Rosiglitazone Modulates the Innate Immune Response toPlasmodium falciparumInfection and Improves Outcome in Experimental Cerebral Malaria

Abstract

For severe malarial syndromes such as cerebral malaria, adverse clinical outcomes are often immune-mediated rather than caused by the parasite directly; however, few therapeutics have been developed to modulate immunopathological host responses to infection. Here we report that PPARγ agonists (e.g. rosiglitazone), FDA-approved for unrelated conditions, modulate host response to malaria by enhancing phagocytic clearance of malaria-parasitized erythrocytes and by decreasing inflammatory responses to infection via inhibition of Plasmodium falciparum glycosylphosphatidylinositol-induced MAPK and NF-κB activation. We show that rosiglitazone modifies inflammatory response to experimental malaria infection in vivo and improves survival in experimental cerebral malaria in the Plasmodium berghei ANKA model even when initiated as late as day 5 post-infection. Furthermore, rosiglitazone reduces parasite burden in a CD36-dependent manner in the Plasmodium chaubaudi hyperparasitemia model. These data suggest that PPARγ agonists represent a novel class of host immunomodulatory drugs that may have application in the management of severe malaria syndromes.

Synthesis of Artemiside and Its Effects in Combination with Conventional Drugs against Severe Murine Malaria

“…This might be a hint to consider drug combinations that also include components that reduce oxidant stress. In addition, immunomodulators that could alleviate CM should be considered for adjunctive therapy due to the inflammatory etiological nature of CM (and severe malaria in general) in both human malaria and experimental models (16,22,26,29,30,41). Obviously, an adjunctive drug also should be examined in combination with the antiplasmodial drugs to exclude any deleterious antagonistic effects.…”

Differential Macrophage Polarization from Pneumocystis in Immunocompetent and Immunosuppressed Hosts: Potential Adjunctive Therapy during Pneumonia

“…More specifically, during infections it is well accepted that M2 macrophages act to ameliorate disease severity and protect the host from detrimental effects of an excessive inflammatory response (19)(20)(21)(22). Pneumocystis pneumonia is best treated using antibiotics such as trimethoprim-sulfamethoxazole (23).…”

Use of Peroxisome Proliferator‐Activated Receptor γ Agonists as Adjunctive Treatment forPlasmodium falciparumMalaria: A Randomized, Double‐Blind, Placebo‐Controlled Trial

“…Parasites and parasite products, such as P. falciparum glycosylphosphatidylinositol (pf GPI) and hemozoin complexed with parasite DNA, induce the release of proinflammatory cytokines (eg, tumor necrosis factor [TNF]) via interaction with pattern recognition receptors, including TLR2, TLR9, and CD36 [8][9][10]. CD36 has been shown to mediate macrophage clearance of P. falciparum-parasitized erythrocytes in vitro and to contribute to survival in experimental models of malaria [10][11][12][13][14][15]. On the basis of these observations, we hypothesized that pharmacological modulation of innate immunity, through pattern recognition receptors and related pathways, might increase parasite clearance, modify deleterious host inflammatory responses to infection, and improve clinical outcome of P. falciparum malaria.…”