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.
journal_name
Cell Repjournal_title
Cell reportsauthors
Kaushansky A,Ye AS,Austin LS,Mikolajczak SA,Vaughan AM,Camargo N,Metzger PG,Douglass AN,MacBeath G,Kappe SHdoi
10.1016/j.celrep.2013.02.010subject
Has Abstractpub_date
2013-03-28 00:00:00pages
630-7issue
3issn
2211-1247pii
S2211-1247(13)00069-7journal_volume
3pub_type
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