AbstractBackgroundPlasmodium 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 parasitePlasmodium knowlesiimpacts Flt3L or DC in human malaria. This study investigated circulating DC and Flt3L associations in adult malaria and in submicroscopic experimental infection.MethodsPlasma Flt3L concentration and blood CD141⁺DC, CD1c⁺DC and plasmacytoid DC (pDC) numbers were assessed in (i) volunteers experimentally infected withP. falciparumand in Malaysian patients with uncomplicated (ii)P. falciparumor (iii)P. knowlesimalaria.ResultsPlasmodium knowlesicaused a decline in all circulating DC subsets in adults with malaria. Plasma Flt3L was elevated in acuteP. falciparumandP. knowlesimalaria 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.ConclusionsIn adults, submicroscopicPlasmodiuminfection 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 zoonoticP. knowlesiis similar to otherPlasmodiumspp in compromising DC in adult malaria.