Abstract
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 by the parasite and/or immune inhibition in response to infection. To identify pathways commonly inhibited after malaria infection, we infected C57BL/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 host genes playing an important role in malaria infection. Strong interferon responses were observed after infection with the N67 strain, whereas initial inhibition and later activation of hematopoietic pathways were found after infection with 17XNL parasite, showing unique responses to individual parasite strains. Inhibitions 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. As a proof of principle, treatment of N67-infected mice with antibodies against T cell receptors OX40 or CD28 to activate the inhibited pathways enhanced host survival. Controlled activation of these pathways may provide important strategies for better disease management and for developing an effective vaccine.
Highlights
Infection of malaria parasites triggers dynamic and complex immune responses, and a coordinated response is required for successful resolution of a malaria infection[1,2]
Plasmodium y. nigeriensis N67 (N67) triggers an early IFN-I response leading to suppression of parasitemia day 7 post infection (p.i), whereas its isogenic parasite P. y. nigeriensis N67C stimulates a strong inflammatory response resulting in host death by day 7 p.i
Our understanding of host immune responses to malaria infections is incomplete, the pathways inhibited after malaria infection, which has impeded the development of an effective vaccine and disease treatment[26]
Summary
Infection of malaria parasites triggers dynamic and complex immune responses, and a coordinated response is required for successful resolution of a malaria infection[1,2]. The types and levels of immune response are dependent on host genetic background and parasite species or strains[12,13], which may lead to contradictory results or conclusions regarding the mechanism of host response to malaria infections. A common theme of elevated pro-inflammatory cytokine/chemokine responses and differential expression of genes in erythropoiesis, glycolysis, B cell activation, and immunoglobulin production in different malaria species or strains were reported in various microarray analyses[22,23,24,25]. Infected adult carriers in endemic areas are likely to develop certain mechanisms to control parasitemia, and at the same time, suppress some inflammatory responses that cause fever and other malaria symptoms. Based on results from these analyses and as a proof of principle, we designed experiments to modulate selected inhibited immune pathways and showed improved host survival, which may provide an important avenue for developing strategies for better disease control and vaccine development
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