Decorations in Play a Key Role in Eliciting Functional Immune Responses Against Heterologous Serovars in Animal Models

Overview

Journal Front Cell Infect Microbiol

Specialties Cell Biology
Infectious Diseases
Microbiology

Date 2024 Mar 15

PMID 38487353

Authors

Gianmarco Gasperini

Luisa Massai

Daniele De Simone

Maria Michelina Raso

Elena Palmieri

Renzo Alfini

Omar Rossi

Neil Ravenscroft

Michelle M Kuttel

Francesca Micoli

Affiliations

Soon will be listed here.

Abstract

Introduction: Different serovars of Salmonella enterica cause systemic diseases in humans including enteric fever, caused by S. Typhi and S. Paratyphi A, and invasive nontyphoidal salmonellosis (iNTS), caused mainly by S. Typhimurium and S. Enteritidis. No vaccines are yet available against paratyphoid fever and iNTS but different strategies, based on the immunodominant O-Antigen component of the lipopolysaccharide, are currently being tested. The O-Antigens of S. enterica serovars share structural features including the backbone comprising mannose, rhamnose and galactose as well as further modifications such as O-acetylation and glucosylation. The importance of these O-Antigen decorations for the induced immunogenicity and cross-reactivity has been poorly characterized.

Methods: These immunological aspects were investigated in this study using Generalized Modules for Membrane Antigens (GMMA) as delivery systems for the different O-Antigen variants. This platform allowed the rapid generation and in vivo testing of defined and controlled polysaccharide structures through genetic manipulation of the O-Antigen biosynthetic genes.

Results: Results from mice and rabbit immunization experiments highlighted the important role played by secondary O-Antigen decorations in the induced immunogenicity. Moreover, molecular modeling of O-Antigen conformations corroborated the likelihood of cross-protection between S. enterica serovars.

Discussion: Such results, if confirmed in humans, could have a great impact on the design of a simplified vaccine composition able to maximize functional immune responses against clinically relevant Salmonella enterica serovars.

Citing Articles

Impact on Human Health of spp. and Their Lipopolysaccharides: Possible Therapeutic Role and Asymptomatic Presence Consequences.

Mikolajczyk M, Zlotkowska D, Mikolajczyk A Int J Mol Sci. 2024; 25(22).

PMID: 39595937 PMC: 11593640. DOI: 10.3390/ijms252211868.

Design of a Glycoconjugate Vaccine Against Paratyphi A.

Alfini R, Carducci M, Massai L, De Simone D, Mariti M, Rossi O Vaccines (Basel). 2024; 12(11).

PMID: 39591175 PMC: 11599127. DOI: 10.3390/vaccines12111272.

Modeling 1-Cyano-4-Dimethylaminopyridine Tetrafluoroborate (CDAP) Chemistry to Design Glycoconjugate Vaccines with Desired Structural and Immunological Characteristics.

Nappini R, Alfini R, Durante S, Salvini L, Raso M, Palmieri E Vaccines (Basel). 2024; 12(7).

PMID: 39066345 PMC: 11281720. DOI: 10.3390/vaccines12070707.

References

MacLennan C, Martin L, Micoli F . Vaccines against invasive Salmonella disease: current status and future directions. Hum Vaccin Immunother. 2014; 10(6):1478-93. PMC: 4185946. DOI: 10.4161/hv.29054. View

De Benedetto G, Alfini R, Cescutti P, Caboni M, Lanzilao L, Necchi F . Characterization of O-antigen delivered by Generalized Modules for Membrane Antigens (GMMA) vaccine candidates against nontyphoidal Salmonella. Vaccine. 2016; 35(3):419-426. DOI: 10.1016/j.vaccine.2016.11.089. View

Rossi O, Citiulo F, Giannelli C, Cappelletti E, Gasperini G, Mancini F . A next-generation GMMA-based vaccine candidate to fight shigellosis. NPJ Vaccines. 2023; 8(1):130. PMC: 10480147. DOI: 10.1038/s41541-023-00725-8. View

Kintz E, Heiss C, Black I, Donohue N, Brown N, Davies M . Salmonella enterica Serovar Typhi Lipopolysaccharide O-Antigen Modification Impact on Serum Resistance and Antibody Recognition. Infect Immun. 2017; 85(4). PMC: 5364305. DOI: 10.1128/IAI.01021-16. View

Okoro C, Kingsley R, Connor T, Harris S, Parry C, Al-Mashhadani M . Intracontinental spread of human invasive Salmonella Typhimurium pathovariants in sub-Saharan Africa. Nat Genet. 2012; 44(11):1215-21. PMC: 3491877. DOI: 10.1038/ng.2423. View

Phillips J, Braun R, Wang W, Gumbart J, Tajkhorshid E, Villa E . Scalable molecular dynamics with NAMD. J Comput Chem. 2005; 26(16):1781-802. PMC: 2486339. DOI: 10.1002/jcc.20289. View

Mancini F, Gasperini G, Rossi O, Aruta M, Raso M, Alfini R . Dissecting the contribution of O-Antigen and proteins to the immunogenicity of Shigella sonnei generalized modules for membrane antigens (GMMA). Sci Rep. 2021; 11(1):906. PMC: 7806729. DOI: 10.1038/s41598-020-80421-y. View

Hoiseth S, Stocker B . Aromatic-dependent Salmonella typhimurium are non-virulent and effective as live vaccines. Nature. 1981; 291(5812):238-9. DOI: 10.1038/291238a0. View

Dobinson H, Gibani M, Jones C, Thomaides-Brears H, Voysey M, Darton T . Evaluation of the Clinical and Microbiological Response to Salmonella Paratyphi A Infection in the First Paratyphoid Human Challenge Model. Clin Infect Dis. 2017; 64(8):1066-1073. PMC: 5439345. DOI: 10.1093/cid/cix042. View

10.

Mancini F, Micoli F, Necchi F, Pizza M, Scorza F, Rossi O . GMMA-Based Vaccines: The Known and The Unknown. Front Immunol. 2021; 12:715393. PMC: 8368434. DOI: 10.3389/fimmu.2021.715393. View

11.

Lanzilao L, Stefanetti G, Saul A, MacLennan C, Micoli F, Rondini S . Strain Selection for Generation of O-Antigen-Based Glycoconjugate Vaccines against Invasive Nontyphoidal Salmonella Disease. PLoS One. 2015; 10(10):e0139847. PMC: 4596569. DOI: 10.1371/journal.pone.0139847. View

12.

Ravenscroft N, Cescutti P, Gavini M, Stefanetti G, MacLennan C, Martin L . Structural analysis of the O-acetylated O-polysaccharide isolated from Salmonella paratyphi A and used for vaccine preparation. Carbohydr Res. 2015; 404:108-16. DOI: 10.1016/j.carres.2014.12.002. View

13.

Micoli F, Alfini R, Di Benedetto R, Necchi F, Schiavo F, Mancini F . GMMA Is a Versatile Platform to Design Effective Multivalent Combination Vaccines. Vaccines (Basel). 2020; 8(3). PMC: 7564227. DOI: 10.3390/vaccines8030540. View

14.

Dolecek C, Tran T, Nguyen N, Le T, Ha V, Phung Q . A multi-center randomised controlled trial of gatifloxacin versus azithromycin for the treatment of uncomplicated typhoid fever in children and adults in Vietnam. PLoS One. 2008; 3(5):e2188. PMC: 2374894. DOI: 10.1371/journal.pone.0002188. View

15.

Broadbent S, Davies M, van der Woude M . Phase variation controls expression of Salmonella lipopolysaccharide modification genes by a DNA methylation-dependent mechanism. Mol Microbiol. 2010; 77(2):337-53. PMC: 2909390. DOI: 10.1111/j.1365-2958.2010.07203.x. View

16.

Reeves P, Cunneen M, Liu B, Wang L . Genetics and evolution of the Salmonella galactose-initiated set of o antigens. PLoS One. 2013; 8(7):e69306. PMC: 3715488. DOI: 10.1371/journal.pone.0069306. View

17.

Kingsley R, Msefula C, Thomson N, Kariuki S, Holt K, Gordon M . Epidemic multiple drug resistant Salmonella Typhimurium causing invasive disease in sub-Saharan Africa have a distinct genotype. Genome Res. 2009; 19(12):2279-87. PMC: 2792184. DOI: 10.1101/gr.091017.109. View

18.

Micoli F, Nakakana U, Scorza F . Towards a Four-Component GMMA-Based Vaccine against . Vaccines (Basel). 2022; 10(2). PMC: 8880054. DOI: 10.3390/vaccines10020328. View

19.

Humphrey W, Dalke A, Schulten K . VMD: visual molecular dynamics. J Mol Graph. 1996; 14(1):33-8, 27-8. DOI: 10.1016/0263-7855(96)00018-5. View

20.

Carlin N, Svenson S, Lindberg A . Role of monoclonal O-antigen antibody epitope specificity and isotype in protection against experimental mouse typhoid. Microb Pathog. 1987; 2(3):171-83. DOI: 10.1016/0882-4010(87)90019-2. View