Drugs designed to inhibit human p38 mitogen-activated protein kinase activation treat Toxoplasma gondii and Encephalitozoon cuniculi infection

Department of Medicine (Hematology and Medical Oncology), Tulane University School of Medicine, 1430 Tulane Avenue SL-78, New Orleans, LA 70112, USA; Department of Surgery, University of Michigan, 1500 East Medical Center Drive, Room TC2101, Ann Arbor, Michigan 48109-0346, USA; San Antonio Cancer Institute, University of Texas Health Sciences Center, 2040 Babcock Rd., suite 201, San Antonio, TX 78229; Louisianna State University Health Sciences Center, New Orleans, LA 70112; Department of Microbiology, Immunology and Tropical Medicine, George Washington University School of Medicine, Washington DC, 20037; The R. W. Johnson Pharmaceutical Research Institute, Raritan, New Jersey

	Abstract

We recently showed that the pyridinylimidazoles SB203580 and SB202190, drugs designed to block human p38 mitogen-activated protein kinase (MAPK) activation also inhibited replication of the medically important intracellular parasite, Toxoplasma gondii in cultured human fibroblasts through a direct effect on the parasite. We now show that additional pyridinylimidazole and imidazopyrimidine p38 MAPK inhibitors inhibit intracellular T. gondii replication in vitro and protect mice against fatal T. gondii infection. Mice surviving infection following treatment with p38 MAPK inhibitors were resistant to subsequent T. gondii challenge, demonstrating induction of protective immunity. Thus, drugs originally developed to block human p38 MAPK activation are useful to treat T. gondii infection without inducing significant immunosuppression. MAPK inhibitors combined with the approved anti-Toxoplasma drugs sulfadiazine or pyrimethamine resulted in improved survival in mice challenged with a fatal T. gondii inoculum. A MAPK inhibitor also treated mice infected with the Microsporidium parasite Encephalitozoon cuniculi, suggesting that MAPK inhibitors represent a novel class of agents that may have a broad spectrum of anti-parasitic activity. Preliminary studies implicate a T. gondii MAPK homologue as the target of drug action, suggesting possibilities of more selective agents.