Steps toward development of a non-human primate model of cerebral malaria
Description
In an effort to develop a rhesus monkey model of cerebral malaria, we selected for Plasmodium knowlesi parasites that cytoadhered to rhesus brain endothelial cells, and for a second less adherent population. We then inoculated these parasites into rhesus macaques. Although the highly adherent pRBCs showed a pattern of deep tissue sequestration, neither parasite population produced severe disease in the monkeys or significant increases in serum TNF. When we compared ICAM-1 expression in rhesus and human brain endothelial cells in vitro, we found that rhesus brain endothelial cells produced less ICAM-1, even after stimulation with recombinant rhesus TNF, than human endothelial cells. This down-regulation of ICAM-1 appeared to be controlled at the transcriptional level because NF-kappaB and ICAM-1 mRNA expression after stimulation with TNF were much lower in rhesus brain endothelial cells than human brain endothelial cells. Although IFN-gamma pretreatment of rhesus monkeys produced significant increases in serum TNF within 2 h after challenge with LPS, this method did not yield high TNF levels in P. knowlesi-infected animals. In fact, it elicited high levels of IL-4 and IL-10. In summary, these studies provide evidence indicating that the TNF axis in rhesus monkeys is down-regulated in comparison to humans: (1) Lower systemic (serum) TNF levels, with higher IL-4 and IL-10 levels, (2) Reduced NF-kappaB responses to TNF, and (3) Reduced ICAM-1 mRNA and protein expression in responses to TNF