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, respectively) and nonlytically enhances the permeability of interendothelial cell adherence junctions in response to
vascular endothelial growth factor (
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 activation of the mTOR signaling pathway. In contrast to
infection of cells with nonpathogenic Tula virus (TULV), we observed that exposure of ANDV-infected MECs and LECs to hypoxic conditions resulted in a 3- to 6-fold increase in monolayer permeability and the formation of giant cells 3× to 5× normal size. ANDV
infection in combination with hypoxic conditions resulted in the enhancement of
hypoxia-inducible factor 1α (HIF1α)-directed
VEGF A,
angiopoietin 4, and EGLN3 transcriptional responses. Constitutive mTOR signaling induces the formation of giant cells via phosphorylation of S6K, and mTOR regulates
hypoxia and
VEGF A-induced cellular responses. We found that S6K was hyperphosphorylated in ANDV-infected,
hypoxia-treated MECs and LECs and that
rapamycin treatment for 1 h 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 endothelial cell permeability and suggest a role for
rapamycin in therapeutically stabilizing the endothelium of microvascular and lymphatic vessels during ANDV
infection.