Jessica R Loughland1,2, Tonia Woodberry3, Damian Oyong3, Kim A Piera3, Fiona H Amante4, Bridget E Barber3,4,5, Matthew J Grigg3,5, Timothy William5,6,7, Christian R Engwerda4, Nicholas M Anstey3,8, James S McCarthy4, Michelle J Boyle3,4, Gabriela Minigo9,10. 1. Menzies School of Health Research and Charles Darwin University, Darwin, Australia. Jessica.Loughland@qimrberghofer.edu.au. 2. QIMR Berghofer Medical Research Institute, Brisbane, Australia. Jessica.Loughland@qimrberghofer.edu.au. 3. Menzies School of Health Research and Charles Darwin University, Darwin, Australia. 4. QIMR Berghofer Medical Research Institute, Brisbane, Australia. 5. Gleneagles Hospital, Kota Kinabalu, Sabah, Malaysia. 6. Infectious Diseases Society Kota Kinabalu Sabah-Menzies School of Research Clinical Research Unit, Kota Kinabalu, Sabah, Malaysia. 7. Queen Elizabeth Hospital-Clinical Research Centre, Ministry of Health, Kota Kinabalu, Malaysia. 8. Royal Darwin Hospital, Darwin, Australia. 9. Menzies School of Health Research and Charles Darwin University, Darwin, Australia. Gabriela.Minigo@cdu.edu.au. 10. College of Health and Human Sciences, Charles Darwin University, Darwin, Australia. Gabriela.Minigo@cdu.edu.au.
Abstract
BACKGROUND: Plasmodium falciparum malaria increases plasma levels of the cytokine Fms-like tyrosine kinase 3 ligand (Flt3L), a haematopoietic factor associated with dendritic cell (DC) expansion. It is unknown if the zoonotic parasite Plasmodium knowlesi impacts Flt3L or DC in human malaria. This study investigated circulating DC and Flt3L associations in adult malaria and in submicroscopic experimental infection. METHODS: Plasma Flt3L concentration and blood CD141+ DC, CD1c+ DC and plasmacytoid DC (pDC) numbers were assessed in (i) volunteers experimentally infected with P. falciparum and in Malaysian patients with uncomplicated (ii) P. falciparum or (iii) P. knowlesi malaria. RESULTS: Plasmodium knowlesi caused a decline in all circulating DC subsets in adults with malaria. Plasma Flt3L was elevated in acute P. falciparum and P. knowlesi malaria with no increase in a subclinical experimental infection. Circulating CD141+ DCs, CD1c+ DCs and pDCs declined in all adults tested, for the first time extending the finding of DC subset decline in acute malaria to the zoonotic parasite P. knowlesi. CONCLUSIONS: In adults, submicroscopic Plasmodium infection causes no change in plasma Flt3L but does reduce circulating DCs. Plasma Flt3L concentrations increase in acute malaria, yet this increase is insufficient to restore or expand circulating CD141+ DCs, CD1c+ DCs or pDCs. These data imply that haematopoietic factors, yet to be identified and not Flt3L, involved in the sensing/maintenance of circulating DC are impacted by malaria and a submicroscopic infection. The zoonotic P. knowlesi is similar to other Plasmodium spp in compromising DC in adult malaria.
BACKGROUND:Plasmodium falciparummalaria increases plasma levels of the cytokine Fms-like tyrosine kinase 3 ligand (Flt3L), a haematopoietic factor associated with dendritic cell (DC) expansion. It is unknown if the zoonotic parasite Plasmodium knowlesi impactsFlt3L or DC in humanmalaria. This study investigated circulating DC and Flt3L associations in adult malaria and in submicroscopic experimental infection. METHODS: Plasma Flt3L concentration and blood CD141+ DC, CD1c+ DC and plasmacytoid DC (pDC) numbers were assessed in (i) volunteers experimentally infected with P. falciparum and in Malaysian patients with uncomplicated (ii) P. falciparum or (iii) P. knowlesi malaria. RESULTS:Plasmodium knowlesi caused a decline in all circulating DC subsets in adults with malaria. Plasma Flt3L was elevated in acute P. falciparum and P. knowlesi malaria with no increase in a subclinical experimental infection. Circulating CD141+ DCs, CD1c+ DCs and pDCs declined in all adults tested, for the first time extending the finding of DC subset decline in acute malaria to the zoonotic parasiteP. knowlesi. CONCLUSIONS: In adults, submicroscopic Plasmodiuminfection causes no change in plasma Flt3L but does reduce circulating DCs. Plasma Flt3L concentrations increase in acute malaria, yet this increase is insufficient to restore or expand circulating CD141+ DCs, CD1c+ DCs or pDCs. These data imply that haematopoietic factors, yet to be identified and not Flt3L, involved in the sensing/maintenance of circulating DC are impacted by malaria and a submicroscopic infection. The zoonotic P. knowlesi is similar to other Plasmodium spp in compromising DC in adult malaria.
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