Systematic detection of host pathways universally inhibited by Plasmodium yoelii parasites for immune intervention

Malaria is a disease with diverse symptoms depending on host immune status and pathogenicity of Plasmodium parasites. The continuous parasite growth within a host suggests mechanisms of immune evasion and/or inhibition. To identify pathways commonly inhibited by malaria infection, we infected C67BL/6 mice with four Plasmodium yoelii strains causing different disease phenotypes and 24 progeny of a genetic cross. mRNAs from mouse spleens day 1 and/or day 4 post infection (p.i.) were hybridized to a mouse microarray to identify activated or inhibited pathways, upstream regulators, and linkages to parasite genetic loci. Strong interferon responses were observed after infection with N67 strain, whereas initial inhibition and later activation of hematopoiesis pathways were found after infection with 17XNL parasite. Inhibition of pathways such as Th1 activation, dendritic cell (DC) maturation, and NFAT immune regulation were observed in mice infected with all the parasite strains day 4 p.i., suggesting universally inhibited immune pathways. Treatment of infected mice with antibodies against T cell receptors OX40 or CD28 to activate malaria-inhibited pathways enhanced host survival. Controlled activation of these pathways may provide important strategies for better disease management and for developing an effective vaccine.

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Xia L, Wu J, Pattaradilokrat S, Tumas K, He X, Peng YC, Huang R, Myers TG, Long CA, Wang R, Su XZ