title: Suppression of host p53 is critical for Plasmodium liver-stage infection.
abstract: Plasmodium parasites infect the liver and replicate inside hepatocytes before they invade erythrocytes and trigger clinical malaria. Analysis of host signaling pathways affected by liver-stage infection could provide critical insights into host-pathogen interactions and reveal targets for intervention. Using protein lysate microarrays, we found that Plasmodium yoelii rodent malaria parasites perturb hepatocyte regulatory pathways involved in cell survival, proliferation, and autophagy. Notably, the prodeath protein p53 was substantially decreased in infected hepatocytes, suggesting that it could be targeted by the parasite to foster survival. Indeed, mice that express increased levels of p53 showed reduced liver-stage parasite burden, whereas p53 knockout mice suffered increased liver-stage burden. Furthermore, boosting p53 levels with the use of the small molecule Nutlin-3 dramatically reduced liver-stage burden in vitro and in vivo. We conclude that perturbation of the hepatocyte p53 pathway critically impacts parasite survival. Thus, host pathways might constitute potential targets for host-based antimalarial prophylaxis.
authors.affiliation: Malaria Program, Seattle Biomedical Research Institute, Seattle, WA 98109, USA.
authors.forename: Alexis
authors.initials: A
authors.lastname: Kaushansky
authors.forename: Albert S
authors.initials: AS
authors.lastname: Ye
authors.forename: Laura S
authors.initials: LS
authors.lastname: Austin
authors.forename: Sebastian A
authors.initials: SA
authors.lastname: Mikolajczak
authors.forename: Ashley M
authors.initials: AM
authors.lastname: Vaughan
authors.forename: Nelly
authors.initials: N
authors.lastname: Camargo
authors.forename: Peter G
authors.initials: PG
authors.lastname: Metzger
authors.forename: Alyse N
authors.initials: AN
authors.lastname: Douglass
authors.forename: Gavin
authors.initials: G
authors.lastname: MacBeath
authors.forename: Stefan H I
authors.initials: SH
authors.lastname: Kappe
mesh_terms: D000818:Animals; D001343:Autophagy; D049109:Cell Proliferation; D002470:Cell Survival; D022781:Hepatocytes / Q000378:metabolism / Q000469:parasitology; D006790:Host-Parasite Interactions; D007093:Imidazoles / Q000494:pharmacology; D008018:Life Cycle Stages; D008099:Liver / Q000469:parasitology*; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D010879:Piperazines / Q000494:pharmacology; D010967:Plasmodium yoelii / Q000254:growth & development / Q000378:metabolism / Q000472:pathogenicity*; D040081:Protein Array Analysis; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism
chemical_list: D007093:Imidazoles; D010879:Piperazines; D016159:Tumor Suppressor Protein p53; C482205:nutlin 3