Malaria prevalence metrics in low- and middle-income countries: an assessment of precision in nationally-representative surveys |
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Authors: | Alegana Victor A Wright Jim Bosco Claudio Okiro Emelda A Atkinson Peter M Snow Robert W Tatem Andrew J Noor Abdisalan M |
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Institution: | 1.Department of Genetics and Complex Diseases, Harvard T. H. Chan School of Public Health, Boston, MA, 02115, USA ;2.Institute of Cell Biology, University of Bern, 3012, Bern, Switzerland ;3.Wellcome Center for Molecular Parasitology, University of Glasgow, Glasgow, G12 8TA, Scotland, UK ;4.Rodent Histopathology Core, Harvard Medical School, Boston, MA, 02115, USA ; |
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Abstract: | Maladaptive immune responses during cerebral malaria (CM) result in high mortality despite opportune anti-malarial chemotherapy. Rapamycin, an FDA-approved immunomodulator, protects against experimental cerebral malaria (ECM) in mice through effects on the host. However, the potential for reduced adaptive immunity with chronic use, combined with an incomplete understanding of mechanisms underlying protection, limit translational potential as an adjunctive therapy in CM. The results presented herein demonstrate that a single dose of rapamycin, provided as late as day 4 or 5 post-infection, protected mice from ECM neuropathology and death through modulation of distinct host responses to infection. Rapamycin prevented parasite cytoadherence in peripheral organs, including white adipose tissue, via reduction of CD36 expression. Rapamycin also altered the splenic immune response by reducing the number of activated T cells with migratory phenotype, while increasing local cytotoxic T cell activation. Finally, rapamycin reduced brain endothelial ICAM-1 expression concomitant with reduced brain pathology. Together, these changes potentially contributed to increased parasite elimination while reducing CD8 T cell migration to the brain. Rapamycin exerts pleotropic effects on host immunity, vascular activation and parasite sequestration that rescue mice from ECM, and thus support the potential clinical use of rapamycin as an adjunctive therapy in CM. |
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