The malaria circumsporozoite protein has two functional domains, each with distinct roles as sporozoites journey from mosquito to mammalian host

Alida Coppi, Ramya Natarajan, Gabriele Pradel, Brandy L. Bennett, Eric R. James, Mario A. Roggero, Giampietro Corradin, Cathrine Persson, Rita Tewari, Photini Sinnis

Research output: Contribution to journalArticle

Abstract

Plasmodium sporozoites make a remarkable journey from the mosquito midgut to the mammalian liver. The sporozoite's major surface protein, circumsporozoite protein (CSP), is a multifunctional protein required for sporozoite development and likely mediates several steps of this journey. In this study, we show that CSP has two conformational states, an adhesive conformation in which the C-terminal cell-adhesive domain is exposed and a nonadhesive conformation in which the N terminus masks this domain. We demonstrate that the cell-adhesive domain functions in sporozoite development and hepatocyte invasion. Between these two events, the sporozoite must travel from the mosquito midgut to the mammalian liver, and N-terminal masking of the cell-adhesive domain maintains the sporozoite in a migratory state. In the mammalian host, proteolytic cleavage of CSP regulates the switch to an adhesive conformation, and the highly conserved region I plays a critical role in this process. If the CSP domain architecture is altered such that the celladhesive domain is constitutively exposed, the majority of sporozoites do not reach their target organs, and in the mammalian host, they initiate a blood stage infection directly from the inoculation site. These data provide structure-function information relevant to malaria vaccine development.

Original languageEnglish (US)
Pages (from-to)341-356
Number of pages16
JournalJournal of Experimental Medicine
Volume208
Issue number2
DOIs
StatePublished - Feb 14 2011
Externally publishedYes

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Sporozoites
Culicidae
Malaria
Adhesives
Proteins
Malaria Vaccines
Plasmodium
Liver
Masks
Hepatocytes
Membrane Proteins
Infection

ASJC Scopus subject areas

  • Immunology
  • Immunology and Allergy

Cite this

The malaria circumsporozoite protein has two functional domains, each with distinct roles as sporozoites journey from mosquito to mammalian host. / Coppi, Alida; Natarajan, Ramya; Pradel, Gabriele; Bennett, Brandy L.; James, Eric R.; Roggero, Mario A.; Corradin, Giampietro; Persson, Cathrine; Tewari, Rita; Sinnis, Photini.

In: Journal of Experimental Medicine, Vol. 208, No. 2, 14.02.2011, p. 341-356.

Research output: Contribution to journalArticle

Coppi, Alida ; Natarajan, Ramya ; Pradel, Gabriele ; Bennett, Brandy L. ; James, Eric R. ; Roggero, Mario A. ; Corradin, Giampietro ; Persson, Cathrine ; Tewari, Rita ; Sinnis, Photini. / The malaria circumsporozoite protein has two functional domains, each with distinct roles as sporozoites journey from mosquito to mammalian host. In: Journal of Experimental Medicine. 2011 ; Vol. 208, No. 2. pp. 341-356.
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