title: Reversible Conformational Change in the Plasmodium falciparum Circumsporozoite Protein Masks Its Adhesion Domains.
abstract: The extended rod-like Plasmodium falciparum circumsporozoite protein (CSP) is comprised of three primary domains: a charged N terminus that binds heparan sulfate proteoglycans, a central NANP repeat domain, and a C terminus containing a thrombospondin-like type I repeat (TSR) domain. Only the last two domains are incorporated in RTS,S, the leading malaria vaccine in phase 3 trials that, to date, protects about 50% of vaccinated children against clinical disease. A seroepidemiological study indicated that the N-terminal domain might improve the efficacy of a new CSP vaccine. Using a panel of CSP-specific monoclonal antibodies, well-characterized recombinant CSPs, label-free quantitative proteomics, and in vitro inhibition of sporozoite invasion, we show that native CSP is N-terminally processed in the mosquito host and undergoes a reversible conformational change to mask some epitopes in the N- and C-terminal domains until the sporozoite interacts with the liver hepatocyte. Our findings show the importance of understanding processing and the biophysical change in conformation, possibly due to a mechanical or molecular signal, and may aid in the development of a new CSP vaccine.
authors.affiliation: Laboratory of Malaria Immunology and Vaccinology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, Maryland, USA.
authors.forename: Raul
authors.initials: R
authors.lastname: Herrera
authors.affiliation: Laboratory of Malaria Immunology and Vaccinology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, Maryland, USA.
authors.forename: Charles
authors.initials: C
authors.lastname: Anderson
authors.affiliation: Laboratory of Malaria Immunology and Vaccinology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, Maryland, USA.
authors.forename: Krishan
authors.initials: K
authors.lastname: Kumar
authors.affiliation: Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, Maryland, USA.
authors.forename: Alvaro
authors.initials: A
authors.lastname: Molina-Cruz
authors.affiliation: Laboratory of Malaria Immunology and Vaccinology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, Maryland, USA.
authors.forename: Vu
authors.initials: V
authors.lastname: Nguyen
authors.affiliation: Laboratory of Malaria Immunology and Vaccinology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, Maryland, USA.
authors.forename: Martin
authors.initials: M
authors.lastname: Burkhardt
authors.affiliation: Laboratory of Malaria Immunology and Vaccinology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, Maryland, USA.
authors.forename: Karine
authors.initials: K
authors.lastname: Reiter
authors.affiliation: Laboratory of Malaria Immunology and Vaccinology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, Maryland, USA.
authors.forename: Richard
authors.initials: R
authors.lastname: Shimp
authors.affiliation: Infectious Disease Research Institute, Seattle, Washington, USA.
authors.forename: Randall F
authors.initials: RF
authors.lastname: Howard
authors.affiliation: Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, Maryland, USA.
authors.forename: Prakash
authors.initials: P
authors.lastname: Srinivasan
authors.affiliation: Waters Corp., Milford, Massachusetts, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Nold
authors.affiliation: Johns Hopkins Malaria Research Institute and Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Ragheb
authors.affiliation: Johns Hopkins Malaria Research Institute and Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland, USA.
authors.forename: Lirong
authors.initials: L
authors.lastname: Shi
authors.affiliation: Laboratory of Malaria Immunology and Vaccinology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, Maryland, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: DeCotiis
authors.affiliation: Laboratory of Malaria Immunology and Vaccinology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, Maryland, USA.
authors.forename: Joan
authors.initials: J
authors.lastname: Aebig
authors.affiliation: Laboratory of Malaria Immunology and Vaccinology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, Maryland, USA.
authors.forename: Lynn
authors.initials: L
authors.lastname: Lambert
authors.affiliation: Laboratory of Malaria Immunology and Vaccinology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, Maryland, USA.
authors.forename: Kelly M
authors.initials: KM
authors.lastname: Rausch
authors.affiliation: Laboratory of Malaria Immunology and Vaccinology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, Maryland, USA.
authors.forename: Olga
authors.initials: O
authors.lastname: Muratova
authors.affiliation: Laboratory of Cellular Imaging and Macromolecular Biophysics, National Institute of Biomedical Imaging and Bioengineering, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Albert
authors.initials: A
authors.lastname: Jin
authors.affiliation: Infectious Disease Research Institute, Seattle, Washington, USA.
authors.forename: Steven G
authors.initials: SG
authors.lastname: Reed
authors.affiliation: Johns Hopkins Malaria Research Institute and Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland, USA.
authors.forename: Photini
authors.initials: P
authors.lastname: Sinnis
authors.affiliation: Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, Maryland, USA.
authors.forename: Carolina
authors.initials: C
authors.lastname: Barillas-Mury
authors.affiliation: Laboratory of Malaria Immunology and Vaccinology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, Maryland, USA.
authors.forename: Patrick E
authors.initials: PE
authors.lastname: Duffy
authors.affiliation: Laboratory of Malaria Immunology and Vaccinology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, Maryland, USA.
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: MacDonald
authors.affiliation: Laboratory of Malaria Immunology and Vaccinology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, Maryland, USA dnarum@niaid.nih.gov.
authors.forename: David L
authors.initials: DL
authors.lastname: Narum
mesh_terms: D000818:Animals; D000852:Anopheles / Q000469:parasitology; D000913:Antibodies, Protozoan / Q000276:immunology; D000939:Epitopes / Q000737:chemistry / Q000235:genetics / Q000276:immunology; D022781:Hepatocytes / Q000276:immunology / Q000469:parasitology; D006801:Humans; D016778:Malaria, Falciparum / Q000276:immunology / Q000469:parasitology*; D010963:Plasmodium falciparum / Q000737:chemistry / Q000235:genetics / Q000254:growth & development / Q000276:immunology*; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D015800:Protozoan Proteins / Q000737:chemistry* / Q000235:genetics / Q000276:immunology*; D034101:Sporozoites / Q000737:chemistry / Q000254:growth & development / Q000276:immunology*
chemical_list: D000913:Antibodies, Protozoan; D000939:Epitopes; D015800:Protozoan Proteins