Abstract
The cellular and molecular mechanisms underpinning the unusually high virulence of highly pathogenic avian influenza H5N1 viruses in mammalian species remains unknown. Here, we investigated if the cell tropism of H5N1 virus is a determinant of enhanced virulence in mammalian species. We engineered H5N1 viruses with restricted cell tropism through the exploitation of cell type-specific microRNA expression by incorporating microRNA target sites into the viral genome. Restriction of H5N1 replication in endothelial cells via miR-126 ameliorated disease symptoms, prevented systemic viral spread and limited mortality, despite showing similar levels of peak viral replication in the lungs as compared to control virus-infected mice. Similarly, restriction of H5N1 replication in endothelial cells resulted in ameliorated disease symptoms and decreased viral spread in ferrets. Our studies demonstrate that H5N1 infection of endothelial cells results in excessive production of cytokines and reduces endothelial barrier integrity in the lungs, which culminates in vascular leakage and viral pneumonia. Importantly, our studies suggest a need for a combinational therapy that targets viral components, suppresses host immune responses, and improves endothelial barrier integrity for the treatment of highly pathogenic H5N1 virus infections.
Highlights
Influenza A viruses, members of the Orthomyxoviridae family, pose a constant threat to human health with seasonal epidemics and occasional pandemics
Our studies show that H5N1 infection of endothelial cells causes severe disease and death
To investigate if the enhanced virulence associated with H5N1 infection is due to broad cell tropism, we engineered H5N1 viruses (A/Vietnam/1203/2004) with restricted cell tropism based on the strategy developed by the tenOever group [27,28,29]
Summary
Influenza A viruses, members of the Orthomyxoviridae family, pose a constant threat to human health with seasonal epidemics and occasional pandemics. Influenza A viruses circulating in zoonotic reservoirs have intermittently caused widespread infections and even pandemics in humans [2,3]. Influenza A virus strains such as H5N1, H7N7, and H7N9 have crossed the species barrier from domestic poultry to cause fatal infections in humans [6,7]. These avian viruses are incapable of causing sustained human-to-human transmission and the majority of these infections have been the result of direct contact with infected poultry; recent studies indicate that less than 5 mutations are sufficient to render avian H5N1 viruses transmissible via respiratory droplets [8,9]. A better understanding of the pathogenic nature of avian influenza A viruses is important for devising novel therapeutic strategies and preventing future pandemics
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