PROFILES OF CYTOKINE PRODUCTION IN RELATION WITH SUSCEPTIBILITY TO CEREBRAL MALARIA

Infection with Plasmodium berghei ANKA (PbA) leads, in susceptible str ains of mice, to the development of cerebral malaria (CM), a lethal sy ndrome that reproduces some features of human CM. To study a possible relationship between genetic susceptibility to CM and the cytokine exp ression pattern, we quantitatively evaluated gene expression on RNA ex tracted from various organs of malaria-infected mice, using strains th at are susceptible and resistant to CM. Northern blot analysis and sem i-quantitative PCR showed that CM is associated with an increased TNF- alpha mRNA accumulation in the brain of mice developing the neurologic complications of CM. An increased IFN-gamma mRNA accumulation and a d ecreased expression of IL-4 and TGF-beta genes were also observed in m ice susceptible to CM. In vitro restimulation studies using crude mala rial Ag showed that lymphoid cell proliferation was higher in CM-susce ptible than in CM-resistant infected mice. Moreover, susceptible mice produced large amounts of IFN-gamma, in a dose-dependent manner, in re sponse to PbA Ag, whereas cells from resistant mice failed to produce significant amounts of this cytokine. Conversely, IL-2 and IL-4 produc tion was significantly higher in infected CM-resistant mouse cells. No difference was seen in the production of IL-3 and IL-5 between resist ant and susceptible PbA-infected mice. Upon stimulation with various m alarial Ag, comparable amounts of TNF-alpha were produced by macrophag es of either strain of mice. Taken together, these findings indicate t hat susceptibility to CM resides at the level of T cells rather than m acrophages. Furthermore, the cytokine production profile is consistent with a predominant Th1-like response in mice developing cerebral comp lications of malaria.