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

Abstract

Andes virus (ANDV) is a South

Virus interactions with endothelial cell receptors: implications for viral pathogenesis

“…Similar to patient responses, hantaviruses enhance the permeability of chemically- or O 2 level-induced hypoxia in MECs and LECs. This constitutively activates a downstream mTOR-directed pathway that normally regulates hypoxic responses, VEGF signaling and cellular quiescence [42, 82–85]. Interestingly, hantavirus infected LECs are also hyperresponsive to VEGF and hypoxia and activate mTOR signaling responses that are inhibited by rapamycin as well as VEGF-C, which exclusively acts on LEC VEGFR3 receptors [42, 86, 87].…”

“…This constitutively activates a downstream mTOR-directed pathway that normally regulates hypoxic responses, VEGF signaling and cellular quiescence [42, 82–85]. Interestingly, hantavirus infected LECs are also hyperresponsive to VEGF and hypoxia and activate mTOR signaling responses that are inhibited by rapamycin as well as VEGF-C, which exclusively acts on LEC VEGFR3 receptors [42, 86, 87]. These findings link hantavirus pathogenesis to LEC receptor usage and further suggest a role for hantavirus infection of LECs as a determinant of fluid accumulation within HPS patients.…”

“…Consistent with hantavirus dysregulation of α v β 3- VEGFR2 responses, days after infection cell associated hantavirus coats the surface of endothelial cells [80, 119]. Hypoxia induced VEGF responses of HPS patients [120–123] are likely to enhance VEGFR2-Src signaling responses, which direct VE-cadherin internalization and dissociate adherens junctions (AJs) [7, 42, 43, 81, 86, 114]. VE-cadherin internalization decreases fluid barrier functions of the endothelium [97, 98] and may contribute to localized increases in vascular permeability [17, 29, 124] and edema during hantavirus infection [6, 18, 89, 121, 125].…”

“…Although lymphatics are often forgotten, these vessels clear fluid from tissues and in lymph nodes LECs constitutively express MHCII and are sentinel antigen presenting cells that determine tolerance and clearance responses [38, 41]. Recent studies indicating that hantaviruses infect and dysregulate normal LEC functions further suggest roles for lymphatic EC receptor responses that alter pulmonary fluid clearance functions of hantavirus pulmonary syndrome (HPS) patients [39, 42, 43]. This review explores the ways in which dengue and hantaviruses contact and alter endothelial cell surface receptors and their corresponding signaling pathways, leading to hemorrhagic disease and vascular permeability.…”

Hantavirus interferon regulation and virulence determinants

“…Mechanisms by which hantaviruses disrupt fluid barrier integrity and clearance functions of the endothelium are just beginning to be disclosed. Vascular permeability induced by hantaviruses is likely to be multifactorial in nature and result from virally altered EC responses and signaling pathways, tissue hypoxia and immune cell and platelet functions (Gavrilovskaya et al, 2012a; Gavrilovskaya et al, 2012b; Gavrilovskaya et al, 2010, 2012c, 2013; Gorbunova et al, 2010; Gorbunova et al, 2013; Gorbunova et al, 2011; Hammerbeck and Hooper, 2011; Kilpatrick et al, 2004; Koster and Mackow, 2012; Mori et al, 1999; Raymond et al, 2005; Taylor et al, 2013; Terajima et al, 1999; Vaheri et al, 2013). This is likely to occur through a collaboration of interactions which bypass redundant vascular systems that control critical fluid barrier functions.…”