The analysis of stochastic interferon-beta gene expression in virus-infected mammalian cells reveals that the levels of components required for virtually every step in the virus induction pathway are limiting

A Baum

A Garcia-Sastre

A Prakash

A Sigal

B. L Kelly

B. R tenOever

D Levin

D. P Calado

E Apostolou

E Ford

E Meylan

F You

G Balazsi

G. A Hollander

G. K Smyth

H Kato

H Poeck

H Yoshida

Hemali Phatnani

Hidde L. Ploegh

J Banchereau

J Drahos

J Hu

J Hu-Li

J Rehwinkel

J Wang

J. C Hall

Jiangwen Zhang

K Honda

K Senger

K Takahasi

K Yang

K. A Fitzgerald

L Gitlin

L Guo

M Sato

M Yoneyama

M. U Gack

Mingwei Zhao

N Tamassia

O Takeuchi

R Colina

R Zawatzky

R. B Seth

S Chen

S Cui

S Scheu

S Sharma

S. L Spencer

Stefanie Scheu

T Enoch

T Kawai

Tom Maniatis

X Wang

PLoS Biology

English

PubMed

Zhao Mingwei

Zhang Jiangwen

Phatnani Hemali

Scheu Stefanie

Maniatis Tom

Public Library of Science (PLOS)

Stochastic Expression of the Interferon-β Gene

Virus infection of mammalian cells induces the production of high levels of type I interferons (IFNα and β), cytokines that orchestrate antiviral innate and adaptive immunity. Previous studies have shown that only a fraction of the infected cells produce IFN. However, the mechanisms responsible for this stochastic expression are poorly understood. Here we report an in depth analysis of IFN-expressing and non-expressing mouse cells infected with Sendai virus. Mouse embryonic fibroblasts in which an internal ribosome entry site/yellow fluorescent protein gene was inserted downstream from the endogenous IFNβ gene were used to distinguish between the two cell types, and they were isolated from each other using fluorescence-activated cell sorting methods. Analysis of the separated cells revealed that stochastic IFNβ expression is a consequence of cell-to-cell variability in the levels and/or activities of limiting components at every level of the virus induction process, ranging from viral replication and expression, to the sensing of viral RNA by host factors, to activation of the signaling pathway, to the levels of activated transcription factors. We propose that this highly complex stochastic IFNβ gene expression evolved to optimize both the level and distribution of type I IFNs in response to virus infection.Molecular and Cellular BiologyVersion of Recor

Zhao, Mingwei

Zhang, Jiangwen

Phatnani, Hemali

Scheu, Stefanie

Maniatis, Thomas

Harvard University - DASH

<div><p>Virus infection of mammalian cells induces the production of high levels of type I interferons (IFNα and β), cytokines that orchestrate antiviral innate and adaptive immunity. Previous studies have shown that only a fraction of the infected cells produce IFN. However, the mechanisms responsible for this stochastic expression are poorly understood. Here we report an in depth analysis of IFN-expressing and non-expressing mouse cells infected with Sendai virus. Mouse embryonic fibroblasts in which an internal ribosome entry site/yellow fluorescent protein gene was inserted downstream from the endogenous IFNβ gene were used to distinguish between the two cell types, and they were isolated from each other using fluorescence-activated cell sorting methods. Analysis of the separated cells revealed that stochastic IFNβ expression is a consequence of cell-to-cell variability in the levels and/or activities of limiting components at every level of the virus induction process, ranging from viral replication and expression, to the sensing of viral RNA by host factors, to activation of the signaling pathway, to the levels of activated transcription factors. We propose that this highly complex stochastic IFNβ gene expression evolved to optimize both the level and distribution of type I IFNs in response to virus infection.</p> </div

Mingwei Zhao (167087)

Jiangwen Zhang (45394)

Hemali Phatnani (187081)

Stefanie Scheu (63765)

Tom Maniatis (66839)

The Francis Crick Institute

Crossref

Virus infection of mammalian cells induces the production of high levels of type I interferons (IFNα and β), cytokines that orchestrate antiviral innate and adaptive immunity. Previous studies have shown that only a fraction of the infected cells produce IFN. However, the mechanisms responsible for this stochastic expression are poorly understood. Here we report an in depth analysis of IFN-expressing and non-expressing mouse cells infected with Sendai virus. Mouse embryonic fibroblasts in which an internal ribosome entry site/yellow fluorescent protein gene was inserted downstream from the endogenous IFNβ gene were used to distinguish between the two cell types, and they were isolated from each other using fluorescence-activated cell sorting methods. Analysis of the separated cells revealed that stochastic IFNβ expression is a consequence of cell-to-cell variability in the levels and/or activities of limiting components at every level of the virus induction process, ranging from viral replication and expression, to the sensing of viral RNA by host factors, to activation of the signaling pathway, to the levels of activated transcription factors. We propose that this highly complex stochastic IFNβ gene expression evolved to optimize both the level and distribution of type I IFNs in response to virus infection

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Stochastic expression of the interferon-β gene.

Virus infection of mammalian cells induces the production of high levels of type I interferons (IFNalpha and beta), cytokines that orchestrate antiviral innate and adaptive immunity. Previous studies have shown that only a fraction of the infected cells produce IFN. However, the mechanisms responsible for this stochastic expression are poorly understood. Here we report an in depth analysis of IFN-expressing and non-expressing mouse cells infected with Sendai virus. Mouse embryonic fibroblasts in which an internal ribosome entry site/yellow fluorescent protein gene was inserted downstream from the endogenous IFNbeta gene were used to distinguish between the two cell types, and they were isolated from each other using fluorescence-activated cell sorting methods. Analysis of the separated cells revealed that stochastic IFNbeta expression is a consequence of cell-to-cell variability in the levels and/or activities of limiting components at every level of the virus induction process, ranging from viral replication and expression, to the sensing of viral RNA by host factors, to activation of the signaling pathway, to the levels of activated transcription factors. We propose that this highly complex stochastic IFNbeta gene expression evolved to optimize both the level and distribution of type I IFNs in response to virus infection.published_or_final_versio

Zhao, M

Zhang, J

Phatnan, H

Scheu, S

Maniatis, T

HKU Scholars Hub

Stochastic Expression of the Interferon-beta Gene

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http://dash.harvard.edu/bitstream/handle/1/11248786/3265471.pdf?sequence=1

Stochastic Expression of the Interferon-β Gene

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