmonella enterica [ICD11: XN5VC ]gsk.comInvasive nontyphoidal Salmonella disease (iNTS) is a leading cause of death and morbidity in Africa. The most common pathogens are Salmonella enterica serovars Typhimurium and Enteritidis. The O-antigen portion of their lipopolysaccharide is a target of protective immunity and vaccines targeting O-antigen are currently in development. Here we investigate the use of Generalized Modules for Membrane Antigens (GMMA) as delivery system for S. Typhimurium and S. Enteritidis O-antigen. Gram-negative bacteria naturally shed outer membrane in a blebbing process. By deletion of the tolR gene, the level of shedding was greatly enhanced. Further genetic modifications were introduced into the GMMA-producing strains in order to reduce reactogenicity, by detoxifying the lipid A moiety of lipopolysaccharide. We found that genetic mutations can impact on expression of O-antigen chains. All S. Enteritidis GMMA characterized had an O-antigen to protein w/w ratio higher than 0.6, while the ratio was 0.7 for S. Typhimurium ∆tolR GMMA, but decreased to less than 0.1 when further mutations for lipid A detoxification were introduced. Changes were also observed in O-antigen chain length and level and/or position of O-acetylation. When tested in mice, the GMMA induced high levels of anti-O-antigen-specific IgG functional antibodies, despite variation in density and O-antigen structural modifications. In conclusion, simplicity of manufacturing process and low costs of production, coupled with encouraging immunogenicity data, make GMMA an attractive strategy to further investigate for the development of a vaccine against iNTS.
O-antigen, Salmonella typhimurium, vaccine, Salmonella enteritidis, GMMA, Outer membrane vesicles
Structure type: polymer chemical repeating unit|
3. (CSDB ID: 12890) | report error |
| L-gro-a-D-manHepp-(1-7)-+ | a-D-Galp-(1-6)-+ | EtN-(1---P---P---4)-+ | | | a-D-GlcpNAc-(1-2)-a-D-Glcp-(1-2)-a-D-Galp-(1-3)-a-D-Glcp-(1-3)-L-gro-a-D-manHepp-(1-3)-L-gro-a-D-manHepp-(1-5)-Kdo | P-4)-+ | Show graphically |
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Salmonella enterica sv. Typhimurium 1418 ΔtolR ΔwbaP
(later renamed to: Salmonella enterica ssp. enterica sv. Typhimurium 1418 ΔtolR ΔwbaP)
(Ancestor NCBI TaxID 90371,
species name lookup)
, ICD11: XN0QE ]; malaria [ICD11: XN5FW ]; anemia [ICD11: 3A9Z ]; infection due to Salmonella enterica [ICD11: XN5VC ]gsk.comInvasive nontyphoidal Salmonella disease, for which licensed vaccines are not available, is a leading cause of bloodstream infections in Africa. The O-antigen portion of lipopolysaccharide is a good target for protective immunity. Covalent conjugation of the O-antigen to a carrier protein increases its immunogenicity and O-antigen based glycoconjugate vaccines are currently under investigation at the preclinical stage. We developed a conjugation chemistry for linking O-antigen to CRM197 carrier protein, through sequential insertion of adipic acid dihydrazide (ADH) and adipic acid bis( N-hydroxysuccinimide) ester (SIDEA) as linkers, without impacting O-antigen chain epitopes. Here the resulting sugar-protein connectivity has been investigated in detail. The core portion of the lipopolysaccharide was used as a model molecule to prepare CRM197 conjugates, making structural investigations easier. The first step of reductive amination with ADH involves the terminal 3-deoxy-d- manno-oct-2-ulosonic acid (KDO) residue of the core region. The second reaction step resulted not to be selective, as SIDEA reacted with both ADH and pyrophosphorylethanolamine (PPEtN) of the core region, independently from the pH at which the reaction was performed. Peptide mapping analysis of the deglycosylated core-CRM197 conjugates confirmed that lysine residues of CRM197 were linked to SIDEA not only through KDO-ADH but also through PPEtN. This analysis also confirmed that the conjugation chemistry is random on the protein, involving a large number of lysine residues, particularly the surface exposed ones. The method for core-CRM197 characterization was successfully extended to O-antigen-CRM197 conjugate, confirming the results obtained with the core. This study not only allowed full characterization of OAg-CRM197 conjugates, but can be applied to optimize synthesis and characterization of other OAg-based glycoconjugate vaccines. Analytical methods to investigate saccharide-protein connectivity are also of fundamental importance to study the relationship between glycoconjugate structure and immune response induced.
Lipopolysaccharide, synthesis, disease, O-antigen, Kdo, epitopes, Salmonella, core region, vaccines, immunogenicity, conjugate, model, CRM197, glycoconjugate vaccine, Peptide Mapping
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