Rosiglitazone modulates the innate immune response to Plasmodium falciparum infection and improves outcome in experimental cerebral malaria.
For severe malarial syndromes such as cerebral malaria, adverse clinical outcomes are often mediated by the immune system rather than caused by the parasite directly. However, few therapeutic agents have been developed to modulate the host's immunopathological responses to infection. Here, we report that the peroxisome proliferator-activated receptor gamma (PPARgamma) agonist rosiglitazone modulated the 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 activation of the mitogen-activated protein kinase (MAPK) and nuclear factor-kappaB (NF-kappaB) signaling pathways. We found that, in the Plasmodium berghei strain ANKA experimental model of cerebral malaria, rosiglitazone modified the inflammatory response to malarial infection and improved the survival rate even when treatment was initiated as late as day 5 after infection. Furthermore, rosiglitazone reduced the parasitemia in a CD36-dependent manner in the Plasmodium chabaudi chabaudi hyperparasitemia model. These data suggest that PPARgamma agonists represent a novel class of host immunomodulatory drugs that may be useful for treatment of severe malaria syndromes.
Serghides
Lena
L
Tropical Disease Unit, Division of Infectious Diseases, Department of Medicine, Toronto General Hospital, Toronto, Canada.
Patel
Samir N
SN
Ayi
Kodjo
K
Lu
Ziyue
Z
Gowda
D Channe
DC
Liles
W Conrad
WC
Kain
Kevin C
KC
D000818:Animals; D018955:CD36 Antigens / Q000032:analysis; D005434:Flow Cytometry; D006801:Humans; D007113:Immunity, Innate / Q000187:drug effects*; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000276:immunology; D008264:Macrophages / Q000187:drug effects / Q000276:immunology; D016779:Malaria, Cerebral / Q000276:immunology*; D016778:Malaria, Falciparum / Q000097:blood / Q000276:immunology*; D051379:Mice; D010587:Phagocytosis; D010963:Plasmodium falciparum / Q000187:drug effects / Q000276:immunology*; D000077154:Rosiglitazone; D015398:Signal Transduction; D017741:Survivors; D045162:Thiazolidinediones / Q000494:pharmacology*
D018955:CD36 Antigens; D045162:Thiazolidinediones; D000077154:Rosiglitazone