title: Endothelial cell tropism is a determinant of H5N1 pathogenesis in mammalian species.
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.
authors.affiliation: Department of Microbiology, University of Chicago, Chicago, IL, United States of America.|Howard Taylor Ricketts Laboratory, University of Chicago, Argonne, IL, United States of America.
authors.forename: Smanla
authors.initials: S
authors.lastname: Tundup
authors.affiliation: Department of Microbiology, University of Chicago, Chicago, IL, United States of America.|Howard Taylor Ricketts Laboratory, University of Chicago, Argonne, IL, United States of America.
authors.forename: Matheswaran
authors.initials: M
authors.lastname: Kandasamy
authors.affiliation: Department of Microbiology, University of Chicago, Chicago, IL, United States of America.
authors.forename: Jasmine T
authors.initials: JT
authors.lastname: Perez
authors.affiliation: Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America.
authors.forename: Nacho
authors.identifier: 0000-0001-5464-7086
authors.initials: N
authors.lastname: Mena
authors.affiliation: Department of Microbiology, Emory University, Atlanta, GA, United States of America.
authors.forename: John
authors.initials: J
authors.lastname: Steel
authors.affiliation: Comparative Pathology Laboratory, University of Georgia, Athens, GA, United States of America.
authors.forename: Tamas
authors.initials: T
authors.lastname: Nagy
authors.affiliation: Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America.
authors.forename: Randy A
authors.initials: RA
authors.lastname: Albrecht
authors.affiliation: Department of Microbiology, University of Chicago, Chicago, IL, United States of America.|Howard Taylor Ricketts Laboratory, University of Chicago, Argonne, IL, United States of America.
authors.forename: Balaji
authors.identifier: 0000-0003-1964-0967
authors.initials: B
authors.lastname: Manicassamy
mesh_terms: D000818:Animals; D015153:Blotting, Western; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000821:virology*; D005260:Female; D005289:Ferrets; D005434:Flow Cytometry; D057809:HEK293 Cells; D006801:Humans; D053124:Influenza A Virus, H5N1 Subtype / Q000472:pathogenicity* / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009976:Orthomyxoviridae Infections / Q000473:pathology*; D060888:Real-Time Polymerase Chain Reaction; D056189:Viral Tropism / Q000502:physiology*; D014774:Virulence