AbstractMalaria caused by Plasmodium remains a major global health problem, with 3.2 billion people estimated at risk of infection. Protective immunity to malaria is slow to develop, incomplete and short-lived. Impairment of dendritic cell (DC) function is one way Plasmodium falciparum evades host immune responses.
In malaria-naive adult volunteers, peripheral DC were examined before and after intra-venous inoculation of P. falciparum or P. vivax infected red blood cells. The viability, number, maturation (HLA-DR, CD86) and cytokine production (TNF, IL-12, IL-10 and IFN-α) to toll like receptor (TLR) stimulation of plasmacytoid DC (pDC) and myeloid DC (CD1c+, CD141+ and CD16+ mDC) were measured using flow cytometry. Total RNA sequencing examined longitudinal pDC gene expression changes in 5 adults before and at peak infection.
During a first Plasmodium infection CD1c+ mDC, CD141+ mDC and pDC (not CD16+ mDC) decline with increased apoptosis. HLA-DR expression significantly reduced on CD1c+ mDC, CD141+ mDC and pDC, but remained stable on CD16+ mDC. P. falciparum infection compromised CD1c+ mDC failed to upregulate HLA-DR and CD86 upon TLR stimulation and produced significantly more TNF (with unchanged IL-12). In contrast, pDC and CD16+ mDC retained appropriate maturation and cytokine responsiveness in a first P. falciparum infection. A primary P. falciparum infection altered a small set of pDC genes.
DC subsets are differentially impacted during a primary Plasmodium infection. CD1c+ mDC are functionally compromised while pDC and CD16+ mDC retain function. We hypothesise Plasmodium induced DC subset modulation hampers immune responsiveness and assists parasite expansion. Understanding how and why DC subsets are disproportionately impacted by P. falciparum and P. vivax may aid development of strategies to prevent parasite immune evasion and enhance protective immune responses, and potentially guide vaccine strategies for malaria elimination.
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|Date of Award||Dec 2016|
|Supervisor||Tonia Woodberry (Supervisor) & Gabriela Minigo (Supervisor)|