Regulation of immune responses to malaria during acute Plasmodium infection in humans and the rhesus monkey
Description
Malaria is the most prevalent human infectious disease in the world. The simian parasites P. cynomolgi and P. knowlesi cause infections in rhesus monkeys similar to vivax and falciparum malaria, respectively, in humans. Examination of the cytokine responses produced during these infectious should deepen our understanding of malarial immunity and improve on the current model systems. With the re-emergence of malaria in endemic countries of South America, the study of mesoendemic malaria is also becoming a key component of disease control. Based on prior murine studies, we hypothesized that acute Plasmodium infection in both simian and human malarias selectively augments the expression of type 1/pro-inflammatory cytokines; these responses are subsequently down-regulated by type 2/anti-inflammatory cytokines. In this study, systemic expression of IL-4, IL-10, IL-12, IFN-gamma and TNF-alpha was related to parasitologic, clinical and serologic parameters during the course of P. cynomolgi and P. knowlesi infectious in rhesus monkeys. The courses of the two simian infections---in terms of parasitemia and clinical effects---are different. Immune responses to P. cynomolgi infection in the monkeys are mediated by anti-parasite, pro-inflammatory cytokines during primary infection. After repeat infection, these responses transition to protective type 2 ones via IL-10 immunomodulation. Cytokine profiles in P. knowlesi-infected monkeys are more varied and do not follow a distinct pattern. Systemic cytokine expression and cytokine profiles were also observed during the acquisition of natural immunity in P. falciparum and P. vivax-infected patients from Buenaventura, a mesoendemic malarious region in Columbia. Cross-sectional analysis shows more frequent inflammatory responses in vivax patients, with more type 1 responses in falciparum patients. Follow-up studies reveal that specific immune responses seem to develop more during mesoendemic P. falciparum malaria, whereas non-specific inflammatory responses continue to dominate during mesoendemic P. vivax infections. Based on these observations, a comparison between the simian and human parasites can be made. Both P. vivax and P. cynomolgi malarias lead to consistent pro-inflammatory cytokine profiles early during infection. P. knowlesi and P. falciparum infections stimulate specific (type 1 and type 2) but more varied cytokine profiles