Endothelial cell tropism is a determinant of H5N1 pathogenesis in mammalian species

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 H...

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Bibliographic Details
Published in:PLoS pathogens 2017-03, Vol.13 (3), p.e1006270-e1006270
Main Authors: Tundup, Smanla, Kandasamy, Matheswaran, Perez, Jasmine T, Mena, Nacho, Steel, John, Nagy, Tamas, Albrecht, Randy A, Manicassamy, Balaji
Format: Article
Language:English
Subjects:
Animals
Avian flu
Avian influenza viruses
Biology and life sciences
Blotting, Western
Comparative analysis
Cytokines
Disease control
Disease Models, Animal
Endothelial cells
Endothelial Cells - virology
Endothelium
Exploitation
Female
Ferrets
Flow Cytometry
Gene expression
Genetic aspects
Genetic engineering
Genomes
Health aspects
HEK293 Cells
Humans
Immune response
Infections
Influenza A Virus, H5N1 Subtype - pathogenicity
Influenza A Virus, H5N1 Subtype - physiology
Integrity
Laboratories
Leakage
Lungs
Male
Mammals
Medicine and health sciences
Mice
Mice, Inbred C57BL
MicroRNA
MicroRNAs
miRNA
Molecular modelling
Orthomyxoviridae Infections - pathology
Pandemics
Pathogenesis
Pneumonia
Real-Time Polymerase Chain Reaction
Replication
Ribonucleic acid
RNA
Species
Studies
Tropism
Viral Tropism - physiology
Virology
Virulence
Viruses
Zoonoses
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Summary: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.
ISSN:1553-7374
1553-7366
1553-7374
DOI:10.1371/journal.ppat.1006270