Hypoxia Induces Permeability and Giant Cell Responses of ANDV Infected Pulmonary Endothelial Cells by Activating the mTOR-S6K Signaling Pathway.

Department of Molecular Genetics and Microbiology, Stony Brook University, Stony Brook, NY 11794-5122.
Journal of Virology (Impact Factor: 4.65). 09/2013; DOI: 10.1128/JVI.02103-13
Source: PubMed

ABSTRACT Andes virus (ANDV) is a South American hantavirus that causes a highly lethal hantavirus pulmonary syndrome (HPS) characterized by hypoxia, thrombocytopenia and vascular leakage leading to acute pulmonary edema. ANDV infects human pulmonary microvascular and lymphatic endothelial cells (MECs and LECs) and nonlytically enhances the permeability of inter-endothelial cell adherence junctions in response to VEGF. Recent findings also indicate that ANDV causes the formation of giant endothelial cells. Here we demonstrate that hypoxic conditions alone enhance permeability and giant cell responses of ANDV infected MECs and LECs through mTOR signaling pathway activation. In contrast to infecting cells with nonpathogenic TULV, we observed that exposing ANDV infected MECs and LECs to hypoxic conditions resulted in a 3-6 fold increase in monolayer permeability and the formation of giant cells 3-5 x normal size. ANDV infection in combination with hypoxic conditions resulted in the enhancement of HIF1α directed VEGFA, Angiopoietin 4 and EGLN3 transcriptional responses. Constitutive mTOR signaling induces the formation of giant cells via phosphorylation of S6K and mTOR regulates hypoxia and VEGFA induced cellular responses. We found that S6K was hyperphosphorylated in ANDV infected, hypoxia treated, MECs and LECs and that rapamycin treatment for 1 hour inhibited mTOR signaling responses and blocked permeability and giant cell formation in ANDV infected monolayers. These findings indicate that ANDV infection and hypoxic conditions enhance mTOR signaling responses resulting in enhanced EC permeability and suggest a role for rapamycin in therapeutically stabilizing the endothelium of microvascular and lymphatic vessels during ANDV infection.

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