Plasmodium falciparum Infection Induces Expression of a Mosquito Salivary Protein (Agaphelin) That Targets Neutrophil Function and Inhibits Thrombosis without Impairing Hemostasis

0435190 - BC 2015 RIV US eng J - Journal Article
Waisberg, M. - Molina-Cruz, A. - Mizurini, D.M. - Gera, N. - Sousa, B.C. - Ma, D. - Leal, A.C. - Gomes, T. - Kotsyfakis, Michalis - Ribeiro, J.M.C. - Lukszo, J. - Reiter, K. - Porcella, S.F. - Oliveira, C. J. - Monteiro, R.Q. - Barillas-Mury, C. - Pierce, S.K. - Francischetti, I.M.B.
Plasmodium falciparum Infection Induces Expression of a Mosquito Salivary Protein (Agaphelin) That Targets Neutrophil Function and Inhibits Thrombosis without Impairing Hemostasis.
PLoS Pathogens. Roč. 10, č. 9 (2014), e1004338. ISSN 1553-7366. E-ISSN 1553-7374
R&D Projects: GA ČR GAP502/12/2409
Institutional support: RVO:60077344
Keywords : factor pathway inhibitor * platelet aggregation * in vivo * serine proteases * arterial thrombosis * gene expression * structure prediction
Subject RIV: EB - Genetics ; Molecular Biology
Impact factor: 7.562, year: 2014

Background: Invasion of mosquito salivary glands (SGs) by Plasmodium falciparum sporozoites is an essential step in the malaria life cycle. How infection modulates gene expression, and affects hematophagy remains unclear. Principal Findings: Using Affimetrix chip microarray, we found that at least 43 genes are differentially expressed in the glands of Plasmodium falciparum-infected Anopheles gambiae mosquitoes. Among the upregulated genes, one codes for Agaphelin, a 58-amino acid protein containing a single Kazal domain with a Leu in the P1 position. Agaphelin displays high homology to orthologs present in Aedes sp and Culex sp salivary glands, indicating an evolutionarily expanded family. Kinetics and surface plasmon resonance experiments determined that chemically synthesized Agaphelin behaves as a slow and tight inhibitor of neutrophil elastase (K-D similar to 10 nM), but does not affect other enzymes, nor promotes vasodilation, or exhibit antimicrobial activity. TAXIscan chamber assay revealed that Agaphelin inhibits neutrophil chemotaxis toward fMLP, affecting several parameter associated with cell migration. In addition, Agaphelin reduces paw edema formation and accumulation of tissue myeloperoxidase triggered by injection of carrageenan in mice. Agaphelin also blocks elastase/cathepsin-mediated platelet aggregation, abrogates elastase-mediated cleavage of tissue factor pathway inhibitor, and attenuates neutrophil-induced coagulation. Notably, Agaphelin inhibits neutrophil extracellular traps (NETs) formation and prevents FeCl3-induced arterial thrombosis, without impairing hemostasis.
Permanent Link: http://hdl.handle.net/11104/0239107