title: AAV8-mediated in vivo overexpression of miR-155 enhances the protective capacity of genetically attenuated malarial parasites.
abstract: Malaria, caused by protozoan Plasmodium parasites, remains a prevalent infectious human disease due to the lack of an efficient and safe vaccine. This is directly related to the persisting gaps in our understanding of the parasite's interactions with the infected host, especially during the clinically silent yet essential liver stage of Plasmodium development. Previously, we and others showed that genetically attenuated parasites (GAP) that arrest in the liver induce sterile immunity, but only upon multiple administrations. Here, we comprehensively studied hepatic gene and miRNA expression in GAP-injected mice, and found both a broad activation of IFNγ-associated pathways and a significant increase of murine microRNA-155 (miR-155), that was especially pronounced in non-parenchymal cells including liver-resident macrophages (Kupffer cells). Remarkably, ectopic upregulation of this miRNA in the liver of mice using robust hepatotropic adeno-associated virus 8 (AAV8) vectors enhanced GAP's protective capacity substantially. In turn, this AAV8-mediated miR-155 expression permitted a reduction of GAP injections needed to achieve complete protection against infectious parasite challenge from previously three to only one. Our study highlights a crucial role of mammalian miRNAs in Plasmodium liver infection in vivo and concurrently implies their great potential as future immune-augmenting agents in improved vaccination regimes against malaria and other diseases.
authors.affiliation: Centre for Infectious Diseases, Parasitology, Heidelberg University Hospital, Heidelberg, Germany; Centre for Infectious Diseases, Virology, Heidelberg University Hospital, Heidelberg, Germany.
authors.forename: Franziska
authors.initials: F
authors.lastname: Hentzschel
authors.affiliation: Centre for Infectious Diseases, Parasitology, Heidelberg University Hospital, Heidelberg, Germany.
authors.forename: Christiane
authors.initials: C
authors.lastname: Hammerschmidt-Kamper
authors.affiliation: Centre for Infectious Diseases, Virology, Heidelberg University Hospital, Heidelberg, Germany.
authors.forename: Kathleen
authors.initials: K
authors.lastname: Börner
authors.affiliation: Centre for Infectious Diseases, Parasitology, Heidelberg University Hospital, Heidelberg, Germany.
authors.forename: Kirsten
authors.initials: K
authors.lastname: Heiss
authors.affiliation: ViroQuant Research Group Modeling, BioQuant, University of Heidelberg, Heidelberg, Germany; Cluster of Excellence CellNetworks, Heidelberg, Germany; Medical Faculty Carl Gustav Carus, Institute for Medical Informatics and Biometry, Dresden University of Technology, Dresden, Germany; Institute of Computational Biology, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany.
authors.forename: Bettina
authors.initials: B
authors.lastname: Knapp
authors.affiliation: Centre for Infectious Diseases, Parasitology, Heidelberg University Hospital, Heidelberg, Germany.
authors.forename: Julia M
authors.initials: JM
authors.lastname: Sattler
authors.affiliation: ViroQuant Research Group Modeling, BioQuant, University of Heidelberg, Heidelberg, Germany; Cluster of Excellence CellNetworks, Heidelberg, Germany; Medical Faculty Carl Gustav Carus, Institute for Medical Informatics and Biometry, Dresden University of Technology, Dresden, Germany.
authors.forename: Lars
authors.initials: L
authors.lastname: Kaderali
authors.affiliation: University Hospital Düsseldorf, Gastroenterology, Hepatology and Infectious Diseases, Düsseldorf, Germany.
authors.forename: Mirco
authors.initials: M
authors.lastname: Castoldi
authors.affiliation: Department of Surgery, Division of Transplantation, University of California San Francisco, San Francisco, California, USA.
authors.forename: Jay G
authors.initials: JG
authors.lastname: Bindman
authors.affiliation: Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California San Francisco, San Francisco, California, USA.
authors.forename: Yann
authors.initials: Y
authors.lastname: Malato
authors.affiliation: Department of Surgery, Division of Transplantation, University of California San Francisco, San Francisco, California, USA; Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California San Francisco, San Francisco, California, USA; Liver Center, University of California San Francisco, San Francisco, California, USA.
authors.forename: Holger
authors.initials: H
authors.lastname: Willenbring
authors.affiliation: Centre for Infectious Diseases, Parasitology, Heidelberg University Hospital, Heidelberg, Germany. Electronic address: ann-kristin.mueller@uni-heidelberg.de.
authors.forename: Ann-Kristin
authors.initials: AK
authors.lastname: Mueller
authors.affiliation: Centre for Infectious Diseases, Virology, Heidelberg University Hospital, Heidelberg, Germany; Cluster of Excellence CellNetworks, Heidelberg, Germany. Electronic address: dirk.grimm@bioquant.uni-heidelberg.de.
authors.forename: Dirk
authors.initials: D
authors.lastname: Grimm
mesh_terms: D000818:Animals; D000229:Dependovirus / Q000235:genetics*; D004195:Disease Models, Animal; D005822:Genetic Vectors / Q000008:administration & dosage*; D057809:HEK293 Cells; D006801:Humans; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008288:Malaria / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D017780:Malaria Vaccines / Q000008:administration & dosage* / Q000235:genetics; D008297:Male; D051379:Mice; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D010962:Plasmodium berghei / Q000472:pathogenicity; D012333:RNA, Messenger / Q000276:immunology*; D015854:Up-Regulation; D014613:Vaccines, Attenuated / Q000235:genetics
chemical_list: C524942:MIRN155 microRNA, human; D017780:Malaria Vaccines; D035683:MicroRNAs; D012333:RNA, Messenger; D014613:Vaccines, Attenuated