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.
Highlights
Arenaviruses are bisegmented, negative sense RNA viruses with enveloped virions that use an ambisense coding strategy [1]
We showed that siRNA-mediated downregulation of RIG-I or IRF3 production in A549 cells resulted in drastic reduction of STAT1 phosphorylation and IFN-stimulated gene (ISG) induction in response to Candid#1 infection
For this we assessed PS flipping from the inner to the outer layers of cell membrane, which was detected via Annexin V binding
Summary
Arenaviruses are bisegmented, negative sense RNA viruses with enveloped virions that use an ambisense coding strategy [1]. The large segment of the arenavirus genome encodes for a RNAdependent RNA polymerase (L) with endonuclease cap snatching activity [2] and a small RING finger protein (Z) with matrix-like functions [3]. The small segment encodes for the viral nucleoprotein (NP), endowed with a 39 to 59 exoribonuclease activity [4], and the glycoprotein precursor (GPC). The members of the Arenaviridae family are divided into two serologically and geographically distinct groups: New and Old World arenaviruses [6]. Five members of the New World clade B arenaviruses (Junin, Guanarito, Sabia, Machupo and Chapare), and the Old World Lassa virus (LASV) and Lujo virus [7] can cause severe hemorrhagic fever disease in humans [8]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
