Abstract
Plasmacytoid dendritic cells (pDC) are activators of innate and adaptive immune responses that express HLA-DR, toll-like receptor (TLR) 7, TLR9 and produce type I interferons. The role of human pDC in malaria remains poorly characterised. pDC activation and cytokine production were assessed in 59 malaria-naive volunteers during experimental infection with 150 or 1,800 P. falciparum-parasitized red blood cells. Using RNA sequencing, longitudinal changes in pDC gene expression were examined in five adults before and at peak-infection. pDC responsiveness to TLR7 and TLR9 stimulation was assessed in-vitro. Circulating pDC remained transcriptionally stable with gene expression altered for 8 genes (FDR < 0.07). There was no upregulation of co-stimulatory molecules CD86, CD80, CD40, and reduced surface expression of HLA-DR and CD123 (IL-3R-α). pDC loss from the circulation was associated with active caspase-3, suggesting pDC apoptosis during primary infection. pDC remained responsive to TLR stimulation, producing IFN-α and upregulating HLA-DR, CD86, CD123 at peak-infection. In clinical malaria, pDC retained HLA-DR but reduced CD123 expression compared to convalescence. These data demonstrate pDC retain function during a first blood-stage P. falciparum exposure despite sub-microscopic parasitaemia downregulating HLA-DR. The lack of evident pDC activation in both early infection and malaria suggests little response of circulating pDC to infection.
Highlights
Innate recognition of Plasmodium parasites is critical for the induction of appropriate anti-malarial immune responses[1]
CD86 upregulation has been reported in children with severe malaria[15], P. falciparum infected pregnant women[20] and some patients with acute vivax malaria[23], whilst HLA-DR is not upregulated in severe malaria[15, 24]
Circulating Plasmacytoid dendritic cells (pDC) gene expression is predominantly stable after primary pre-patent P. falciparum Controlled human malaria infection (CHMI)
Summary
Innate recognition of Plasmodium parasites is critical for the induction of appropriate anti-malarial immune responses[1]. Circulating pDC in P. falciparum infected Fulani, an ethnic group less susceptible to symptomatic malaria, on the contrary, display a mature phenotype with upregulated CD86 and HLA-DR expression and strong TLR9 responsiveness[25]. Less than 1% of pDC expressed CD86, CD40 or CD80 before infection or at peak parasitaemia (Fig. 1C).
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