Journal article
Endothelial cell tropism is a determinant of H5N1 pathogenesis in mammalian species
PLoS pathogens, Vol.13(3), pp.e1006270-e1006270
03/2017
DOI: 10.1371/journal.ppat.1006270
PMCID: PMC5362246
PMID: 28282445
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.
Details
- Title: Subtitle
- Endothelial cell tropism is a determinant of H5N1 pathogenesis in mammalian species
- Creators
- Smanla Tundup - Howard Taylor Ricketts Laboratory, University of Chicago, Argonne, IL, United States of AmericaBalaji Manicassamy - Howard Taylor Ricketts Laboratory, University of Chicago, Argonne, IL, United States of AmericaMatheswaran Kandasamy - Howard Taylor Ricketts Laboratory, University of Chicago, Argonne, IL, United States of AmericaJasmine T Perez - Department of Microbiology, University of Chicago, Chicago, IL, United States of AmericaNacho Mena - Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, United States of AmericaJohn Steel - Department of Microbiology, Emory University, Atlanta, GA, United States of AmericaTamas Nagy - Comparative Pathology Laboratory, University of Georgia, Athens, GA, United States of AmericaRandy A Albrecht - Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America
- Resource Type
- Journal article
- Publication Details
- PLoS pathogens, Vol.13(3), pp.e1006270-e1006270
- DOI
- 10.1371/journal.ppat.1006270
- PMID
- 28282445
- PMCID
- PMC5362246
- NLM abbreviation
- PLoS Pathog
- ISSN
- 1553-7366
- eISSN
- 1553-7374
- Publisher
- Public Library of Science
- Grant note
- DOI: 10.13039/100000002, name: National Institutes of Health, award: Pathway to Independence award (AI095320); DOI: 10.13039/100000002, name: National Institutes of Health, award: Developmental Project- Great Lakes Regional Center of Excellence; DOI: 10.13039/100007234, name: University of Chicago, award: StartUp
- Language
- English
- Date published
- 03/2017
- Academic Unit
- Microbiology and Immunology
- Record Identifier
- 9984083271402771
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