Sequential Acquisition of T Cells and Antibodies to Nontyphoidal Salmonella in Malawian Children

Abstract

Background. Salmonella Typhimurium (STm) remain a prominent cause of bacteremia in sub-Saharan Africa. Complement-fixing antibodies to STm develop by 2 years of age. We hypothesized that STm-specific CD4+ T cells develop alongside this process.Methods. Eighty healthy Malawian children aged 0–60 months were recruited. STm-specific CD4+ T cells producing interferon γ, tumor necrosis factor α, and interleukin 2 were quantified using intracellular cytokine staining. Antibodies to STm were measured by serum bactericidal activity (SBA) assay, and anti-STm immunoglobulin G antibodies by enzyme-linked immunosorbent assay.Results. Between 2006 and 2011, STm bacteremias were detected in 449 children <5 years old. STm-specific CD4+ T cells were acquired in infancy, peaked at 14 months, and then declined. STm-specific SBA was detectable in newborns, declined in the first 8 months, and then increased to a peak at age 35 months. Acquisition of SBA correlated with acquisition of anti–STm–lipopolysaccharide (LPS) immunoglobulin G (r = 0.329 [95% confidence interval, .552–.062]; P = .01) but not anti–STm–outer membrane protein or anti–STm-flagellar protein (FliC).Conclusions. Acquisition of STm-specific CD4+ T cells in early childhood is consistent with early exposure to STm or cross-reactive protein antigens priming this T-cell development. STm-specific CD4+ T cells seem insufficient to protect against invasive nontyphoidal Salmonella disease, but sequential acquisition of SBA to STm LPS is associated with a decline in its incidence.

Immunity to intestinal pathogens: lessons learned from Salmonella

“…This observation suggests that Salmonella ‐specific antibody can contribute to protective immunity during secondary infection as a supplement to Salmonella ‐specific CD4 + and CD8 + T cells. Indeed, this concept fits well with human studies showing that antibody is likely to be effective in immunity to typhoidal and non‐typhoidal Salmonella . However, recent studies using B‐cell‐deficient mice or transgenic mice with peripheral B cells, but no secreted antibody, demonstrate that B‐cell‐mediated protection against secondary Salmonella infection can also be antibody‐independent .…”

Antimicrobial resistance and management of invasive Salmonella disease

“…These include the loss of IL-17 producing CD4 cells in the gut mucosa permitting rapid invasion [41] and dysregulated excess production of anti-LPS IgG that inhibits serum killing of extracellular Salmonella , in a concentration-dependent fashion [42]. Once in the intracellular niche, reduction and dysregulation of pro-inflammatory cytokine responses in HIV-infected individuals [43] allows intracellular survival and persistence, leading to frequent recrudescence of bacteremia, with identical strains of NTS [28,44]. In contrast to the findings in adults with HIV, a lack of protective antibody is implicated in the susceptibility of African children to iNTS disease; antibody is likely to be important both for cellular and cell-free control of NTS infection in children [32,45,46].…”

Modeling and Cost Benefit Analysis to Guide Deployment of POC Diagnostics for Non-typhoidalSalmonellaInfections with Antimicrobial Resistance

“…While the reality of immune dynamics is more complicated than our simplifying assumption, we found significant evidence that young children and HIV-positive people do not gain functional immunity to NTS. Even with previous exposure, children do not gain immunity until around 36 months of age 36,49,50 , particularly with common added factors of malaria, malnutrition, recent antimicrobial use, sickle cell, etc. HIV-positive people have also been observed to exhibit susceptibility to NTS after infection (recrudescence is also observed) 5,51 .…”