Salmonella enterica Serovar Typhi Lipopolysaccharide O-Antigen Modification Impact on Serum Resistance and Antibody Recognition.
Salmonella entericaserovar Typhi is a human-restricted Gram-negative bacterial pathogen responsible for causing an estimated 27 million cases of typhoid fever annually, leading to 217,000 deaths, and current vaccines do not offer full protection. The O-antigen side chain of the lipopolysaccharide is an immunodominant antigen, can define host-pathogen interactions, and is under consideration as a vaccine target for some Gram-negative species. The composition of the O-antigen can be modified by the activity of glycosyltransferase (gtr) operons acquired by horizontal gene transfer. Here we investigate the role of twogtroperons that we identified in theSTyphi genome. Strains were engineered to express specificgtroperons. Full chemical analysis of the O-antigens of these strains identifiedgtr-dependent glucosylation and acetylation. The glucosylated form of the O-antigen mediated enhanced survival in human serum and decreased complement binding. A single nucleotide deviation from an epigenetic phase variation signature sequence rendered the expression of this glucosylatinggtroperon uniform in the population. In contrast, the expression of the acetylatinggtrCgene is controlled by epigenetic phase variation. Acetylation did not affect serum survival, but phase variation can be an immune evasion mechanism, and thus, this modification may contribute to persistence in a host. In murine immunization studies, both O-antigen modifications were generally immunodominant. Our results emphasize that natural O-antigen modifications should be taken into consideration when assessing responses to vaccines, especially O-antigen-based vaccines, and that theSalmonellagtrrepertoire may confound the protective efficacy of broad-rangingSalmonellalipopolysaccharide conjugate vaccines.
Centre for Immunology and Infection, Hull York Medical School and Department of Biology, University of York, York, United Kingdom E.Kintz@uea.ac.uk Marjan.vanderwoude@york.ac.uk.
Erica
http://orcid.org/0000-0002-6829-5701
E
Kintz
Complex Carbohydrate Research Center, The University of Georgia, Athens, Georgia, USA.
Christian
C
Heiss
Complex Carbohydrate Research Center, The University of Georgia, Athens, Georgia, USA.
Ian
I
Black
Centre for Immunology and Infection, Hull York Medical School and Department of Biology, University of York, York, United Kingdom.
Nicholas
N
Donohue
Centre for Immunology and Infection, Hull York Medical School and Department of Biology, University of York, York, United Kingdom.
Naj
N
Brown
Centre for Immunology and Infection, Hull York Medical School and Department of Biology, University of York, York, United Kingdom.
Mark R
MR
Davies
Complex Carbohydrate Research Center, The University of Georgia, Athens, Georgia, USA.
Parastoo
P
Azadi
The Hospital for Tropical Diseases, Wellcome Trust Major Overseas Programme, Oxford University Clinical Research Unit, Ho Chi Minh City, Vietnam.|Centre for Tropical Medicine, Oxford University, Oxford, United Kingdom.
Stephen
S
Baker
Centre for Immunology and Infection, Hull York Medical School and Department of Biology, University of York, York, United Kingdom.
Paul M
PM
Kaye
Centre for Immunology and Infection, Hull York Medical School and Department of Biology, University of York, York, United Kingdom E.Kintz@uea.ac.uk Marjan.vanderwoude@york.ac.uk.
Marjan
http://orcid.org/0000-0002-0446-8829
M
van der Woude
D000818:Animals; D000907:Antibodies, Bacterial / Q000276:immunology* / Q000494:pharmacology; D001426:Bacterial Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D001483:Base Sequence; D004195:Disease Models, Animal; D005260:Female; D015964:Gene Expression Regulation, Bacterial; D006801:Humans; D007106:Immune Sera / Q000276:immunology* / Q000494:pharmacology; D007114:Immunization; D008745:Methylation; D051379:Mice; D019081:O Antigens / Q000276:immunology* / Q000378:metabolism; D009876:Operon; D012485:Salmonella typhi / Q000145:classification / Q000187:drug effects / Q000235:genetics / Q000276:immunology*; D014435:Typhoid Fever / Q000276:immunology / Q000382:microbiology
D000907:Antibodies, Bacterial; D001426:Bacterial Proteins; D007106:Immune Sera; D019081:O Antigens
O-antigen; Salmonella enterica; lipopolysaccharide; phase variation; serum resistance