T-Cell Responses Are Associated with Survival in Acute Melioidosis Patients

Abstract

BackgroundMelioidosis is an increasingly recognised cause of sepsis and death across South East Asia and Northern Australia, caused by the bacterium Burkholderia pseudomallei. Risk factors include diabetes, alcoholism and renal disease, and a vaccine targeting at-risk populations is urgently required. A better understanding of the protective immune response in naturally infected patients is essential for vaccine design.MethodsWe conducted a longitudinal clinical and immunological study of 200 patients with melioidosis on admission, 12 weeks (n = 113) and 52 weeks (n = 65) later. Responses to whole killed B. pseudomallei were measured in peripheral blood mononuclear cells (PBMC) by interferon-gamma (IFN-γ) ELIspot assay and flow cytometry and compared to those of control subjects in the region with diabetes (n = 45) and without diabetes (n = 43).ResultsWe demonstrated strong CD4+ and CD8+ responses to B. pseudomallei during acute disease, 12 weeks and 52 weeks later. 28-day mortality was 26% for melioidosis patients, and B. pseudomallei-specific cellular responses in fatal cases (mean 98 IFN-γ cells per million PBMC) were significantly lower than those in the survivors (mean 142 IFN-γ cells per million PBMC) in a multivariable logistic regression model (P = 0.01). A J-shaped curve association between circulating neutrophil count and mortality was seen with an optimal count of 4000 to 8000 neutrophils/μl.Melioidosis patients with known diabetes had poor diabetic control (median glycated haemoglobin HbA1c 10.2%, interquartile range 9.2–13.1) and showed a stunted B. pseudomallei-specific cellular response during acute illness compared to those without diabetes.ConclusionsThe results demonstrate the role of both CD4+ and CD8+ T-cells in protection against melioidosis, and an interaction between diabetes and cellular responses. This supports development of vaccine strategies that induce strong T-cell responses for the control of intracellular pathogens such as B. pseudomallei.

A nonsense mutation in TLR5 is associated with survival and reduced IL-10 and TNF-α levels in human melioidosis

“…pseudomallei and the development of adaptive immunity, suppressed T-cell responses to B . pseudomallei are associated with death from acute melioidosis [19]. However, we did not find evidence that the TLR5 c.1174C>T variant drives the T-cell IFN-γ response, IHA titer, or anti-FliC antibody response during acute melioidosis, suggesting that the mechanism of enhanced survival in carriers of the TLR5 variant may be independent of these adaptive immunological responses.…”

“…pseudomallei at a young age, indicating that environmental exposure to the bacterium and the development of adaptive immune responses in the absence of clinical infection is common [18]. A previous study in this cohort reported reduced T-cell responses in patients with acute melioidosis that did not survive [19], raising the possibility that c.1174C>T may protect against death by enhancing T-cell mediated immunity against B . pseudomallei .…”

Melioidosis and glanders modulation of the innate immune system: barriers to current and future vaccine approaches

“…Therefore, vaccine designs directed at providing complete protection also need to induce cell-mediated immunity (For example, [58,87]). Consistent with this, human patient survivors of culture-confirmed acute melioidosis displayed an increased frequency of CD4 + and CD8 + T cells, while a decrease in CD4 + and CD8 + IFN-γ-producing T cells was specifically correlated with increased mortality, further highlighting a pivotal contribution by cellular immunity to control melioidosis [106]. Furthermore, vaccines eliciting Th1-like biased immune responses or incorporating Th1-promoting adjuvants have been demonstrated to be protective against melioidosis and glanders in mice and may have the potential to induce sterile immunity (As reviewed in [61] [56] [4]).…”

Boosting of post‐exposure human T‐cell and B‐cell recall responses in vivo by Burkholderia pseudomallei‐related proteins

“…This correlates with our previous studies showing that human antibodies and PBMCs can recognize FliC and OmpA proteins, and the magnitude of the response from human seropositive individuals is higher than for seronegative individuals. 9,52 Hence, the difference of IFN-c production in response to B. pseudomallei between seropositive and seronegative individuals seen Antibody avidities of IgM and IgG were evaluated by using indirect ELISA following treatment with 7 M urea (n = 5). 9,51,52 During IFN-c production upon stimulation of human seropositive PBMCs with B. pseudomallei, NK cells are transient and are prominent in the first 24 hr of stimulation whereas CD4 and CD8 T cells have more contribution in the later phase of stimulation by a primary response through terminally differentiated effector memory T cells.…”