title: Host-based Prophylaxis Successfully Targets Liver Stage Malaria Parasites.
abstract: Eliminating malaria parasites during the asymptomatic but obligate liver stages (LSs) of infection would stop disease and subsequent transmission. Unfortunately, only a single licensed drug that targets all LSs, Primaquine, is available. Targeting host proteins might significantly expand the repertoire of prophylactic drugs against malaria. Here, we demonstrate that both Bcl-2 inhibitors and P53 agonists dramatically reduce LS burden in a mouse malaria model in vitro and in vivo by altering the activity of key hepatocyte factors on which the parasite relies. Bcl-2 inhibitors act primarily by inducing apoptosis in infected hepatocytes, whereas P53 agonists eliminate parasites in an apoptosis-independent fashion. In combination, Bcl-2 inhibitors and P53 agonists act synergistically to delay, and in some cases completely prevent, the onset of blood stage disease. Both families of drugs are highly effective at doses that do not cause substantial hepatocyte cell death in vitro or liver damage in vivo. P53 agonists and Bcl-2 inhibitors were also effective when administered to humanized mice infected with Plasmodium falciparum. Our data demonstrate that host-based prophylaxis could be developed into an effective intervention strategy that eliminates LS parasites before the onset of clinical disease and thus opens a new avenue to prevent malaria.
authors: Seattle Biomedical Research Institute, Seattle, Washington, United States.
authors: Alyse N
authors: AN
authors: Douglass
authors: Seattle Biomedical Research Institute, Seattle, Washington, United States.
authors: Heather S
authors: HS
authors: Kain
authors: Seattle Biomedical Research Institute, Seattle, Washington, United States.
authors: Marian
authors: M
authors: Abdullahi
authors: Seattle Biomedical Research Institute, Seattle, Washington, United States.
authors: Nadia
authors: N
authors: Arang
authors: Seattle Biomedical Research Institute, Seattle, Washington, United States; Department of Global Health, University of Washington, Seattle, Washington, United States.
authors: Laura S
authors: LS
authors: Austin
authors: Seattle Biomedical Research Institute, Seattle, Washington, United States.
authors: Sebastian A
authors: SA
authors: Mikolajczak
authors: Department of Laboratory Medicine and the Center for Emerging and Re-emerging Infectious Diseases, University of Washington, Seattle, Washington, United States.
authors: Zachary P
authors: ZP
authors: Billman
authors: Seattle Biomedical Research Institute, Seattle, Washington, United States.
authors: Jen C C
authors: JCC
authors: Hume
authors: Department of Laboratory Medicine and the Center for Emerging and Re-emerging Infectious Diseases, University of Washington, Seattle, Washington, United States.
authors: Sean C
authors: SC
authors: Murphy
authors: Seattle Biomedical Research Institute, Seattle, Washington, United States; Department of Global Health, University of Washington, Seattle, Washington, United States.
authors: Stefan H I
authors: SHI
authors: Kappe
authors: Seattle Biomedical Research Institute, Seattle, Washington, United States. Electronic address: alexis.kaushansky@seattlebiomed.org.
authors: Alexis
authors: A
authors: Kaushansky
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000008:administration & dosage / Q000494:pharmacology*; D002460:Cell Line; D004195:Disease Models, Animal; D005260:Female; D007093:Imidazoles / Q000008:administration & dosage / Q000494:pharmacology; D007211:Indoles; D008018:Life Cycle Stages / Q000187:drug effects*; D008099:Liver / Q000469:parasitology*; D008288:Malaria / Q000188:drug therapy / Q000378:metabolism / Q000469:parasitology* / Q000517:prevention & control; D016778:Malaria, Falciparum / Q000188:drug therapy / Q000378:metabolism / Q000469:parasitology / Q000517:prevention & control; D051379:Mice; D008822:Mice, Transgenic; D059208:Parasite Load; D010879:Piperazines / Q000008:administration & dosage / Q000494:pharmacology; D010961:Plasmodium / Q000187:drug effects* / Q000502:physiology*; D010963:Plasmodium falciparum / Q000187:drug effects / Q000502:physiology; D056990:Post-Exposure Prophylaxis; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D011758:Pyrroles / Q000008:administration & dosage / Q000494:pharmacology; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D000962:Antimalarials; D007093:Imidazoles; D007211:Indoles; D010879:Piperazines; D019253:Proto-Oncogene Proteins c-bcl-2; D011758:Pyrroles; D016159:Tumor Suppressor Protein p53; C482205:nutlin 3; C520962:obatoclax
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