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Title: Identification and Validation of Ifit1 as an Important Innate Immune Bottleneck

Abstract

The innate immune system plays important roles in a number of disparate processes. Foremost, innate immunity is a first responder to invasion by pathogens and triggers early defensive responses and recruits the adaptive immune system. The innate immune system also responds to endogenous damage signals that arise from tissue injury. Recently it has been found that innate immunity plays an important role in neuroprotection against ischemic stroke through the activation of the primary innate immune receptors, Toll-like receptors (TLRs). Using several large-scale transcriptomic data sets from mouse and mouse macrophage studies we identified targets predicted to be important in controlling innate immune processes initiated by TLR activation. Targets were identified as genes with high betweenness centrality, so-called bottlenecks, in networks inferred from statistical associations between gene expression patterns. A small set of putative bottlenecks were identified in each of the data sets investigated including interferon-stimulated genes (Ifit1, Ifi47, Tgtp and Oasl2) as well as genes uncharacterized in immune responses (Axud1 and Ppp1r15a). We further validated one of these targets, Ifit1, in mouse macrophages by showing that silencing it suppresses induction of predicted downstream genes by lipopolysaccharide (LPS)-mediated TLR4 activation through an unknown direct or indirect mechanism. Our study demonstrates themore » utility of network analysis for identification of interesting targets related to innate immune function, and highlights that Ifit1 can exert a positive regulatory effect on downstream genes.« less

Authors:
; ; ; ; ;
Publication Date:
Research Org.:
Pacific Northwest National Lab. (PNNL), Richland, WA (United States)
Sponsoring Org.:
USDOE
OSTI Identifier:
1050797
Report Number(s):
PNNL-SA-82946
400412000; TRN: US201218%%1566
DOE Contract Number:  
AC05-76RL01830
Resource Type:
Journal Article
Journal Name:
PLoS One
Additional Journal Information:
Journal Volume: 7; Journal Issue: 6
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; 60 APPLIED LIFE SCIENCES; DAMAGE; DATA; GENES; IMMUNITY; INDUCTION; LIPOPOLYSACCHARIDES; MACROPHAGES; NETWORK ANALYSIS; PATHOGENS; RECEPTORS; SIGNALS; TARGETS; systems biology; innate immunity; network analysis; network topology; stroke

Citation Formats

McDermott, Jason E., Vartanian, Keri B., Mitchell, Hugh D., Stevens, S.L., Sanfilippo, Antonio P., and Stenzel-Poore, Mary. Identification and Validation of Ifit1 as an Important Innate Immune Bottleneck. United States: N. p., 2012. Web. doi:10.1371/journal.pone.0036465.
McDermott, Jason E., Vartanian, Keri B., Mitchell, Hugh D., Stevens, S.L., Sanfilippo, Antonio P., & Stenzel-Poore, Mary. Identification and Validation of Ifit1 as an Important Innate Immune Bottleneck. United States. doi:10.1371/journal.pone.0036465.
McDermott, Jason E., Vartanian, Keri B., Mitchell, Hugh D., Stevens, S.L., Sanfilippo, Antonio P., and Stenzel-Poore, Mary. Wed . "Identification and Validation of Ifit1 as an Important Innate Immune Bottleneck". United States. doi:10.1371/journal.pone.0036465.
@article{osti_1050797,
title = {Identification and Validation of Ifit1 as an Important Innate Immune Bottleneck},
author = {McDermott, Jason E. and Vartanian, Keri B. and Mitchell, Hugh D. and Stevens, S.L. and Sanfilippo, Antonio P. and Stenzel-Poore, Mary},
abstractNote = {The innate immune system plays important roles in a number of disparate processes. Foremost, innate immunity is a first responder to invasion by pathogens and triggers early defensive responses and recruits the adaptive immune system. The innate immune system also responds to endogenous damage signals that arise from tissue injury. Recently it has been found that innate immunity plays an important role in neuroprotection against ischemic stroke through the activation of the primary innate immune receptors, Toll-like receptors (TLRs). Using several large-scale transcriptomic data sets from mouse and mouse macrophage studies we identified targets predicted to be important in controlling innate immune processes initiated by TLR activation. Targets were identified as genes with high betweenness centrality, so-called bottlenecks, in networks inferred from statistical associations between gene expression patterns. A small set of putative bottlenecks were identified in each of the data sets investigated including interferon-stimulated genes (Ifit1, Ifi47, Tgtp and Oasl2) as well as genes uncharacterized in immune responses (Axud1 and Ppp1r15a). We further validated one of these targets, Ifit1, in mouse macrophages by showing that silencing it suppresses induction of predicted downstream genes by lipopolysaccharide (LPS)-mediated TLR4 activation through an unknown direct or indirect mechanism. Our study demonstrates the utility of network analysis for identification of interesting targets related to innate immune function, and highlights that Ifit1 can exert a positive regulatory effect on downstream genes.},
doi = {10.1371/journal.pone.0036465},
journal = {PLoS One},
number = 6,
volume = 7,
place = {United States},
year = {2012},
month = {6}
}