Suppression of Host p53 Is Critical for Plasmodium Liver-Stage Infection

• Published in: Cell reports (Cambridge) 2013-03, Vol.3 (3), p.630-637
• Main Authors: Kaushansky, Alexis, Ye, Albert S., Austin, Laura S., Mikolajczak, Sebastian A., Vaughan, Ashley M., Camargo, Nelly, Metzger, Peter G., Douglass, Alyse N., MacBeath, Gavin, Kappe, Stefan H.I.
• Format: Article
• Language: English
• Subjects: Animals; Autophagy; Cell Proliferation; Cell Survival; Hepatocytes - metabolism; Hepatocytes - parasitology; Host-Parasite Interactions; Imidazoles - pharmacology; Life Cycle Stages; Liver - parasitology; Mice; Mice, Transgenic; Mutation; Piperazines - pharmacology; Plasmodium yoelii; Plasmodium yoelii - growth & development; Plasmodium yoelii - metabolism; Plasmodium yoelii - pathogenicity; Protein Array Analysis; Tumor Suppressor Protein p53 - antagonists & inhibitors; Tumor Suppressor Protein p53 - genetics; Tumor Suppressor Protein p53 - metabolism
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2013.02.010

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. [Display omitted] ► Protein lysate arrays are a useful tool for the study of host–pathogen interactions ► Hepatocyte signaling is substantially perturbed in response to Plasmodium infection ► Regulation of host p53 is required for efficient Plasmodium development ► Elevated levels of p53 eliminate Plasmodium parasites during the liver stage Malaria is the deadliest parasitic disease in the world, yet little is known about the host response to the obligate liver stage. Kappe and colleagues demonstrate that a wide variety of signaling events is initiated in response to infection and that dampening the tumor suppressor p53 is critical for parasite survival and development in a rodent model. Genetically or pharmacologically targeting this pathway inhibits parasite development, paving the way for host-based prophylaxis against malaria.