title: Modulation of innate immune signaling by the secreted form of the West Nile virus NS1 glycoprotein.
abstract: West Nile virus (WNV) employs several different strategies to escape the innate immune response. We have previously demonstrated that the WNV NS1 protein interferes with signal transduction from Toll-like receptor 3 (TLR3). NS1 is a glycoprotein that can be found intracellularly or associated with the plasma membrane. In addition, NS1 is secreted to high levels during flavivirus infections. We investigated whether the secreted form of NS1 inhibits innate immune signaling pathways in uninfected cells. Secreted NS1 (sNS1) was purified from supernatants of cells engineered to express the protein. Purified sNS1 associated with and repressed TLR3-induced cytokine production by HeLa cells, and inhibited signaling from TLR3 and other TLRs in bone marrow-derived macrophages and dendritic cells. Footpad administration of sNS1 showed the protein associated predominantly with macrophages and dendritic cells in the draining lymph node. Additionally, sNS1 significantly reduced TLR3 signaling and WNV replicon particle-mediated cytokine transcription in popliteal lymph nodes.
authors.affiliation: Department of Biological Sciences, North Carolina State University, Raleigh, NC CB7614, USA.
authors.forename: Kristen R
authors.initials: KR
authors.lastname: Crook
authors.affiliation: Department of Biological Sciences, North Carolina State University, Raleigh, NC CB7614, USA.
authors.forename: Mindy
authors.initials: M
authors.lastname: Miller-Kittrell
authors.affiliation: Department of Biological Sciences, North Carolina State University, Raleigh, NC CB7614, USA.
authors.forename: Clayton R
authors.initials: CR
authors.lastname: Morrison
authors.affiliation: Department of Biological Sciences, North Carolina State University, Raleigh, NC CB7614, USA. Electronic address: frank_scholle@ncsu.edu.
authors.forename: Frank
authors.initials: F
authors.lastname: Scholle
mesh_terms: D000818:Animals; D006367:HeLa Cells; D006801:Humans; D007113:Immunity, Innate; D008156:Luciferases / Q000378:metabolism; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D022423:Myeloid Cells / Q000276:immunology / Q000378:metabolism; D011070:Poly I-C / Q000494:pharmacology; D015398:Signal Transduction / Q000276:immunology*; D013047:Specific Pathogen-Free Organisms; D051196:Toll-Like Receptor 3 / Q000037:antagonists & inhibitors; D017361:Viral Nonstructural Proteins / Q000276:immunology* / Q000502:physiology; D014902:West Nile virus / Q000276:immunology* / Q000378:metabolism
chemical_list: D051196:Toll-Like Receptor 3; D017361:Viral Nonstructural Proteins; C531936:nonstructural protein 1, West Nile virus; D008156:Luciferases; D011070:Poly I-C
keywords: Flaviviridae; Innate immunity; Nonstructural protein; Toll like receptor; West Nile virus