title: Targeting host calpain proteases decreases influenza A virus infection.
abstract: Influenza A viruses (IAV) trigger contagious acute respiratory diseases. A better understanding of the molecular mechanisms of IAV pathogenesis and host immune responses is required for the development of more efficient treatments of severe influenza. Calpains are intracellular proteases that participate in diverse cellular responses, including inflammation. Here, we used in vitro and in vivo approaches to investigate the role of calpain signaling in IAV pathogenesis. Calpain expression and activity were found altered in IAV-infected bronchial epithelial cells. With the use of small-interfering RNA (siRNA) gene silencing, specific synthetic inhibitors of calpains, and mice overexpressing calpastatin, we found that calpain inhibition dampens IAV replication and IAV-triggered secretion of proinflammatory mediators and leukocyte infiltration. Remarkably, calpain inhibition has a protective impact in IAV infection, since it significantly reduced mortality of mice challenged not only by seasonal H3N2- but also by hypervirulent H5N1 IAV strains. Hence, our study suggests that calpains are promising therapeutic targets for treating IAV acute pneumonia.
authors.affiliation: Institut Pasteur, Unité de Défense Innée et Inflammation, Paris, France; Institut National de la Santé et de la Recherche Médicale U874, Paris, France;
authors.forename: Fany
authors.initials: F
authors.lastname: Blanc
authors.affiliation: Institut Pasteur, Unité de Défense Innée et Inflammation, Paris, France; Institut National de la Santé et de la Recherche Médicale U874, Paris, France;
authors.forename: Laetitia
authors.initials: L
authors.lastname: Furio
authors.affiliation: Institut Pasteur, Unité de Génétique Moléculaire des Virus ARN, Paris, France;
authors.forename: Dorothée
authors.initials: D
authors.lastname: Moisy
authors.affiliation: School of Public Health, The University of Hong Kong, Hong Kong, China;
authors.forename: Hui-Ling
authors.initials: HL
authors.lastname: Yen
authors.affiliation: Institut Pasteur, Unité de Défense Innée et Inflammation, Paris, France; Institut National de la Santé et de la Recherche Médicale U874, Paris, France;
authors.forename: Michel
authors.initials: M
authors.lastname: Chignard
authors.affiliation: Institut National de la Santé et de la Recherche Médicale UMR-S1155, Paris, France;
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Letavernier
authors.affiliation: Institut Pasteur, Unité de Génétique Moléculaire des Virus ARN, Paris, France;
authors.forename: Nadia
authors.initials: N
authors.lastname: Naffakh
authors.affiliation: The HKU-Pasteur Research Pole, School of Public Health, The University of Hong Kong, Hong Kong, China;
authors.forename: Chris Ka Pun
authors.initials: CK
authors.lastname: Mok
authors.affiliation: Institut Pasteur, Unité de Défense Innée et Inflammation, Paris, France; Institut National de la Santé et de la Recherche Médicale U874, Paris, France; Institut National de la Santé et de la Recherche Médicale U1100, Centre d'Etude des Pathologies Respiratoires, Tours, France; and Université François Rabelais, Tours, France si-tahar@univ-tours.fr.
authors.forename: Mustapha
authors.initials: M
authors.lastname: Si-Tahar
mesh_terms: D000818:Animals; D002154:Calpain / Q000502:physiology*; D016207:Cytokines / Q000378:metabolism; D004285:Dogs; D004847:Epithelial Cells / Q000276:immunology / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic; D015967:Gene Expression Regulation, Viral; D006801:Humans; D053124:Influenza A Virus, H5N1 Subtype / Q000276:immunology*; D007251:Influenza, Human / Q000201:enzymology* / Q000276:immunology / Q000821:virology; D061985:Madin Darby Canine Kidney Cells; D008810:Mice, Inbred C57BL; D051192:Receptors, Pattern Recognition / Q000378:metabolism; D015398:Signal Transduction; D014779:Virus Replication
chemical_list: D016207:Cytokines; D051192:Receptors, Pattern Recognition; D002154:Calpain
keywords: immunity; inflammation; lung; signal transduction