The Therapeutic Effect of Pamidronate on Lethal Avian Influenza A H7N9 Virus Infected Humanized Mice.
A novel avian influenza virus H7N9 infection occurred among human populations since 2013. Although the lack of sustained human-to-human transmission limited the epidemics caused by H7N9, the late presentation of most patients and the emergence of neuraminidase-resistant strains made the development of novel antiviral strategy against H7N9 in urgent demands. In this study, we evaluated the potential of pamidronate, a pharmacological phosphoantigen that can specifically boost human Vδ2-T-cell, on treating H7N9 virus-infected humanized mice. Our results showed that intraperitoneal injection of pamidronate could potently decrease the morbidity and mortality of H7N9-infected mice through controlling both viral replication and inflammation in affected lungs. More importantly, pamidronate treatment starting from 3 days after infection could still significantly ameliorate the severity of diseases in infected mice and improve their survival chance, whereas orally oseltamivir treatment starting at the same time showed no therapeutic effects. As for the mechanisms underlying pamidronate-based therapy, our in vitro data demonstrated that its antiviral effects were partly mediated by IFN-γ secreted from human Vδ2-T cells. Meanwhile, human Vδ2-T cells could directly kill virus-infected host cells in a perforin-, granzyme B- and CD137-dependent manner. As pamidronate has been used for osteoporosis treatment for more than 20 years, pamidronate-based therapy represents for a safe and readily available option for clinical trials to treat H7N9 infection.
Department of Paediatrics & Adolescent Medicine, University of Hong Kong, Hong Kong, China.
Jian
J
Zheng
State Key Laboratory of Emerging Infectious Diseases, Department of Microbiology, University of Hong Kong, Hong Kong, China.
Wai-Lan
WL
Wu
Department of Paediatrics & Adolescent Medicine, University of Hong Kong, Hong Kong, China.
Yinping
Y
Liu
Department of Paediatrics & Adolescent Medicine, University of Hong Kong, Hong Kong, China.
Zheng
Z
Xiang
Guangzhou Institute of Respiratory Diseases, Guangzhou Medical University, Guangzhou, China.
Ming
M
Liu
State Key Laboratory of Emerging Infectious Diseases, Department of Microbiology, University of Hong Kong, Hong Kong, China.
Kwok-Hung
KH
Chan
State Key Laboratory of Emerging Infectious Diseases, Department of Microbiology, University of Hong Kong, Hong Kong, China.
Siu-Ying
SY
Lau
Department of Paediatrics & Adolescent Medicine, University of Hong Kong, Hong Kong, China.
Kwok-Tai
KT
Lam
State Key Laboratory of Emerging Infectious Diseases, Department of Microbiology, University of Hong Kong, Hong Kong, China.
Kelvin Kai-Wang
KK
To
State Key Laboratory of Emerging Infectious Diseases, Department of Microbiology, University of Hong Kong, Hong Kong, China.
Jasper Fuk-Woo
JF
Chan
State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China.
Lanjuan
L
Li
State Key Laboratory of Emerging Infectious Diseases, Department of Microbiology, University of Hong Kong, Hong Kong, China.
Honglin
H
Chen
Department of Paediatrics & Adolescent Medicine, University of Hong Kong, Hong Kong, China.
Yu-Lung
YL
Lau
State Key Laboratory of Emerging Infectious Diseases, Department of Microbiology, University of Hong Kong, Hong Kong, China.
Kwok-Yung
KY
Yuen
Department of Paediatrics & Adolescent Medicine, University of Hong Kong, Hong Kong, China.
Wenwei
W
Tu
D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D050071:Bone Density Conservation Agents / Q000494:pharmacology; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000502:physiology; D004164:Diphosphonates / Q000494:pharmacology*; D006801:Humans; D007124:Immunoenzyme Techniques; D064766:Influenza A Virus, H7N9 Subtype / Q000472:pathogenicity*; D007251:Influenza, Human / Q000188:drug therapy* / Q000276:immunology / Q000821:virology; D008168:Lung / Q000187:drug effects* / Q000821:virology; D051379:Mice; D018345:Mice, Knockout; D009976:Orthomyxoviridae Infections / Q000188:drug therapy* / Q000276:immunology / Q000821:virology; D000077268:Pamidronate; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016176:T-Lymphocyte Subsets; D014779:Virus Replication / Q000187:drug effects*
D050071:Bone Density Conservation Agents; D004268:DNA-Binding Proteins; D004164:Diphosphonates; D012333:RNA, Messenger; C499308:Rag2 protein, mouse; D000077268:Pamidronate