title: Type I interferon is a therapeutic target for virus-induced lethal vascular damage.
abstract: The outcome of a viral infection reflects the balance between virus virulence and host susceptibility. The clone 13 (Cl13) variant of lymphocytic choriomeningitis virus--a prototype of Old World arenaviruses closely related to Lassa fever virus--elicits in C57BL/6 and BALB/c mice abundant negative immunoregulatory molecules, associated with T-cell exhaustion, negligible T-cell-mediated injury, and high virus titers that persist. Conversely, here we report that in NZB mice, despite the efficient induction of immunoregulatory molecules and high viremia, Cl13 generated a robust cytotoxic T-cell response, resulting in thrombocytopenia, pulmonary endothelial cell loss, vascular leakage, and death within 6-8 d. These pathogenic events required type I IFN (IFN-I) signaling on nonhematopoietic cells and were completely abrogated by IFN-I receptor blockade. Thus, IFN-I may play a prominent role in hemorrhagic fevers and other acute virus infections associated with severe vascular pathology, and targeting IFN-I or downstream effector molecules may be an effective therapeutic approach.
authors.affiliation: Departments of Immunology and Microbial Science and mbaobo@scripps.edu rbaccala@scripps.edu.
authors.forename: Roberto
authors.initials: R
authors.lastname: Baccala
authors.affiliation: Departments of Immunology and Microbial Science and.
authors.forename: Megan J
authors.initials: MJ
authors.lastname: Welch
authors.affiliation: Departments of Immunology and Microbial Science and.
authors.forename: Rosana
authors.initials: R
authors.lastname: Gonzalez-Quintial
authors.affiliation: Departments of Immunology and Microbial Science and.
authors.forename: Kevin B
authors.initials: KB
authors.lastname: Walsh
authors.affiliation: Departments of Immunology and Microbial Science and.
authors.forename: John R
authors.initials: JR
authors.lastname: Teijaro
authors.affiliation: Departments of Immunology and Microbial Science and.
authors.forename: Anthony
authors.initials: A
authors.lastname: Nguyen
authors.affiliation: Departments of Immunology and Microbial Science and.
authors.forename: Cherie T
authors.initials: CT
authors.lastname: Ng
authors.affiliation: Departments of Immunology and Microbial Science and.
authors.forename: Brian M
authors.initials: BM
authors.lastname: Sullivan
authors.affiliation: Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA 92037.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Zarpellon
authors.affiliation: Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA 92037.
authors.forename: Zaverio M
authors.initials: ZM
authors.lastname: Ruggeri
authors.affiliation: Departments of Immunology and Microbial Science and.
authors.forename: Juan Carlos
authors.initials: JC
authors.lastname: de la Torre
authors.affiliation: Departments of Immunology and Microbial Science and.
authors.forename: Argyrios N
authors.initials: AN
authors.lastname: Theofilopoulos
authors.affiliation: Departments of Immunology and Microbial Science and mbaobo@scripps.edu rbaccala@scripps.edu.
authors.forename: Michael B A
authors.initials: MB
authors.lastname: Oldstone
mesh_terms: D000818:Animals; D018893:Bronchoalveolar Lavage; D002460:Cell Line; D006224:Cricetinae; D016207:Cytokines / Q000378:metabolism; D005260:Female; D007370:Interferon Type I / Q000378:metabolism*; D007835:Lassa Fever / Q000821:virology*; D007836:Lassa virus; D008216:Lymphocytic Choriomeningitis / Q000821:virology; D008217:Lymphocytic choriomeningitis virus / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008814:Mice, Inbred NZB; D008822:Mice, Transgenic; D015398:Signal Transduction; D013234:Stem Cells / Q000737:chemistry; D013602:T-Lymphocytes, Cytotoxic / Q000821:virology; D014652:Vascular Diseases / Q000821:virology*; D014775:Virus Activation
chemical_list: D016207:Cytokines; D007370:Interferon Type I
keywords: IFN-alpha; LCMV; immunopathology; lung; platelet loss