Abstract
Lassa virus (LASV) is a mammarenavirus that can cause lethal Lassa fever disease with no FDA-approved vaccine and limited treatment options. Fatal LASV infections are associated with innate immune suppression. We have previously shown that the small matrix Z protein of LASV, but not of a nonpathogenic arenavirus Pichinde virus (PICV), can inhibit the cellular RIG-I-like receptors (RLRs), but its biological significance has not been evaluated in an infectious virus due to the multiple essential functions of the Z protein required for the viral life cycle. In this study, we developed a stable HeLa cell line (HeLaiRIGN) that could be rapidly and robustly induced by doxycycline (Dox) treatment to express RIG-I N-terminal effector, with concomitant production of type I interferons (IFN-Is). We also generated recombinant tri-segmented PICVs, rP18tri-LZ, and rP18tri-PZ, which encode LASV Z and PICV Z, respectively, as an extra mScarlet fusion protein that is nonessential for the viral life cycle. Upon infection, rP18tri-LZ consistently expressed viral genes at a higher level than rP18tri-PZ. rP18tri-LZ also showed a higher level of a viral infection than rP18tri-PZ did in HeLa-iRIGN cells, especially upon Dox induction. The heterologous Z gene did not alter viral growth in Vero and A549 cells by growth curve analysis, while LASV Z strongly increased and prolonged viral gene expression, especially in IFN-competent A549 cells. Our study provides important insights into the biological role of LASV Z-mediated RIG-I inhibition and implicates LASV Z as a potential virulence factor.
Original language | English (US) |
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Journal | Journal of virology |
Volume | 96 |
Issue number | 16 |
DOIs | |
State | Published - Aug 2022 |
Bibliographical note
Publisher Copyright:Copyright © 2022 American Society for Microbiology. All Rights Reserved.
Keywords
- Lassa
- Lassa virus
- Pichinde
- Pichinde virus
- RIG-I
- RIG-I signaling
- Z protein
- arenavirus
- inducible expression
- innate immune evasion
- innate immunity
- recombinant viruses
- tri-segmented arenavirus
- viral virulence
PubMed: MeSH publication types
- Journal Article
- Research Support, N.I.H., Extramural