Cytokine responses during acute simian Plasmodium cynomolgi and Plasmodium knowlesi infections.

Experimental infection of non-human primates with simian malaria parasites offers a controlled system to study malarial immunity. Plasmodium cynomolgi (P. vivax-like) and P. knowlesi (P. falciparum-like) infections in the rhesus monkey were used as a model to test the hypothesis that initial acute infection stimulates type 1/pro-inflammatory cytokine expression followed by a gradual type 2/anti-inflammatory response upon re-infection. This study analyzed cytokine gene expression (interleukin-12, interferon-gamma, tumor necrosis factor-alpha = type 1; interleukin-4, interleukin-10 = type 2) using a semi-quantitative reverse transcriptase-polymerase chain reaction in monkeys infected with each of the parasites (three per group). Clinicoparasitologic and serologic parameters were also monitored. Monkeys were re-infected to assess whether enhanced immunity could increase parasite clearance. The immune response to P. cynomolgi infection in rhesus monkeys seemed to be mediated by anti-parasite, pro-inflammatory responses during primary infection with a transition to protective type 2 responses after repeat infection. The immune responses to P. knowlesi infection were more varied. Anti-inflammatory responses were more prevalent during primary infection. Repeat infection stimulated a wide variety of responses; most included expression of tumor necrosis factor-alpha, a cytokine that has been associated with inflammatory and host-destructive effects (weight loss, fever, anemia). These observations further confirmed that the simian malaria/rhesus monkey model is well suited for studies on the regulation of immunity to acute Plasmodium infection.