The CD14+CD16+ Inflammatory Monocyte Subset Displays Increased Mitochondrial Activity and Effector Function During Acute Plasmodium vivax Malaria

Abstract

Infection with Plasmodium vivax results in strong activation of monocytes, which are important components of both the systemic inflammatory response and parasite control. The overall goal of this study was to define the role of monocytes during P. vivax malaria. Here, we demonstrate that P. vivax–infected patients display significant increase in circulating monocytes, which were defined as CD14+CD16− (classical), CD14+CD16+ (inflammatory), and CD14loCD16+ (patrolling) cells. While the classical and inflammatory monocytes were found to be the primary source of pro-inflammatory cytokines, the CD16+ cells, in particular the CD14+CD16+ monocytes, expressed the highest levels of activation markers, which included chemokine receptors and adhesion molecules. Morphologically, CD14+ were distinguished from CD14lo monocytes by displaying larger and more active mitochondria. CD14+CD16+ monocytes were more efficient in phagocytizing P. vivax-infected reticulocytes, which induced them to produce high levels of intracellular TNF-α and reactive oxygen species. Importantly, antibodies specific for ICAM-1, PECAM-1 or LFA-1 efficiently blocked the phagocytosis of infected reticulocytes by monocytes. Hence, our results provide key information on the mechanism by which CD14+CD16+ cells control parasite burden, supporting the hypothesis that they play a role in resistance to P. vivax infection.

Plasmodium falciparum Infection of Human Volunteers Activates Monocytes and CD16 + Dendritic Cells and Induces Upregulation of CD16 and CD1c Expression

“…In both classical and intermediate monocytes, expression of the peptide antigen-presenting molecule HLA-DR significantly increased during blood-stage infection (P Ͻ 0.001 at the DT and DT ϩ3) and the costimulatory molecule CD86 was significantly upregulated at DT ϩ3 (P Ͻ 0.001). Activation appeared slightly stronger in the CD14 ϩ CD16 ϩ intermediate monocyte subset than in the classical CD14 ϩ CD16 Ϫ monocytes, which is in line with a previous study on monocytes in P. vivax infection (22). Among the DCs, the CD1c, BDCA-2, and BDCA-3 DCs did not upregulate expression of HLA-DR or CD86 during parasitemia.…”

“…Upon reaching detectable blood-stage parasitemia and after treatment, monocytes increased in frequency: classical monocytes peaked on the DT (P Ͻ 0.001) and intermediate monocytes on DT ϩ3 (P Ͻ 0.001). Such transient increases in monocyte frequencies during acute infection that resolve after treatment have also been observed in P. vivax-infected patients (22). While pDC levels remained slightly increased on DT ϩ3 (P Ͻ 0.01), BDCA-3 mDCs showed a significant decrease in frequency on the DT (P Ͻ 0.001) and at DT ϩ3 (P Ͻ 0.01).…”

“…In line with this, HLA-DR expression on CD16 ϩ CD14 lo monocytes increased upon curative treatment of P. vivax infection (22). On the other hand, CD16 ϩ CD14 lo monocytes in these P. vivax-infected patients showed the highest levels of tumor necrosis factor alpha (TNF-␣) and interleukin-6 (IL-6) transcription, indicating an activated status of these cells (22). Further studies are needed to resolve these discrepancies, which might also relate to the degree of parasitemia.…”

“…In both ethnic cohorts, however, CD16 mDCs showed reduced HLA-DR expression. In line with this, HLA-DR expression on CD16 ϩ CD14 lo monocytes increased upon curative treatment of P. vivax infection (22). On the other hand, CD16 ϩ CD14 lo monocytes in these P. vivax-infected patients showed the highest levels of tumor necrosis factor alpha (TNF-␣) and interleukin-6 (IL-6) transcription, indicating an activated status of these cells (22).…”

Monocyte dysregulation and systemic inflammation during pediatric falciparum malaria

“…Increased proportions of circulating CD16 + intermediate and nonclassical monocytes have been associated with acute falciparum malaria (25)(26)(27). Evidence suggests that the CD16 + subpopulations have enhanced antiparasitic activity (26,28,29), though there are still significant gaps in our understanding of the functional roles of monocyte subpopulations during malaria. In this study, we characterized systemic inflammation and the monocyte subset phenotypes, monocyte functions relevant to malaria pathogenesis, and monocyte gene expression profiles of Kenyan children at the time of presentation with acute uncomplicated malaria and 6 weeks later, when they were asymptomatic following administration of antimalarial drugs.…”