Lloviu virus VP24 and VP35 proteins function as innate immune antagonists in human and bat cells

Alicia R Feagins; Christopher F Basler

doi:10.1016/j.virol.2015.07.010

Lloviu virus VP24 and VP35 proteins function as innate immune antagonists in human and bat cells

Virology. 2015 Nov:485:145-52. doi: 10.1016/j.virol.2015.07.010. Epub 2015 Aug 6.

Authors

Alicia R Feagins¹, Christopher F Basler²

Affiliations

¹ Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States.
² Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States. Electronic address: chris.basler@mssm.edu.

PMID: 26255028
DOI: 10.1016/j.virol.2015.07.010

Abstract

Lloviu virus (LLOV) is a new member of the filovirus family that also includes Ebola virus (EBOV) and Marburg virus (MARV). LLOV has not been cultured; however, its genomic RNA sequence indicates the coding capacity to produce homologs of the EBOV and MARV VP24, VP35, and VP40 proteins. EBOV and MARV VP35 proteins inhibit interferon (IFN)-alpha/beta production and EBOV VP35 blocks activation of the antiviral kinase PKR. The EBOV VP24 and MARV VP40 proteins inhibit IFN signaling, albeit by different mechanisms. Here we demonstrate that LLOV VP35 suppresses Sendai virus induced IFN regulatory factor 3 (IRF3) phosphorylation, IFN-α/β production, and PKR phosphorylation. Additionally, LLOV VP24 blocks tyrosine phosphorylated STAT1 binding to karyopherin alpha 5 (KPNA5), STAT1 nuclear accumulation, and IFN-induced gene expression. LLOV VP40 lacks detectable IFN antagonist function. These activities parallel EBOV IFN inhibitory functions. EBOV and LLOV VP35 and VP24 proteins also inhibit IFN responses in bat cells. These data suggest that LLOV infection will block innate immune responses in a manner similar to EBOV.

Keywords: Filovirus; Innate immune response; Interferon; Interferon antagonist; Lloviu virus.

Publication types

Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Animals
Cell Line
Chiroptera / virology*
Filoviridae / genetics*
Filoviridae / immunology
Filoviridae / pathogenicity
Gene Expression Regulation
HEK293 Cells
Host-Pathogen Interactions
Humans
Immunity, Innate*
Interferon Regulatory Factor-3 / genetics
Interferon Regulatory Factor-3 / immunology
Interferon-alpha / antagonists & inhibitors
Interferon-alpha / biosynthesis
Interferon-alpha / immunology
Interferon-beta / antagonists & inhibitors
Interferon-beta / biosynthesis
Interferon-beta / immunology
Phosphorylation
Protein Binding
STAT1 Transcription Factor / genetics
STAT1 Transcription Factor / immunology
Sendai virus / genetics
Sendai virus / immunology
Sequence Homology, Amino Acid
Signal Transduction
Viral Matrix Proteins / genetics*
Viral Matrix Proteins / immunology
Viral Proteins / genetics*
Viral Proteins / immunology
Viral Regulatory and Accessory Proteins / genetics*
Viral Regulatory and Accessory Proteins / immunology
alpha Karyopherins / genetics
alpha Karyopherins / immunology
eIF-2 Kinase / antagonists & inhibitors
eIF-2 Kinase / biosynthesis
eIF-2 Kinase / immunology

Substances

IRF3 protein, human
Interferon Regulatory Factor-3
Interferon-alpha
KPNA5 protein, human
STAT1 Transcription Factor
STAT1 protein, human
VP24 protein, Ebola virus
VP35 protein, filovirus
VP40 protein, virus
Viral Matrix Proteins
Viral Proteins
Viral Regulatory and Accessory Proteins
alpha Karyopherins
Interferon-beta
eIF-2 Kinase