Abstract
BackgroundNontyphoidal 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.Methodology/Principal FindingsSera 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.Conclusion/SignificanceIgG 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.
Highlights
African clades of nontyphoidal Salmonella (NTS), S. enterica serovars Typhimurium and Enteritidis, are a major cause of bacteremia in sub-Saharan Africa [1, 2]
Bacteremia caused by nontyphoidal Salmonellae are a major health burden in Africa
While antibody-induced complement-mediated killing protects healthy Africans against Salmonella, increased levels of anti-LPS antibodies in some HIV-infected Africans block this killing
Summary
African clades of nontyphoidal Salmonella (NTS), S. enterica serovars Typhimurium and Enteritidis, are a major cause of bacteremia in sub-Saharan Africa [1, 2]. NTS bacteremia in Africa occurs most frequently among infants and HIV-infected patients [1, 2]. We have previously shown that sera from African children under two years of age lack Salmonella-specific antibodies, resulting in an impaired ability to kill Salmonella. Sera from adults with Salmonella-specific antibodies can induce complementmediated killing of Salmonella and placental transfer of IgG offers protection to infants [5], suggesting a role for antibody in protection against invasive NTS (iNTS) disease. Nontyphoidal strains of Salmonella are a leading cause of death among HIV-infected Africans.
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