title: RIG-I enhanced interferon independent apoptosis upon Junin virus infection.
abstract: Junin virus (JUNV) is the etiological agent of Argentine hemorrhagic fever (AHF), a human disease with a high case-fatality rate. It is widely accepted that arenaviral infections, including JUNV infections, are generally non-cytopathic. In contrast, here we demonstrated apoptosis induction in human lung epithelial carcinoma (A549), human hepatocarcinoma and Vero cells upon infection with the attenuated Candid#1 strain of, JUNV as determined by phosphatidylserine (PS) translocation, Caspase 3 (CASP3) activation, Poly (ADP-ribose) polymerase (PARP) cleavage and/or chromosomal DNA fragmentation. Moreover, as determined by DNA fragmentation, we found that the pathogenic Romero strain of JUNV was less cytopathic than Candid#1 in human hepatocarcinoma and Vero, but more apoptotic in A549 and Vero E6 cells. Additionally, we found that JUNV-induced apoptosis was enhanced by RIG-I signaling. Consistent with the previously reported role of RIG-I like helicase (RLH) signaling in initiating programmed cell death, we showed that cell death or DNA fragmentation of Candid#1-infected A549 cells was decreased upon siRNA or shRNA silencing of components of RIG-I pathway in spite of increased virus production. Similarly, we observed decreased DNA fragmentation in JUNV-infected human hepatocarcinoma cells deficient for RIG-I when compared with that of RIG-I-competent cells. In addition, DNA fragmentation detected upon Candid#1 infection of type I interferon (IFN)-deficient Vero cells suggested a type I IFN-independent mechanism of apoptosis induction in response to JUNV. Our work demonstrated for the first time apoptosis induction in various cells of mammalian origin in response to JUNV infection and partial mechanism of this cell death.
authors.affiliation: Department of Pathology, University of Texas Medical Branch (UTMB), Galveston, Texas, United States of America.
authors.forename: Olga A
authors.initials: OA
authors.lastname: Kolokoltsova
authors.affiliation: Department of Pathology, University of Texas Medical Branch (UTMB), Galveston, Texas, United States of America.
authors.forename: Ashley M
authors.initials: AM
authors.lastname: Grant
authors.affiliation: Department of Pathology, University of Texas Medical Branch (UTMB), Galveston, Texas, United States of America.
authors.forename: Cheng
authors.initials: C
authors.lastname: Huang
authors.affiliation: Department of Pathology, University of Texas Medical Branch (UTMB), Galveston, Texas, United States of America.
authors.forename: Jennifer K
authors.initials: JK
authors.lastname: Smith
authors.affiliation: Department of Pathology, University of Texas Medical Branch (UTMB), Galveston, Texas, United States of America.
authors.forename: Allison L
authors.initials: AL
authors.lastname: Poussard
authors.affiliation: Internal Med-Endocrinology, UTMB, Galveston, Texas, United States of America.
authors.forename: Bing
authors.initials: B
authors.lastname: Tian
authors.affiliation: Internal Med-Endocrinology, UTMB, Galveston, Texas, United States of America.
authors.forename: Allan R
authors.initials: AR
authors.lastname: Brasier
authors.affiliation: Department of Pathology, University of Texas Medical Branch (UTMB), Galveston, Texas, United States of America; Department of Microbiology and Immunology, UTMB, Galveston, Texas, United States of America.
authors.forename: Clarence J
authors.initials: CJ
authors.lastname: Peters
authors.affiliation: Department of Microbiology and Immunology, UTMB, Galveston, Texas, United States of America.
authors.forename: Chien-Te Kent
authors.initials: CT
authors.lastname: Tseng
authors.affiliation: Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, California, United States of America.
authors.forename: Juan C
authors.initials: JC
authors.lastname: de la Torre
authors.affiliation: Department of Pathology, University of Texas Medical Branch (UTMB), Galveston, Texas, United States of America.
authors.forename: Slobodan
authors.initials: S
authors.lastname: Paessler
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000276:immunology / Q000821:virology; D016923:Cell Death / Q000235:genetics; D045744:Cell Line, Tumor; D002522:Chlorocebus aethiops; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases / Q000378:metabolism*; D053938:DNA Fragmentation; D006478:Hemorrhagic Fever, American / Q000235:genetics* / Q000276:immunology / Q000821:virology; D006801:Humans; D007370:Interferon Type I / Q000235:genetics*; D018051:Junin virus / Q000276:immunology*; D008113:Liver Neoplasms / Q000235:genetics / Q000276:immunology / Q000821:virology; D034741:RNA, Small Interfering / Q000235:genetics; D011971:Receptors, Immunologic; D015398:Signal Transduction / Q000235:genetics; D014709:Vero Cells
chemical_list: D007370:Interferon Type I; D034741:RNA, Small Interfering; D011971:Receptors, Immunologic; C452820:RIGI protein, human; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases