title: Bactericidal Immunity to Salmonella in Africans and Mechanisms Causing Its Failure in HIV Infection.
abstract: BACKGROUND
  Nontyphoidal strains of Salmonella are a leading cause of death among HIV-infected Africans. Antibody-induced complement-mediated killing protects healthy Africans against Salmonella, but increased levels of anti-lipopolysaccharide (LPS) antibodies in some HIV-infected African adults block this killing. The objective was to understand how these high levels of anti-LPS antibodies interfere with the killing of Salmonella.
  
  
  RESULTS
  Sera and affinity-purified antibodies from African HIV-infected adults that failed to kill invasive S. Typhimurium D23580 were compared to sera from HIV-uninfected and HIV-infected subjects with bactericidal activity. The failure of sera from certain HIV-infected subjects to kill Salmonella was found to be due to an inherent inhibitory effect of anti-LPS antibodies. This inhibition was concentration-dependent and strongly associated with IgA and IgG2 anti-LPS antibodies (p<0.0001 for both). IgG anti-LPS antibodies, from sera of HIV-infected individuals that inhibit killing at high concentration, induced killing when diluted. Conversely, IgG, from sera of HIV-uninfected adults that induce killing, inhibited killing when concentrated. IgM anti-LPS antibodies from all subjects also induced Salmonella killing. Finally, the inhibitory effect of high concentrations of anti-LPS antibodies is seen with IgM as well as IgG and IgA. No correlation was found between affinity or avidity, or complement deposition or consumption, and inhibition of killing.
  
  
  CONCLUSIONS
  IgG and IgM classes of anti-S. Typhimurium LPS antibodies from HIV-infected and HIV-uninfected individuals are bactericidal, while at very high concentrations, anti-LPS antibodies of all classes inhibit in vitro killing of Salmonella. This could be due to a variety of mechanisms relating to the poor ability of IgA and IgG2 to activate complement, and deposition of complement at sites where it cannot insert in the bacterial membrane. Vaccine trials are required to understand the significance of lack of in vitro killing by anti-LPS antibodies from a minority of HIV-infected individuals with impaired immune homeostasis.
authors.affiliation: Singapore Immunology Network, Agency for Science, Technology and Research, Biopolis, Singapore.
authors.forename: Yun Shan
authors.initials: YS
authors.lastname: Goh
authors.affiliation: Sclavo Behring Vaccines Institute for Global Health, a GlaxoSmith Kline Company, Siena, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Necchi
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: Sclavo Behring Vaccines Institute for Global Health, a GlaxoSmith Kline Company, Siena, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Micoli
authors.affiliation: GlaxoSmith Kline, Siena, Italy.
authors.forename: Massimiliano
authors.initials: M
authors.lastname: Gavini
authors.affiliation: Centre for Translational Inflammation Research, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom.
authors.forename: Stephen P
authors.initials: SP
authors.lastname: Young
authors.affiliation: Malawi-Liverpool-Wellcome Trust Clinical Research Programme, College of Medicine, University of Malawi, Blantyre, Malawi.|Department of Pathology, Division of Microbiology, College of Medicine, University of Malawi, Blantyre, Malawi.
authors.forename: Chisomo L
authors.initials: CL
authors.lastname: Msefula
authors.affiliation: Malawi-Liverpool-Wellcome Trust Clinical Research Programme, College of Medicine, University of Malawi, Blantyre, Malawi.|Department of Basic Medical Sciences, College of Medicine, University of Malawi, Blantyre, Malawi.
authors.forename: Esther N
authors.initials: EN
authors.lastname: Gondwe
authors.affiliation: Centre for Translational Inflammation Research, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom.
authors.forename: Wilson L
authors.initials: WL
authors.lastname: Mandala
authors.affiliation: Department of Gastroenterology, Institute of Translational Medicine, University of Liverpool, Liverpool, United Kingdom.
authors.forename: Melita A
authors.initials: MA
authors.lastname: Gordon
authors.affiliation: Sclavo Behring Vaccines Institute for Global Health, a GlaxoSmith Kline Company, Siena, Italy.
authors.forename: Allan J
authors.initials: AJ
authors.lastname: Saul
authors.affiliation: School of Immunity and Infection, College of Medicine and Dental Sciences, University of Birmingham, Birmingham, 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: D000349:Africa; D000907:Antibodies, Bacterial / Q000097:blood*; D015658:HIV Infections / Q000276:immunology*; D016867:Immunocompromised Host; D007070:Immunoglobulin A / Q000276:immunology; D007074:Immunoglobulin G / Q000276:immunology; D007075:Immunoglobulin M / Q000276:immunology; D008070:Lipopolysaccharides / Q000276:immunology; D012475:Salmonella / Q000276:immunology*; D012480:Salmonella Infections / Q000276:immunology*; D058248:Serum Bactericidal Antibody Assay; D015610:Serum Bactericidal Test
chemical_list: D000907:Antibodies, Bacterial; D007070:Immunoglobulin A; D007074:Immunoglobulin G; D007075:Immunoglobulin M; D008070:Lipopolysaccharides