Inhibition of Translation Initiation by Protein 169: A Vaccinia Virus Strategy to Suppress Innate and Adaptive Immunity and Alter Virus Virulence

PLoS Pathogens
Pavla StrnadovaGeoffrey L Smith

Abstract

Vaccinia virus (VACV) is the prototypic orthopoxvirus and the vaccine used to eradicate smallpox. Here we show that VACV strain Western Reserve protein 169 is a cytoplasmic polypeptide expressed early during infection that is excluded from virus factories and inhibits the initiation of cap-dependent and cap-independent translation. Ectopic expression of protein 169 causes the accumulation of 80S ribosomes, a reduction of polysomes, and inhibition of protein expression deriving from activation of multiple innate immune signaling pathways. A virus lacking 169 (vΔ169) replicates and spreads normally in cell culture but is more virulent than parental and revertant control viruses in intranasal and intradermal murine models of infection. Intranasal infection by vΔ169 caused increased pro-inflammatory cytokines and chemokines, infiltration of pulmonary leukocytes, and lung weight. These alterations in innate immunity resulted in a stronger CD8+ T-cell memory response and better protection against virus challenge. This work illustrates how inhibition of host protein synthesis can be a strategy for virus suppression of innate and adaptive immunity.

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Citations

Jun 18, 2016·Viruses·Jason Liem, Jia Liu
Mar 3, 2018·Viruses·Jonas D AlbarnazGeoffrey L Smith
Nov 2, 2018·Wiley Interdisciplinary Reviews. RNA·Nathan MeadeDerek Walsh
Dec 21, 2018·Immunology·Leidy Y Bastidas-Legarda, Salim I Khakoo
May 5, 2017·Open Biology·Guia CarraraGeoffrey L Smith
Apr 3, 2020·Cellular Microbiology·Anjali GowripalanTimothy P Newsome
Aug 13, 2021·The Journal of General Virology·Harold B RichardBrian P Wellensiek

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Datasets Mentioned

BETA
GM130

Methods Mentioned

BETA
transfection
ELISA
reverse transcription quantitative-PCR
lavage
flow cytometry
PCR
electrophoresis
ion exchange chromatography
blood drawn
size exclusion chromatography

Software Mentioned

GraphPad PRISM
SUnSET
GENEART
Axiovision
ClustalW
FlowJo
Prism
GraphPad

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