Immune-factors regulating the development of experimental cerebral malaria in mice infected or coinfected with Plasmodium spp.

Abstract

During malaria infection, innate responses are triggered to limit the maximum parasite density when it crosses certain threshold. Toll-like receptors signaling pathway, mononuclear phagocytes and NK cell-mediated cytotoxicity are known to have important roles in activation of protective innate immunity to malaria. Therefore, we first assessed role in experimental cerebral malaria (ECM) pathogenesis of molecules (TRIF and IRF3) involved in innate immunity signal transduction. TRIF-deficient mice infected with PbAluc were susceptible to ECM and displayed increased parasite biomass, although peripheral parasitemia was comparable to WT mice. Conversely, mice infected with another parasite strain, PbA-BdS, did not develop ECM despite having similar parasitemia to WT group. IRF3-deficient mice infected with either PbAluc or PbA-BdS were ECM-resistant. Lastly, macrophages and NK cells role in suppression of PbA growth and ECM in mice coinfected with Plasmodium spp. was elucidated. Using transgenic mouse model, MaFIA, which allows conditional ablation of myeloid cells, we showed that depletion of these cells protected coinfected mice against ECM and decreased total parasitemia due to an effect on Py 17X 1.1 growth. However, it had no effect on PbA suppression. Similarly, conditional ablation of NK cells in NKDTR mice excluded involvement of NK cells in PbA suppression, although these mice did not develop ECM.