The neglected role of antibody in protection against bacteremia caused by nontyphoidal strains of Salmonella in African children
Calman A. MacLennan, … , Malcolm E. Molyneux, Mark T. Drayson
Calman A. MacLennan, … , Malcolm E. Molyneux, Mark T. Drayson
Published March 20, 2008
Citation Information: J Clin Invest. 2008;118(4):1553-1562. https://doi.org/10.1172/JCI33998.
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Research Article Immunology

The neglected role of antibody in protection against bacteremia caused by nontyphoidal strains of Salmonella in African children

Abstract

Nontyphoidal strains of Salmonella (NTS) are a common cause of bacteremia among African children. Cell-mediated immune responses control intracellular infection, but they do not protect against extracellular growth of NTS in the blood. We investigated whether antibody protects against NTS bacteremia in Malawian children, because we found this condition mainly occurs before 2 years of age, with relative sparing of infants younger than 4 months old. Sera from all healthy Malawian children tested aged more than 16 months contained anti-Salmonella antibody and successfully killed NTS. Killing was mediated by complement membrane attack complex and not augmented in the presence of blood leukocytes. Sera from most healthy children less than 16 months old lacked NTS-specific antibody, and sera lacking antibody did not kill NTS despite normal complement function. Addition of Salmonella-specific antibody, but not mannose-binding lectin, enabled NTS killing. All NTS strains tested had long-chain lipopolysaccharide and the rck gene, features that resist direct complement-mediated killing. Disruption of lipopolysaccharide biosynthesis enabled killing of NTS by serum lacking Salmonella-specific antibody. We conclude that Salmonella-specific antibody that overcomes the complement resistance of NTS develops by 2 years of life in Malawian children. This finding and the age-incidence of NTS bacteremia suggest that antibody protects against NTS bacteremia and support the development of vaccines against NTS that induce protective antibody.

Authors

Calman A. MacLennan, Esther N. Gondwe, Chisomo L. Msefula, Robert A. Kingsley, Nicholas R. Thomson, Sarah A. White, Margaret Goodall, Derek J. Pickard, Stephen M. Graham, Gordon Dougan, C. Anthony Hart, Malcolm E. Molyneux, Mark T. Drayson

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Figure 2

Killing of NTS by blood and serum from Malawian adults and by C9-deficient serum at 45, 90, and 180 minutes.

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Killing of NTS by blood and serum from Malawian adults and by C9-deficie...
(A) Killing of 8 invasive Malawian S. Typhimurium isolates by whole blood from a healthy adult Malawian donor. (B) Killing of S. Typhimurium isolate D23580 by whole blood (squares), serum (circles), and blood cells washed in RPMI to remove antibody and complement (triangles). (C) Effect of heat inactivation of serum on ability to kill D23580: fresh serum (circles), heat-inactivated serum (squares), and heat-inactivated serum reconstitution with lyophilized complement (triangles). (D) Inability of C9-deficient serum (triangles) to kill D23580. Killing of Salmonella was enabled by addition of exogenous C9 (squares). (E) Killing of D23580 by fresh and heat-inactivated serum: 100% fresh (triangles); 60% fresh, 40% heat-inactivated (diamonds); 20% fresh, 80% heat-inactivated (squares); 10% fresh, 90% heat-inactivated (circles); and 100% heat-inactivated (x). Negative values correspond with a decrease in viable salmonellae compared with the initial concentration of 106 salmonellae/ml. In A, B, C, and E, data indicate blood and/or serum from 1 healthy adult and are representative of 4 healthy adult donors tested. Where error bars are present, data are mean ± 1 SD of 3 experiments.