title: Plasmodium circumsporozoite protein promotes the development of the liver stages of the parasite.
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 NFkappaB nuclear import, thus downregulating the expression of many genes controlled by NFkappaB, 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.
authors.affiliation: Department of Pathology, New York University School of Medicine, New York, NY 10016, USA. singha05@med.nyu.edu
authors.forename: Agam Prasad
authors.initials: AP
authors.lastname: Singh
authors.forename: Carlos A
authors.initials: CA
authors.lastname: Buscaglia
authors.forename: Qian
authors.initials: Q
authors.lastname: Wang
authors.forename: Agata
authors.initials: A
authors.lastname: Levay
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Nussenzweig
authors.forename: John R
authors.initials: JR
authors.lastname: Walker
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Winzeler
authors.forename: Hodaka
authors.initials: H
authors.lastname: Fujii
authors.forename: Beatriz M A
authors.initials: BM
authors.lastname: Fontoura
authors.forename: Victor
authors.initials: V
authors.lastname: Nussenzweig
mesh_terms: D020816:Amino Acid Motifs; D000818:Animals; D002467:Cell Nucleus / Q000378:metabolism; D006367:HeLa Cells; D022781:Hepatocytes / Q000166:cytology / Q000378:metabolism / Q000469:parasitology; D006801:Humans; D028884:Karyopherins / Q000378:metabolism; D008018:Life Cycle Stages; D008099:Liver / Q000166:cytology / Q000469:parasitology*; D008288:Malaria / Q000469:parasitology; D051379:Mice; D008810:Mice, Inbred C57BL; D050505:Mutant Proteins / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D019913:Nuclear Localization Signals / Q000378:metabolism; D010961:Plasmodium / Q000254:growth & development* / Q000378:metabolism*; D021381:Protein Transport; D015800:Protozoan Proteins / Q000737:chemistry / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D028884:Karyopherins; D050505:Mutant Proteins; D016328:NF-kappa B; D019913:Nuclear Localization Signals; D015800:Protozoan Proteins; C041595:circumsporozoite protein, Protozoan