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Invasion of hepatocytes by Plasmodium sporozoites requires cGMP-dependent protein kinase and calcium dependent protein kinase 4.
- Source :
-
Molecular microbiology [Mol Microbiol] 2016 Oct; Vol. 102 (2), pp. 349-363. Date of Electronic Publication: 2016 Aug 09. - Publication Year :
- 2016
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Abstract
- Invasion of hepatocytes by sporozoites is essential for Plasmodium to initiate infection of the mammalian host. The parasite's subsequent intracellular differentiation in the liver is the first developmental step of its mammalian cycle. Despite their biological significance, surprisingly little is known of the signalling pathways required for sporozoite invasion. We report that sporozoite invasion of hepatocytes requires signalling through two second-messengers - cGMP mediated by the parasite's cGMP-dependent protein kinase (PKG), and Ca <superscript>2+</superscript> , mediated by the parasite's calcium-dependent protein kinase 4 (CDPK4). Sporozoites expressing a mutated form of Plasmodium berghei PKG or carrying a deletion of the CDPK4 gene are defective in invasion of hepatocytes. Using specific and potent inhibitors of Plasmodium PKG and CDPK4, we demonstrate that PKG and CDPK4 are required for sporozoite motility, and that PKG regulates the secretion of TRAP, an adhesin that is essential for motility. Chemical inhibition of PKG decreases parasite egress from hepatocytes by inhibiting either the formation or release of merosomes. In contrast, genetic inhibition of CDPK4 does not significantly decrease the number of merosomes. By revealing the requirement for PKG and CDPK4 in Plasmodium sporozoite invasion, our work enables a better understanding of kinase pathways that act in different Plasmodium stages.<br /> (© 2016 John Wiley & Sons Ltd.)
- Subjects :
- Animals
Anopheles parasitology
Calcium metabolism
Calcium-Binding Proteins metabolism
Cyclic GMP metabolism
Hep G2 Cells
Hepatocytes metabolism
Humans
Plasmodium berghei enzymology
Plasmodium berghei genetics
Plasmodium falciparum enzymology
Plasmodium falciparum genetics
Plasmodium falciparum metabolism
Protozoan Proteins metabolism
Signal Transduction
Sporozoites metabolism
Cyclic GMP-Dependent Protein Kinases metabolism
Hepatocytes parasitology
Plasmodium berghei metabolism
Protein Kinases metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1365-2958
- Volume :
- 102
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- Molecular microbiology
- Publication Type :
- Academic Journal
- Accession number :
- 27425827
- Full Text :
- https://doi.org/10.1111/mmi.13466