Plasmacytoid dendritic cells appear inactive during sub-microscopic Plasmodium falciparum blood-stage infection, yet retain their ability to respond to TLR stimulation

Jessica R. Loughland, Gabriela Minigo, Derek S. Sarovich, Matt Field, Peta E. Tipping, Marcela Montes de Oca, Kim A. Piera, Fiona H. Amante, Bridget E. Barber, Matthew J. Grigg, Timothy WILLIAM, Michael F. Good, Denise L. Doolan, Christian R. Engwerda, Nicholas M. Anstey, James S. McCarthy, Tonia Woodberry

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    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.

    Original languageEnglish
    Article number2596
    Pages (from-to)1-11
    Number of pages11
    JournalScientific Reports
    Volume7
    Issue number1
    DOIs
    Publication statusPublished - 1 Dec 2017

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    Loughland, J. R., Minigo, G., Sarovich, D. S., Field, M., Tipping, P. E., Montes de Oca, M., Piera, K. A., Amante, F. H., Barber, B. E., Grigg, M. J., WILLIAM, T., Good, M. F., Doolan, D. L., Engwerda, C. R., Anstey, N. M., McCarthy, J. S., & Woodberry, T. (2017). Plasmacytoid dendritic cells appear inactive during sub-microscopic Plasmodium falciparum blood-stage infection, yet retain their ability to respond to TLR stimulation. Scientific Reports, 7(1), 1-11. [2596]. https://doi.org/10.1038/s41598-017-02096-2