ABSTRACT
Malaria has had the largest impact of any infectious disease on shaping the human genome, exerting enormous selective pressure on genes that improve survival in severe malaria infections. Modern humans originated in Africa and lost skin melanization as they migrated to temperate regions of the globe. Although it is well documented that loss of melanization improved cutaneous Vitamin D synthesis, melanin plays an evolutionary ancient role in insect immunity to malaria and in some instances melanin has been implicated to play an immunoregulatory role in vertebrates. Thus, we tested the hypothesis that melanization may be protective in malaria infections using mouse models. Congenic C57BL/6 mice that differed only in the gene encoding tyrosinase, a key enzyme in the synthesis of melanin, showed no difference in the clinical course of infection by Plasmodium yoelii 17XL, that causes severe anemia, Plasmodium berghei ANKA, that causes severe cerebral malaria or Plasmodium chabaudi AS that causes uncomplicated chronic disease. Moreover, neither genetic deficiencies in vitamin D synthesis nor vitamin D supplementation had an effect on survival in cerebral malaria. Taken together, these results indicate that neither melanin nor vitamin D production improve survival in severe malaria.
Subject(s)
Malaria/prevention & control , Melanins/metabolism , Models, Biological , Animals , Chronic Disease , Humans , Malaria/complications , Malaria/parasitology , Malaria, Cerebral/complications , Malaria, Cerebral/parasitology , Malaria, Cerebral/prevention & control , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Parasitemia/complications , Parasitemia/drug therapy , Plasmodium/physiology , Receptors, Calcitriol/metabolism , Vitamin D/therapeutic useABSTRACT
OBJECTIVE: The coagulation-inflammation cycle has been implicated as a critical component in malaria pathogenesis. Defibrotide (DF), a mixture of DNA aptamers, displays anticoagulant, anti-inflammatory, and endothelial cell (EC)-protective activities and has been successfully used to treat comatose children with veno-occlusive disease. DF was investigated here as a drug to treat cerebral malaria. METHODS AND RESULTS: DF blocks tissue factor expression by ECs incubated with parasitized red blood cells and attenuates prothrombinase activity, platelet aggregation, and complement activation. In contrast, it does not affect nitric oxide bioavailability. We also demonstrated that Plasmodium falciparum glycosylphosphatidylinositol (Pf-GPI) induces tissue factor expression in ECs and cytokine production by dendritic cells. Notably, dendritic cells, known to modulate coagulation and inflammation systemically, were identified as a novel target for DF. Accordingly, DF inhibits Toll-like receptor ligand-dependent dendritic cells activation by a mechanism that is blocked by adenosine receptor antagonist (8-p-sulfophenyltheophylline) but not reproduced by synthetic poly-A, -C, -T, and -G. These results imply that aptameric sequences and adenosine receptor mediate dendritic cells responses to the drug. DF also prevents rosetting formation, red blood cells invasion by P. falciparum and abolishes oocysts development in Anopheles gambiae. In a murine model of cerebral malaria, DF affected parasitemia, decreased IFN-γ levels, and ameliorated clinical score (day 5) with a trend for increased survival. CONCLUSION: Therapeutic use of DF in malaria is proposed.
Subject(s)
Anti-Inflammatory Agents/pharmacology , Anticoagulants/pharmacology , Antimalarials/pharmacology , Blood Coagulation/drug effects , Endothelial Cells/drug effects , Malaria, Cerebral/drug therapy , Plasmodium berghei/drug effects , Plasmodium falciparum/drug effects , Polydeoxyribonucleotides/pharmacology , Animals , Cells, Cultured , Complement Activation/drug effects , Cytokines/blood , Dendritic Cells/drug effects , Dendritic Cells/immunology , Dendritic Cells/parasitology , Disease Models, Animal , Dose-Response Relationship, Drug , Endothelial Cells/immunology , Endothelial Cells/metabolism , Endothelial Cells/parasitology , Female , Glycosylphosphatidylinositols/metabolism , Hemoglobins/metabolism , Humans , Inflammation Mediators/blood , Malaria, Cerebral/blood , Malaria, Cerebral/immunology , Malaria, Cerebral/parasitology , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Nitric Oxide/metabolism , Plasmodium berghei/pathogenicity , Plasmodium falciparum/growth & development , Plasmodium falciparum/metabolism , Plasmodium falciparum/pathogenicity , Platelet Aggregation/drug effects , Receptors, Purinergic P1/drug effects , Receptors, Purinergic P1/metabolism , Severity of Illness Index , Thromboplastin/metabolism , Time FactorsABSTRACT
Plasmodium falciparum has exerted tremendous selective pressure on genes that improve survival in severe malarial infections. Systemic lupus erythematosus (SLE) is an autoimmune disease that is six to eight times more prevalent in women of African descent than in women of European descent. Here we provide evidence that a genetic susceptibility to SLE protects against cerebral malaria. Mice that are prone to SLE because of a deficiency in FcγRIIB or overexpression of Toll-like receptor 7 are protected from death caused by cerebral malaria. Protection appears to be by immune mechanisms that allow SLE-prone mice better to control their overall inflammatory responses to parasite infections. These findings suggest that the high prevalence of SLE in women of African descent living outside of Africa may result from the inheritance of genes that are beneficial in the immune control of cerebral malaria but that, in the absence of malaria, contribute to autoimmune disease.
