CYTOKINE AND EFFECTOR MOLECULE REGULATION AS DETERMINANTS OF HEMATOLOGICAL OUTCOMES IN RHESUS MACAQUES DURING PLASMODIUM COATNEYI-MALARIA

Non-human primates are often used in the development and testing of vaccines and therapeutics for malaria. Infection of rhesus macaques (Macaca mulatta) with Plasmodium coatneyi causes cerebral malaria (CM) at high levels of parasitemia. To prevent mortality, parasitemia is frequently treated prior to this point when cerebral signs are largely absent. The public health significance was to determine the validity of this as a model for studying malarial anemia (MA) by examining hematological profiles, cytokines, and effector molecules shown to be important in childhood MA, including tumor necrosis factor (TNF)-α, interleukin (IL)-10, (IL)-12p40, and interferon (IFN)-γ, and nitric oxide (NO) at eight different time points during the acute infection. Peripheral parasitemia was monitored daily throughout infection. Venepuncture was performed for hematology panels on days 0, 2, 5, 7, 8, (peak parasitemia), 10, 15, 22, 34, 42, 56, and 150 post-infection (PI) for monitoring acute and chronic malaria infection. Complete blood counts (CBC) revealed that monocytes (MO) were highest during the initial rise in parasitemia, neutrophils (NEU) were highest at peak parasitemia, and lymphocytes (LY) remained constant throughout infection, except at peak parasitemia where levels were dramatically reduced. Platelets (PLT) declined shortly after infection and decreased until day 15, where levels sharply increased to higher than baseline values on day 19 PI. Hemoglobin (Hb) was lowest at parasite clearance(day 15 PI). Elevated peripheral blood mononuclear cell (PBMC) transcripts (determined by real time RT-PCR in circulating blood mononuclear cells) and plasma levels (determined by ELISA) were associated with enhanced disease severity (peak parasitemia, thrombocytopenia and anemia). Plasma cytokine levels were not correlated with PBMC transcript levels, suggesting that the plasma cytokine levels may be from multiple cellular sources in addition to PBMC. Low IL-10 relative to TNF-α (IL-10/TNF-α plasma ratio) coincided with the lowest Hb concentration, a finding we have shown in children with MA. Taken together, these results demonstrate similar patterns of cytokine and effector molecule dysregulation in rhesus macaques infected P. coatneyi as that observed in humans with P. falciparum-induced malarial anemia