CTLA‐4 positive T cells in contrast to procalcitonin plasma levels discriminate between severe and uncomplicated Plasmodium falciparum malaria in Ghanaian children

Abstract

Summary Procalcitonin (PCT) plasma levels and the fraction of CTLA‐4‐positive T cells are both elevated in acute Plasmodium falciparum malaria in human adults and the degree of elevation is positively correlated with other markers of disease severity, for example with parasitaemia. However, the clinical manifestations of malaria are strongly age‐dependent and children from endemic areas carry the main disease burden. Therefore, we measured PCT plasma levels and CTLA‐4 expression by T cells in four groups of children from the Ashanti Region in Ghana: asymptomatic children with or without parasitaemia, children with uncomplicated P. falciparum malaria and children with severe disease. PCT levels were highly elevated in both groups with acute malaria but they did not discriminate between uncomplicated and severe disease. In contrast, CTLA‐4‐expression by T cells was increased only in severe malaria. The fraction of CTLA‐4 positive T cells in the blood of children with severe disease differed significantly from that in uncomplicated malaria, which was not elevated in spite of the high parasite loads observed in these children. This was unexpected, as in adults uncomplicated malaria is associated with a dramatic sixfold increase of the fraction of CTLA‐4‐positive T cells. The data from this study support the hypothesis that strong T cell activation as measured here by CTLA‐4 expression is not just the by‐product of a high parasite burden, but that it contributes to the pathogenesis of P. falciparum malaria.

The Role of Negative Costimulators During Parasitic Infections

“…Initiation of antiplasmodial treatment reduced CTLA-4 expression to background levels within a few days [41]. Braun et al reported that CTLA-4 expression by T cells from Ghanaian children was induced exclusively during severe malaria [42]. This finding supports the hypothesis that strong T cell activation as measured by CTLA-4 expression is not only the by-product of a high parasitemia, but contributes directly to the pathogenesis of P. falciparum malaria.…”

“…suppression of T effector functions during leishmaniasis by CD4 + CD25 + CTLA-4 + regulatory T cells [34][35][36] positive correlation between CTLA-4 expression by CD4 + T cells and disease severity in human malaria [41,42] increased incidence of cerebral malaria during P. berghei ANKA (PbA) infection of mice upon CTLA-4 blockade [43] IL-12-and IFN--dependent liver pathology during PbA infection upon CTLA-4 blockade [44] reduced peak parasitemia and earlier parasite clearance in murine P. yoelii NL infection upon CTLA-4 blockade [45] Plasmodium ssp.…”

Procalcitonin assay in systemic inflammation, infection, and sepsis: Clinical utility and limitations

“…Although the range is wide, values as high as 662 ng/mL have been reported (126). Although some authors note a significant positive correlation with severity (126,127), others find no correlation (128). Levels decrease with therapy (127,129).…”

The role of Vitamin D in malaria

“…CTLA-4 is involved in the regulation of T-cells and is up-regulated during the T-cell-mediated immune response. CTLA-4-positive cells are elevated in acute P. falciparum and vivax malarias in humans [66][67][68]. Murine malaria is exacerbated by a CTLA-4 blockade, which induces higher parasitemia than in controls [69][70][71].…”