Plasmodium Circumsporozoite Protein Promotes the Development of the Liver Stages of the Parasite

Agam Prasad Singh, Carlos A. Buscaglia, Qian Wang, Agata Levay, Daniel R. Nussenzweig, John R. Walker, Elizabeth A. Winzeler, Hodaka Fujii, Beatriz M A Fontoura, Victor Nussenzweig

Research output: Contribution to journalArticlepeer-review

142 Scopus citations

Abstract

The liver stages of malaria are clinically silent but have a central role in the Plasmodium life cycle. Liver stages of the parasite containing thousands of merozoites grow inside hepatocytes for several days without triggering an inflammatory response. We show here that Plasmodium uses a PEXEL/VTS motif to introduce the circumsporozoite (CS) protein into the hepatocyte cytoplasm and a nuclear localization signal (NLS) to enter its nucleus. CS outcompetes NFκB nuclear import, thus downregulating the expression of many genes controlled by NFκB, including those involved in inflammation. CS also influences the expression of over one thousand host genes involved in diverse metabolic processes to create a favorable niche for the parasite growth. The presence of CS in the hepatocyte enhances parasite growth of the liver stages in vitro and in vivo. These findings have far reaching implications for drug and vaccine development against the liver stages of the malaria parasite.

Original languageEnglish (US)
Pages (from-to)492-504
Number of pages13
JournalCell
Volume131
Issue number3
DOIs
StatePublished - Nov 2 2007

Keywords

  • CELLBIO
  • CELLIMMUNO
  • HUMDISEASE

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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