title: Hantavirus interferon regulation and virulence determinants.
abstract: Hantaviruses predominantly replicate in primary human endothelial cells and cause 2 diseases characterized by altered barrier functions of vascular endothelium. Most hantaviruses restrict the early induction of interferon-β (IFNβ) and interferon stimulated genes (ISGs) within human endothelial cells to permit their successful replication. PHV fails to regulate IFN induction within human endothelial cells which self-limits PHV replication and its potential as a human pathogen. These findings, and the altered regulation of endothelial cell barrier functions by pathogenic hantaviruses, suggest that virulence is determined by the ability of hantaviruses to alter key signaling pathways within human endothelial cells. Our findings indicate that the Gn protein from ANDV, but not PHV, inhibits TBK1 directed ISRE, kB and IFNβ induction through virulence determinants in the Gn cytoplasmic tail (GnT) that inhibit TBK1 directed IRF3 phosphorylation. Further studies indicate that in response to hypoxia induced VEGF, ANDV infection enhances the permeability and adherens junction internalization of microvascular and lymphatic endothelial cells. These hypoxia/VEGF directed responses are rapamycin sensitive and directed by mTOR signaling pathways. These results demonstrate the presence of at least two hantavirus virulence determinants that act on endothelial cell signaling pathways: one that regulates antiviral IFN signaling responses, and a second that enhances normal hypoxia-VEGF-mTOR signaling pathways to facilitate endothelial cell permeability. These findings suggest signaling pathways as potential targets for therapeutic regulation of vascular deficits that contribute to hantavirus diseases and viral protein targets for attenuating pathogenic hantaviruses.
authors.affiliation: Department of Molecular Genetics and Microbiology, Stony Brook University, Stony Brook, NY 11794-5122, United States. Electronic address: Erich.Mackow@stonybrook.edu.
authors.forename: Erich R
authors.initials: ER
authors.lastname: Mackow
authors.affiliation: Department of Molecular Genetics and Microbiology, Stony Brook University, Stony Brook, NY 11794-5122, United States.
authors.forename: Nadine A
authors.initials: NA
authors.lastname: Dalrymple
authors.affiliation: Department of Molecular Genetics and Microbiology, Stony Brook University, Stony Brook, NY 11794-5122, United States.
authors.forename: Velasco
authors.initials: V
authors.lastname: Cimica
authors.affiliation: Department of Molecular Genetics and Microbiology, Stony Brook University, Stony Brook, NY 11794-5122, United States.
authors.forename: Valery
authors.initials: V
authors.lastname: Matthys
authors.affiliation: Department of Molecular Genetics and Microbiology, Stony Brook University, Stony Brook, NY 11794-5122, United States.
authors.forename: Elena
authors.initials: E
authors.lastname: Gorbunova
authors.affiliation: Department of Molecular Genetics and Microbiology, Stony Brook University, Stony Brook, NY 11794-5122, United States.
authors.forename: Irina
authors.initials: I
authors.lastname: Gavrilovskaya
mesh_terms: D015703:Antigens, CD / Q000235:genetics / Q000276:immunology; D015820:Cadherins / Q000235:genetics / Q000276:immunology; D002196:Capillaries / Q000473:pathology / Q000821:virology; D002199:Capillary Permeability; D042783:Endothelial Cells / Q000276:immunology / Q000473:pathology / Q000821:virology; D004730:Endothelium, Vascular / Q000276:immunology / Q000473:pathology / Q000821:virology; D005786:Gene Expression Regulation; D006476:Orthohantavirus / Q000235:genetics / Q000472:pathogenicity*; D018778:Hantavirus Infections / Q000150:complications / Q000235:genetics / Q000276:immunology* / Q000821:virology; D054884:Host-Pathogen Interactions; D006801:Humans; D000860:Hypoxia / Q000150:complications / Q000235:genetics / Q000276:immunology* / Q000821:virology; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000276:immunology; D050835:Interferon Regulatory Factors / Q000235:genetics* / Q000276:immunology; D016899:Interferon-beta / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000276:immunology; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000276:immunology; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000276:immunology; D014774:Virulence; D014779:Virus Replication; D000099152:Cadherin 5
chemical_list: D015703:Antigens, CD; D015820:Cadherins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D050835:Interferon Regulatory Factors; D016899:Interferon-beta; D017346:Protein Serine-Threonine Kinases; D058570:TOR Serine-Threonine Kinases; D042461:Vascular Endothelial Growth Factor A; D000099152:Cadherin 5; C497442:HIF1A protein, human; C467484:VEGFA protein, human; C546842:MTOR protein, human; C403191:TBK1 protein, human
keywords: Endothelial cell; Hantavirus; Interferon; Pathogenesis; Permeability; TBK1