title: cAMP-Signalling Regulates Gametocyte-Infected Erythrocyte Deformability Required for Malaria Parasite Transmission.
abstract: Blocking Plasmodium falciparum transmission to mosquitoes has been designated a strategic objective in the global agenda of malaria elimination. Transmission is ensured by gametocyte-infected erythrocytes (GIE) that sequester in the bone marrow and at maturation are released into peripheral blood from where they are taken up during a mosquito blood meal. Release into the blood circulation is accompanied by an increase in GIE deformability that allows them to pass through the spleen. Here, we used a microsphere matrix to mimic splenic filtration and investigated the role of cAMP-signalling in regulating GIE deformability. We demonstrated that mature GIE deformability is dependent on reduced cAMP-signalling and on increased phosphodiesterase expression in stage V gametocytes, and that parasite cAMP-dependent kinase activity contributes to the stiffness of immature gametocytes. Importantly, pharmacological agents that raise cAMP levels in transmissible stage V gametocytes render them less deformable and hence less likely to circulate through the spleen. Therefore, phosphodiesterase inhibitors that raise cAMP levels in P. falciparum infected erythrocytes, such as sildenafil, represent new candidate drugs to block transmission of malaria parasites.
authors.affiliation: Laboratoire de Biologie Cellulaire Comparative des Apicomplexes, Faculté de Médicine, Université Paris Descartes-Sorbonne Paris Cité, Paris, France; Inserm U1016, CNRS UMR8104, Institut Cochin, Paris, France.
authors.forename: Ghania
authors.initials: G
authors.lastname: Ramdani
authors.affiliation: Inserm U1016, CNRS UMR8104, Institut Cochin, Paris, France; Laboratoire de Biologie de la Transmission de Plasmodium, Faculté de Médicine, Université Paris Descartes-Sorbonne Paris Cité, Paris, France.
authors.forename: Bernina
authors.initials: B
authors.lastname: Naissant
authors.affiliation: Faculty of Infectious and Tropical Diseases, London School of Hygiene & Tropical Medicine, London, United Kingdom.
authors.forename: Eloise
authors.initials: E
authors.lastname: Thompson
authors.affiliation: Institut Pasteur, Unité de Génétique et Génomique des Insectes Vecteurs, CNRS URA 3012, Paris, France.
authors.forename: Florence
authors.initials: F
authors.lastname: Breil
authors.affiliation: Inserm U1016, CNRS UMR8104, Institut Cochin, Paris, France; Laboratoire de Biologie de la Transmission de Plasmodium, Faculté de Médicine, Université Paris Descartes-Sorbonne Paris Cité, Paris, France; Institut Pasteur, Unité de Génétique et Génomique des Insectes Vecteurs, CNRS URA 3012, Paris, France.
authors.forename: Audrey
authors.initials: A
authors.lastname: Lorthiois
authors.affiliation: Inserm U1016, CNRS UMR8104, Institut Cochin, Paris, France; Laboratoire de Biologie de la Transmission de Plasmodium, Faculté de Médicine, Université Paris Descartes-Sorbonne Paris Cité, Paris, France.
authors.forename: Florian
authors.initials: F
authors.lastname: Dupuy
authors.affiliation: Faculty of Infectious and Tropical Diseases, London School of Hygiene & Tropical Medicine, London, United Kingdom.
authors.forename: Ross
authors.initials: R
authors.lastname: Cummings
authors.affiliation: Inserm U1016, CNRS UMR8104, Institut Cochin, Paris, France; Laboratoire de Biologie de la Transmission de Plasmodium, Faculté de Médicine, Université Paris Descartes-Sorbonne Paris Cité, Paris, France.
authors.forename: Yoann
authors.initials: Y
authors.lastname: Duffier
authors.affiliation: Dipartimento di Scienze Farmacologiche e Biomolecolari (DiSFeB), Università di Milano, Milano, Italy.
authors.forename: Yolanda
authors.initials: Y
authors.lastname: Corbett
authors.affiliation: Institut Pasteur, Unité d'Immunologie Moléculaire des Parasites, CNRS URA 2581, Paris, France.
authors.forename: Odile
authors.initials: O
authors.lastname: Mercereau-Puijalon
authors.affiliation: Institut Pasteur, Unité de Génétique et Génomique des Insectes Vecteurs, CNRS URA 3012, Paris, France.
authors.forename: Kenneth
authors.initials: K
authors.lastname: Vernick
authors.affiliation: Dipartimento di Scienze Farmacologiche e Biomolecolari (DiSFeB), Università di Milano, Milano, Italy.
authors.forename: Donatella
authors.initials: D
authors.lastname: Taramelli
authors.affiliation: Faculty of Infectious and Tropical Diseases, London School of Hygiene & Tropical Medicine, London, United Kingdom.
authors.forename: David A
authors.initials: DA
authors.lastname: Baker
authors.affiliation: Laboratoire de Biologie Cellulaire Comparative des Apicomplexes, Faculté de Médicine, Université Paris Descartes-Sorbonne Paris Cité, Paris, France; Inserm U1016, CNRS UMR8104, Institut Cochin, Paris, France.
authors.forename: Gordon
authors.initials: G
authors.lastname: Langsley
authors.affiliation: Inserm U1016, CNRS UMR8104, Institut Cochin, Paris, France; Laboratoire de Biologie de la Transmission de Plasmodium, Faculté de Médicine, Université Paris Descartes-Sorbonne Paris Cité, Paris, France; Institut Pasteur, Unité de Génétique et Génomique des Insectes Vecteurs, CNRS URA 3012, Paris, France.
authors.forename: Catherine
authors.initials: C
authors.lastname: Lavazec
mesh_terms: D000818:Animals; D009033:Culicidae; D000242:Cyclic AMP / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D004907:Erythrocyte Deformability / Q000502:physiology*; D004912:Erythrocytes / Q000469:parasitology*; D006801:Humans; D016778:Malaria, Falciparum / Q000469:parasitology* / Q000635:transmission; D010963:Plasmodium falciparum / Q000502:physiology*; D015398:Signal Transduction
chemical_list: D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases