title: The aminobisphosphonate pamidronate controls influenza pathogenesis by expanding a gammadelta T cell population in humanized mice.
abstract: There are few antiviral drugs for treating influenza, and the emergence of antiviral resistance has further limited the available therapeutic options. Furthermore, antivirals are not invariably effective in severe influenza, such as that caused by H5N1 viruses. Thus, there is an urgent need to develop alternative therapeutic strategies. Here, we show that human Vγ9Vδ2 T cells expanded by the aminobisphosphonate pamidronate (PAM) kill influenza virus-infected cells and inhibit viral replication in vitro. In Rag2(-/-)γc(-/-) immunodeficient mice reconstituted with human peripheral mononuclear cells (huPBMCs), PAM reduces disease severity and mortality caused by human seasonal H1N1 and avian H5N1 influenza virus, and controls the lung inflammation and viral replication. PAM has no such effects in influenza virus-infected Rag2(-/-)γc(-/-) mice reconstituted with Vγ9Vδ2 T cell-depleted huPBMCs. Our study provides proof-of-concept of a novel therapeutic strategy for treating influenza by targeting the host rather than the virus, thereby reducing the opportunity for the emergence of drug-resistant viruses. As PAM has been commonly used to treat osteoporosis and Paget's disease, this new application of an old drug potentially offers a safe and readily available option for treating influenza.
authors.affiliation: Department of Paediatrics and Adolescent Medicine, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong, China. wwtu@hku.hk
authors.forename: Wenwei
authors.initials: W
authors.lastname: Tu
authors.forename: Jian
authors.initials: J
authors.lastname: Zheng
authors.forename: Yinping
authors.initials: Y
authors.lastname: Liu
authors.forename: Sin Fun
authors.initials: SF
authors.lastname: Sia
authors.forename: Ming
authors.initials: M
authors.lastname: Liu
authors.forename: Gang
authors.initials: G
authors.lastname: Qin
authors.forename: Iris H Y
authors.initials: IH
authors.lastname: Ng
authors.forename: Zheng
authors.initials: Z
authors.lastname: Xiang
authors.forename: Kwok-Tai
authors.initials: KT
authors.lastname: Lam
authors.forename: J S Malik
authors.initials: JS
authors.lastname: Peiris
authors.forename: Yu-Lung
authors.initials: YL
authors.lastname: Lau
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology*; D003602:Cytotoxicity, Immunologic; D004164:Diphosphonates / Q000494:pharmacology*; D006790:Host-Parasite Interactions / Q000187:drug effects / Q000276:immunology; D006801:Humans; D053118:Influenza A Virus, H1N1 Subtype; D053124:Influenza A Virus, H5N1 Subtype; D007251:Influenza, Human / Q000188:drug therapy / Q000276:immunology; D007963:Leukocytes, Mononuclear / Q000276:immunology / Q000637:transplantation; D008168:Lung / Q000187:drug effects / Q000473:pathology / Q000821:virology; D008212:Lymphocyte Depletion; D051379:Mice; D018345:Mice, Knockout; D009976:Orthomyxoviridae Infections / Q000188:drug therapy* / Q000276:immunology* / Q000473:pathology; D000077268:Pamidronate; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000378:metabolism; D016176:T-Lymphocyte Subsets / Q000187:drug effects* / Q000276:immunology*; D014183:Transplantation, Heterologous; D014779:Virus Replication / Q000187:drug effects
chemical_list: D000998:Antiviral Agents; D004164:Diphosphonates; D016692:Receptors, Antigen, T-Cell, gamma-delta; D000077268:Pamidronate