title: Differential Killing of Salmonella enterica Serovar Typhi by Antibodies Targeting Vi and Lipopolysaccharide O:9 Antigen.
abstract: Salmonella enterica serovar Typhi expresses a capsule of Vi polysaccharide, while most Salmonella serovars, including S. Enteritidis and S. Typhimurium, do not. Both S. Typhi and S. Enteritidis express the lipopolysaccharide O:9 antigen, yet there is little evidence of cross-protection from anti-O:9 antibodies. Vaccines based on Vi polysaccharide have efficacy against typhoid fever, indicating that antibodies against Vi confer protection. Here we investigate the role of Vi capsule and antibodies against Vi and O:9 in antibody-dependent complement- and phagocyte-mediated killing of Salmonella. Using isogenic Vi-expressing and non-Vi-expressing derivatives of S. Typhi and S. Typhimurium, we show that S. Typhi is inherently more sensitive to serum and blood than S. Typhimurium. Vi expression confers increased resistance to both complement- and phagocyte-mediated modalities of antibody-dependent killing in human blood. The Vi capsule is associated with reduced C3 and C5b-9 deposition, and decreased overall antibody binding to S. Typhi. However, purified human anti-Vi antibodies in the presence of complement are able to kill Vi-expressing Salmonella, while killing by anti-O:9 antibodies is inversely related to Vi expression. Human serum depleted of antibodies to antigens other than Vi retains the ability to kill Vi-expressing bacteria. Our findings support a protective role for Vi capsule in preventing complement and phagocyte killing of Salmonella that can be overcome by specific anti-Vi antibodies, but only to a limited extent by anti-O:9 antibodies.
authors.affiliation: School of Immunity and Infection, College of Medicine and Dental Sciences, University of Birmingham, Birmingham, United Kingdom.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Hart
authors.affiliation: School of Immunity and Infection, College of Medicine and Dental Sciences, University of Birmingham, Birmingham, United Kingdom.
authors.forename: Colette M
authors.initials: CM
authors.lastname: O'Shaughnessy
authors.affiliation: School of Immunity and Infection, College of Medicine and Dental Sciences, University of Birmingham, Birmingham, United Kingdom.
authors.forename: Matthew K
authors.initials: MK
authors.lastname: Siggins
authors.affiliation: School of Immunity and Infection, College of Medicine and Dental Sciences, University of Birmingham, Birmingham, United Kingdom.
authors.forename: Saeeda
authors.initials: S
authors.lastname: Bobat
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, United Kingdom.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Kingsley
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, United Kingdom.
authors.forename: David A
authors.initials: DA
authors.lastname: Goulding
authors.affiliation: Centre for International Health, University of Otago, Dunedin, New Zealand.|Kilimanjaro Christian Medical Centre and Kilimanjaro Christian Medical University College, Tumaini University, Moshi, Tanzania.|Division of Infectious Diseases and International Health, Duke University Medical Center, Durham, United States of America.|Duke Global Health Institute, Duke University, Durham, United States of America.
authors.forename: John A
authors.initials: JA
authors.lastname: Crump
authors.affiliation: London School of Hygiene and Tropical Medicine, Keppel Street, London, United Kingdom.
authors.forename: Hugh
authors.initials: H
authors.lastname: Reyburn
authors.affiliation: Sclavo-Behring Vaccines Institute for Global Health, a GlaxoSmithKline Company, Siena, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Micoli
authors.affiliation: Centre for International Health, University of Otago, Dunedin, New Zealand.
authors.forename: Gordon
authors.initials: G
authors.lastname: Dougan
authors.affiliation: School of Immunity and Infection, College of Medicine and Dental Sciences, University of Birmingham, Birmingham, United Kingdom.
authors.forename: Adam F
authors.initials: AF
authors.lastname: Cunningham
authors.affiliation: School of Immunity and Infection, College of Medicine and Dental Sciences, University of Birmingham, Birmingham, United Kingdom.|Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, United Kingdom.|Jenner Institute, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom.
authors.forename: Calman A
authors.initials: CA
authors.lastname: MacLennan
mesh_terms: D000907:Antibodies, Bacterial / Q000096:biosynthesis / Q000494:pharmacology*; D000942:Antigens, Bacterial / Q000276:immunology; D016667:Bacterial Capsules / Q000737:chemistry / Q000276:immunology; D003176:Complement C3 / Q000737:chemistry / Q000494:pharmacology; D015938:Complement Membrane Attack Complex / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D007106:Immune Sera / Q000737:chemistry; D056724:Immunity, Humoral; D007114:Immunization; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors / Q000097:blood / Q000276:immunology; D010586:Phagocytes / Q000187:drug effects* / Q000276:immunology / Q000382:microbiology; D010587:Phagocytosis / Q000187:drug effects / Q000276:immunology; D011135:Polysaccharides, Bacterial / Q000037:antagonists & inhibitors / Q000097:blood / Q000276:immunology; D061251:Primary Cell Culture; D012480:Salmonella Infections / Q000276:immunology / Q000382:microbiology / Q000517:prevention & control; D012485:Salmonella typhi / Q000276:immunology*; D012486:Salmonella typhimurium / Q000276:immunology*; D013045:Species Specificity; D014435:Typhoid Fever / Q000276:immunology / Q000382:microbiology / Q000517:prevention & control*; D014436:Typhoid-Paratyphoid Vaccines / Q000008:administration & dosage* / Q000037:antagonists & inhibitors / Q000097:blood / Q000276:immunology
chemical_list: D000907:Antibodies, Bacterial; D000942:Antigens, Bacterial; D003176:Complement C3; D015938:Complement Membrane Attack Complex; D007106:Immune Sera; D008070:Lipopolysaccharides; D011135:Polysaccharides, Bacterial; D014436:Typhoid-Paratyphoid Vaccines; C057664:Vi polysaccharide vaccine, typhoid