Role of Antilipopolysaccharide Antibodies in Serum Bactericidal Activity against Salmonella enterica Serovar Typhimurium in Healthy Adults and Children in the United States

Abstract

Recent observations from Africa have rekindled interest in the role of serum bactericidal antibodies in protecting against systemic infection with Salmonella enterica serovar Typhimurium. To determine whether the findings are applicable to other populations, we analyzed serum samples collected from healthy individuals in the United States. We found that all but 1 of the 49 adult samples tested had robust bactericidal activity against S. Typhimurium in a standard in vitro assay. The activity was dependent on complement and could be reproduced by immunoglobulin G (IgG) purified from the sera. The bactericidal activity was inhibited by competition with soluble lipopolysaccharide (LPS) from S. Typhimurium but not from Escherichia coli, consistent with recognition of a determinant in the O-antigen polysaccharide. Sera from healthy children aged 10 to 48 months also had bactericidal activity, although it was significantly less than in the adults, correlating with lower levels of LPS-specific IgM and IgG. The lone sample in our collection that lacked bactericidal activity was able to inhibit killing of S. Typhimurium by the other sera. The inhibition correlated with the presence of an LPS-specific IgM and was associated with decreased complement deposition on the bacterial surface. Our results indicate that healthy individuals can have circulating antibodies to LPS that either mediate or inhibit killing of S. Typhimurium. The findings contrast with the observations from Africa, which linked bactericidal activity to antibodies against an S. Typhimurium outer membrane protein and correlated the presence of inhibitory anti-LPS antibodies with human immunodeficiency virus infection.

IFN-γ–Producing CD4+ T Cells Promote Generation of Protective Germinal Center–Derived IgM+ B Cell Memory against Salmonella Typhi

“…Notably, Abs against porins (4,20) or against LPS (21) are associated with protective humoral immunity. For example, NTS porins elicit an immediate IgM response from B1b B cells that reduces bacterial titers in mice (22).…”

Effect of Human Immunodeficiency Virus Infection on Plasma Bactericidal Activity against Salmonella enterica Serovar Typhimurium

“…Our experiments demonstrated that serum and plasma from the majority of healthy adults in the United States had bactericidal activity against S. Typhimurium and that this activity was mediated by antibodies to an epitope in the outer polysaccharide of LPS (5). We also found that the bactericidal activity was less robust in children Ͻ5 years of age, correlating with lower levels of S. Typhimurium LPSspecific IgM and IgG in this age group (5). In addition to young children, HIV-infected adults represent a second population that has a high risk of invasive NTS disease (9)(10)(11)(12).…”

“…Deidentified serum and plasma samples from healthy adults from the United States were collected during routine health maintenance visits to clinics at the Massachusetts General Hospital. The criteria used for their selection have been described in detail earlier (5). Plasma samples from HIV-positive individuals were collected in clinics at hospitals in the Boston area and elsewhere in the United States, and they were part of a collection maintained by the Ragon Institute.…”

“…These findings, which correlated inversely with the pattern of incidence of invasive salmonellosis (i.e., high in infants and low in older children and adults) suggested an important role for antibodymediated protection in invasive NTS disease. The initial analysis indicated that the bactericidal antibodies present in healthy adults in Malawi were directed against Salmonella outer membrane proteins, but recent work from our laboratory, as well as that from other investigators, has focused on the O antigen of lipopolysaccharide (LPS) as the relevant antigenic target (4)(5)(6)(7)(8). Our experiments demonstrated that serum and plasma from the majority of healthy adults in the United States had bactericidal activity against S. Typhimurium and that this activity was mediated by antibodies to an epitope in the outer polysaccharide of LPS (5).…”

“…The initial analysis indicated that the bactericidal antibodies present in healthy adults in Malawi were directed against Salmonella outer membrane proteins, but recent work from our laboratory, as well as that from other investigators, has focused on the O antigen of lipopolysaccharide (LPS) as the relevant antigenic target (4)(5)(6)(7)(8). Our experiments demonstrated that serum and plasma from the majority of healthy adults in the United States had bactericidal activity against S. Typhimurium and that this activity was mediated by antibodies to an epitope in the outer polysaccharide of LPS (5). We also found that the bactericidal activity was less robust in children Ͻ5 years of age, correlating with lower levels of S. Typhimurium LPSspecific IgM and IgG in this age group (5).…”