Abstract
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.
Highlights
The first human epidemic of avian-origin influenza virus infection caused by subtype H5N1 occurred in 1997 [1]
We firstly examined the pathogenic effects of H7N9 virus by i.n. infecting humanized mice with different doses of H7N9 virus
These results demonstrated that pamidronate could effectively ameliorate disease severity and the mortality caused by H7N9 virus compared to oseltamivir
Summary
The first human epidemic of avian-origin influenza virus infection caused by subtype H5N1 occurred in 1997 [1]. In February 2013, a novel avian-origin influenza A virus H7N9 was firstly identified in patients in Eastern China [2,3,4,5,6]. During the first wave of H7N9 infection among human population in 2013, 143 patients with 46 deaths were confirmed in 11 provinces or municipalities in China, leading to the concern of a new influenza pandemic. The limited human-human transmission of H7N9 virus decreased the possibility of a global pandemic, the return of H7N9 infection trend in early 2014 aroused the concentrations on improving the control and treatment of newly-occurred avian influenza virus [7]. H7N9 strains carrying Arg292Lys mutation in neuraminidase [6] gene were identified in two H7N9-infected patients recently and exhibited resistance to the treatment of adamantanes, oseltamivir and zanamivir [9], which made developing alternative therapeutic strategies to treat H7N9 infection in urgent need
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