Oral Presentation Australasian Society for Immunology Annual Scientific Meeting 2014

The incomplete activation and decline in circulating CD1c (BDCA-1) dendritic cells in falciparum and knowlesi malaria, including a first blood-stage infection. (#29)

Jessica R Loughland 1 , Kim A Piera 1 , Steven Kho 1 , Peta E Tipping 1 , Fiona H Amante 2 , Christian R Engwerda 2 , Timothy William 3 , Matthew J Grigg 1 3 , Bridget E Barber 1 3 , Tsin W Yeo 1 , James S McCarthy 2 , Nicholas M Anstey 1 4 , Gabriela Minigo 1 5 , Tonia Woodberry 1 5
  1. Menzies School of Health Research, Darwin, NT, Australia
  2. QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia
  3. Queen Elizabeth Hospital, Kota Kinabalu, Sabah, Malaysia
  4. Royal Darwin Hospital, Darwin, NT, Australia
  5. equal contribution,

Contact dependent and cytokine mediated signals from CD1c+(BDCA1+) mDC are central to the appropriate activation of naive CD4 and CD8 T cells during infection.  In acute falciparum and vivax malaria, CD1c+mDC decline, but it remains to be determined whether CD1c+mDC that remain circulating in the peripheral blood are functional. 

We investigated CD1c+mDC absolute counts, maturation and cytokine production in a first experimental P. falciparum infection in healthy volunteers and in adult patients with acute uncomplicated P. falciparum or P. knowlesi malaria from Sabah, Malaysia.  CD1c+mDC decreased from day 7 post experimental infection and were significantly reduced in acute malaria compared to ethnicity matched healthy controls. In patients with acute P. knowlesi malaria, CD1c+mDC DC counts remained significantly reduced 7 days after anti-malarial treatment and recovered only 2-4 weeks following treatment. CD1c+mDC loss was partially explained by apoptosis, determined by intracellular staining of cleaved caspase 3. In experimental P. falciparum infection, only a minority of CD1c+mDC were activated, with only 13% (IQR: 9.4-13.3%) expressing the co-stimulatory molecule CD86, and the majority having downregulated HLA-DR expression, suggesting reduced ability to present antigen. This was paralleled by reduced uptake of particulate antigen. In acute malaria, neither HLA-DR or CD86 were up-regulated.  In experimental infection, intracellular cytokine staining of CD1c+mDC in whole blood showed increased TNF secretion but no increase in IL-12 secretion.

Our data demonstrate impaired antigen-uptake and presentation ability of circulating CD1c+mDC.  These cells appear functionally compromised in acute falciparum and knowlesi malaria.  The increased production of TNF by CD1c+mDC in experimental infection indicates these cells can directly contribute to Plasmodium pro-inflammatory immune responses.  Overall, we conclude that CD1c+mDC are functionally and numerically compromised in malaria with impairment persisting at least one week after parasite clearance.