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

• Type of Material: Article
• Authors: Smanla Tundup, University of Chicago; Matheswaran Kandasamy, University of Chicago; Jasmine T. Perez, University of Chicago; Nacho Mena, Icahn School of Medicine; John Steel, Emory University; Tamas Nagy, University of Georgia; Randy A. Albrecht, Icahn School of Medicine; Balaji Manicassamy, University of Chicago
• Language: English
• Date: 2017-03-10
• Publisher: Public Library of Science
• Publication Version: Final Published Version
• Copyright Statement: © 2017 Tundup et al
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1371/journal.ppat.1006270
• Title of Journal or Parent Work: PLoS Pathogens
• ISSN: 1553-7366
• Volume: 13
• Issue: 3
• Start Page: e1006270
• End Page: e1006270
• Grant/Funding Information: This paper was supported by the following grant(s): National Institutes of Health Pathway to Independence award (AI095320) to Balaji Manicassamy.; University of Chicago StartUp to Balaji Manicassamy.; This work was supported by the National Institutes of Health, Pathway to Independence award (AI095320) and Developmental Project- Great Lakes Regional Center of Excellence, and the University of Chicago (StartUp).; The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.; National Institutes of Health Developmental Project- Great Lakes Regional Center of Excellence to Balaji Manicassamy.
• Research Categories: Health Sciences, Pathology; Biology, Microbiology; Biology, Molecular

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.