Suppression of Host p53 Is Critical for Plasmodium Liver-Stage Infection
| Autor: | Sebastian A. Mikolajczak, Ashley M. Vaughan, Gavin MacBeath, Albert S. Ye, Nelly Camargo, Stefan H. I. Kappe, Alyse N. Douglass, Alexis Kaushansky, Laura S. Austin, Peter G. Metzger |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2013 |
| Předmět: |
Cell Survival
Protein Array Analysis Mice Transgenic General Biochemistry Genetics and Molecular Biology Piperazines Article Host-Parasite Interactions 03 medical and health sciences Mice 0302 clinical medicine medicine Autophagy Parasite hosting Animals lcsh:QH301-705.5 030304 developmental biology Cell Proliferation 0303 health sciences Life Cycle Stages biology Cell growth Imidazoles Plasmodium yoelii medicine.disease biology.organism_classification 3. Good health Cell biology medicine.anatomical_structure Liver lcsh:Biology (General) 030220 oncology & carcinogenesis Hepatocyte Knockout mouse Mutation Hepatocytes Signal transduction Tumor Suppressor Protein p53 Malaria |
| Zdroj: | Cell Reports, Vol 3, Iss 3, Pp 630-637 (2013) |
| ISSN: | 2211-1247 |
| Popis: | Summary 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. |
| Databáze: | OpenAIRE |
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