title: Hantavirus infection induces the expression of RANTES and IP-10 without causing increased permeability in human lung microvascular endothelial cells.
abstract: Sin Nombre virus (SNV) and Hantaan virus (HTN) infect endothelial cells and are associated with different patterns of increased vascular permeability during human disease. It is thought that such patterns of increased vascular permeability are a consequence of endothelial activation and subsequent dysfunction mediated by differential immune responses to hantavirus infection. In this study, the ability of hantavirus to directly induce activation of human lung microvascular endothelial cells (HMVEC-Ls) was examined. No virus-specific modulation in the constitutive or cytokine-induced expression of cellular adhesion molecules (CD40, CD54, CD61, CD62E, CD62P, CD106, and major histocompatibility complex classes I and II) or in cytokines and chemokines (eotaxin, tumor necrosis factor alpha, interleukin 1beta [IL-1beta], IL-6, IL-8, MCP-1, MIP-1alpha, and MIP-1beta) was detected at either the protein or message level in hantavirus-infected HMVEC-Ls. Furthermore, no virus-specific enhancement of paracellular or transcellular permeability or changes in the organization and distribution of endothelial intercellular junctional proteins was observed. However, infection with either HTN or SNV resulted in detectable levels of the chemokines RANTES and IP-10 (the 10-kDa interferon-inducible protein) in HMVEC-Ls within 72 h and was associated with nuclear translocation of interferon regulatory factor 3 (IRF-3) and IRF-7. Gamma interferon (IFN-gamma)-induced expression of RANTES and IP-10 could also be detected in uninfected HMVEC-Ls and was associated with nuclear translocation of IRF-1 and IRF-3. Treatment of hantavirus-infected HMVEC-Ls with IFN-gamma for 24 h resulted in a synergistic enhancement in the expression of both RANTES and IP-10 and was associated with nuclear translocation of IRF-1, IRF-3, IRF-7, and NF-kappaB p65. These results reveal a possible mechanism by which hantavirus infection and a TH1 immune response can cooperate to synergistically enhance chemokine expression by HMVEC-Ls and trigger immune-mediated increases in vascular permeability.
authors.affiliation: Department of Pathology and Laboratory Medicine, Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA 30323, USA. JSUNDST@emory.edu
authors.forename: J B
authors.initials: JB
authors.lastname: Sundstrom
authors.forename: L K
authors.initials: LK
authors.lastname: McMullan
authors.forename: C F
authors.initials: CF
authors.lastname: Spiropoulou
authors.forename: W C
authors.initials: WC
authors.lastname: Hooper
authors.forename: A A
authors.initials: AA
authors.lastname: Ansari
authors.forename: C J
authors.initials: CJ
authors.lastname: Peters
authors.forename: P E
authors.initials: PE
authors.lastname: Rollin
mesh_terms: D000818:Animals; D002199:Capillary Permeability; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000096:biosynthesis; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D018946:Chemokine CCL5 / Q000096:biosynthesis*; D054357:Chemokine CXCL10; D019743:Chemokines, CXC / Q000096:biosynthesis*; D004268:DNA-Binding Proteins / Q000235:genetics; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism* / Q000648:ultrastructure; D006476:Orthohantavirus / Q000502:physiology*; D006801:Humans; D007365:Intercellular Junctions / Q000378:metabolism / Q000648:ultrastructure; D050839:Interferon Regulatory Factor-7; D007371:Interferon-gamma / Q000494:pharmacology; D008168:Lung / Q000098:blood supply; D019402:Macrophage Inflammatory Proteins / Q000096:biosynthesis; D051379:Mice; D011817:Rabbits; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D018932:Chemokine CCL2; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D018946:Chemokine CCL5; D054357:Chemokine CXCL10; D019743:Chemokines, CXC; D004268:DNA-Binding Proteins; C494234:IRF7 protein, human; D050839:Interferon Regulatory Factor-7; C494235:Irf7 protein, mouse; D019402:Macrophage Inflammatory Proteins; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma