Hantaviruses predominantly infect endothelial cells (ECs), and in the absence of cell lysis, cause diseases associated with dramatic increases in vascular permeability. Andes virus (ANDV) infection results in acute pulmonary edema and respiratory insufficiency termed hantavirus pulmonary syndrome (HPS). Vast pulmonary capillary beds provide an abundance of ECs for ANDV to infect and infection of ECs provides a primary means for ANDV to increase capillary permeability and cause edema. ANDV infection dramatically enhances EC permeability in response to VEGF and this is not observed following infection by non-pathogenic TULV or in response to TNF1. Our recent findings indicate that ANDV infection of ECs results in the hyperphosphorylation of VEGFR2, increased dissociation of VE-cadherin from AJs and increased paracellular permeability. We have also shown that ANDV induced permeability is inhibited by angiopoietin-1 (Ang-1), or sphingosine-1 phosphate (S1P) which antagonize VEGF directed permeability. These findings suggest that ANDV induced edema may be blocked by inhibiting VEGFR2 signaling pathways. ANDV infection of Syrian hamsters is the only animal model of hantavirus disease which closely mimics HPS, resulting in fatal acute pulmonary edema. This model permits the study of potential therapeutic compounds against ANDV disease and was developed by Jay Hooper the co- investigator on this proposal. In this joint proposal with Jay Hooper, we propose to apply our basic understanding of ANDV induced EC permeability to the Syrian Hamster model of hantavirus disease. Here we will evaluate the efficacy of compounds that enhance EC barrier functions for their ability to prevent HPS-like disease in Syrian hamsters.
Hantaviruses infect the lining of capillaries and cause vascular leakage which result in fluid accumulation in the lungs of patients. We have defined cell receptors and signals which mediate this vascular leakage and this has provided us with targets for therapeutic intervention. Here we evaluate the ability of several existing compounds, already used in humans for other diseases, as potential therapeutic inhibitors of hantavirus permeability. This translational study evaluates inhibitors in an animal model of hantavirus disease and has the potential to provide a drugs to treat hantavirus patients.
|Dalrymple, Nadine A; Cimica, Velasco; Mackow, Erich R (2015) Dengue Virus NS Proteins Inhibit RIG-I/MAVS Signaling by Blocking TBK1/IRF3 Phosphorylation: Dengue Virus Serotype 1 NS4A Is a Unique Interferon-Regulating Virulence Determinant. MBio 6:e00553-15|
|Matthys, Valery S; Cimica, Velasco; Dalrymple, Nadine A et al. (2014) Hantavirus GnT elements mediate TRAF3 binding and inhibit RIG-I/TBK1-directed beta interferon transcription by blocking IRF3 phosphorylation. J Virol 88:2246-59|
|Dalrymple, Nadine A; Mackow, Erich R (2014) Virus interactions with endothelial cell receptors: implications for viral pathogenesis. Curr Opin Virol 7:134-40|
|Cimica, Velasco; Dalrymple, Nadine A; Roth, Eric et al. (2014) An innate immunity-regulating virulence determinant is uniquely encoded by the Andes virus nucleocapsid protein. MBio 5:|
|Mackow, Erich R; Dalrymple, Nadine A; Cimica, Velasco et al. (2014) Hantavirus interferon regulation and virulence determinants. Virus Res 187:65-71|
|Mackow, Erich R; Gorbunova, Elena E; Gavrilovskaya, Irina N (2014) Endothelial cell dysfunction in viral hemorrhage and edema. Front Microbiol 5:733|
|Mackow, Erich R; Gorbunova, Elena E; Dalrymple, Nadine A et al. (2013) Role of vascular and lymphatic endothelial cells in hantavirus pulmonary syndrome suggests targeted therapeutic approaches. Lymphat Res Biol 11:128-35|
|Gavrilovskaya, Irina N; Gorbunova, Elena E; Mackow, Erich R (2013) Hypoxia induces permeability and giant cell responses of Andes virus-infected pulmonary endothelial cells by activating the mTOR-S6K signaling pathway. J Virol 87:12999-3008|
|Gorbunova, Elena E; Gavrilovskaya, Irina N; Mackow, Erich R (2013) Slit2-Robo4 receptor responses inhibit ANDV directed permeability of human lung microvascular endothelial cells. Antiviral Res 99:108-12|
|Matthys, Valery; Mackow, Erich R (2012) Hantavirus regulation of type I interferon responses. Adv Virol 2012:524024|
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