Abstract
BackgroundNontyphoidal Salmonellae frequently cause life-threatening bacteremia in sub-Saharan Africa. Young children and HIV-infected adults are particularly susceptible. High case-fatality rates and increasing antibiotic resistance require new approaches to the management of this disease. Impaired cellular immunity caused by defects in the T helper 1 pathway lead to intracellular disease with Salmonella that can be countered by IFNγ administration. This report identifies the lymphocyte subsets that produce IFNγ early in Salmonella infection.MethodologyIntracellular cytokine staining was used to identify IFNγ production in blood lymphocyte subsets of ten healthy adults with antibodies to Salmonella (as evidence of immunity to Salmonella), in response to stimulation with live and heat-killed preparations of the D23580 invasive African isolate of Salmonella Typhimurium. The absolute number of IFNγ-producing cells in innate, innate-like and adaptive lymphocyte subpopulations was determined.Principal FindingsEarly IFNγ production was found in the innate/innate-like lymphocyte subsets: γδ-T cells, NK cells and NK-like T cells. Significantly higher percentages of such cells produced IFNγ compared to adaptive αβ-T cells (Student's t test, P<0.001 and ≤0.02 for each innate subset compared, respectively, with CD4+- and CD8+-T cells). The absolute numbers of IFNγ-producing cells showed similar differences. The proportion of IFNγ-producing γδ-T cells, but not other lymphocytes, was significantly higher when stimulated with live compared with heat-killed bacteria (P<0.0001).Conclusion/SignificanceOur findings indicate an inherent capacity of innate/innate-like lymphocyte subsets to produce IFNγ early in the response to Salmonella infection. This may serve to control intracellular infection and reduce the threat of extracellular spread of disease with bacteremia which becomes life-threatening in the absence of protective antibody. These innate cells may also help mitigate against the effect on IFNγ production of depletion of Salmonella-specific CD4+-T lymphocytes in HIV infection.
Highlights
Nontyphoidal strains of Salmonella (NTS), in particular Salmonella enterica Typhimurium and Enteritidis
Background numbers of IFNc-producing cells were typically less than 0.1% (Figure 1A–B), while positive control phorbol 12-myristate 13-acetate (PMA)-stimulated cells gave responses of between 20% and 50% IFNc-producing cells (Figure 1C–D)
IFNc production by different lymphocyte subsets was examined in relation to duration of stimulation with Salmonella homogenate in the blood of healthy adult donors using the intracellular cytokine staining (ICS) method described (Figure 2)
Summary
Nontyphoidal strains of Salmonella (NTS), in particular Salmonella enterica Typhimurium and Enteritidis We have previously shown the importance of antibody for complement-mediated cell-independent killing of NTS in the peripheral blood of young African children [3] This protection can be lost in HIV-infected adults due to the presence of high titers of anti-LPS antibodies that block killing of Salmonella by antibodies against outer membrane proteins [13]. In addition to their capacity for extracellular survival, Salmonellae are facultative intracellular bacteria and their ability to survive within cells is essential for virulence [14]. This report identifies the lymphocyte subsets that produce IFNc early in Salmonella infection
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