Mechanisms of Severe Acute Respiratory Syndrome Pathogenesis and Innate Immunomodulation

Frieman, Matthew B.; Baric, Ralph S.

doi:10.1128/mmbr.00015-08

Cited by 106 publications

(112 citation statements)

References 170 publications

(210 reference statements)

Supporting

Mentioning

107

Contrasting

Unclassified

Order By: Relevance

“…The production and action of type I interferons, which are major components of antiviral innate immunity (2,3), are inhibited at multiple levels by SARS coronavirus (4,5). This inhibition is thought to be mediated through viral structural and nonstructural proteins N, ORF3b, ORF6, nsp1, and papain-like protease (6 -12).…”

mentioning

confidence: 99%

Severe Acute Respiratory Syndrome Coronavirus M Protein Inhibits Type I Interferon Production by Impeding the Formation of TRAF3·TANK·TBK1/IKKϵ Complex

Siu¹,

Kok²,

Ng³

et al. 2009

Journal of Biological Chemistry

262

311

View full text Add to dashboard Cite

Severe acute respiratory syndrome (SARS) coronavirus is highly pathogenic in humans and evades innate immunity at multiple levels. It has evolved various strategies to counteract the production and action of type I interferons, which mobilize the front-line defense against viral infection. In this study we demonstrate that SARS coronavirus M protein inhibits gene transcription of type I interferons. M protein potently antagonizes the activation of interferon-stimulated response elementdependent transcription by double-stranded RNA, RIG-I, MDA5, TBK1, IKK⑀, and virus-induced signaling adaptor (VISA) but has no influence on the transcriptional activity of this element when IRF3 or IRF7 is overexpressed. M protein physically associates with RIG-I, TBK1, IKK⑀, and TRAF3 and likely sequesters some of them in membrane-associated cytoplasmic compartments. Consequently, the expression of M protein prevents the formation of TRAF3⅐TANK⅐TBK1/IKK⑀ complex and thereby inhibits TBK1/IKK⑀-dependent activation of IRF3/IRF7 transcription factors. Taken together, our findings reveal a new mechanism by which SARS coronavirus circumvents the production of type I interferons. Severe acute respiratory syndrome (SARS)2 coronavirus causes a highly lethal infectious disease in humans characterized by an aberrant immune response (1). The production and action of type I interferons, which are major components of antiviral innate immunity (2, 3), are inhibited at multiple levels by SARS coronavirus (4, 5). This inhibition is thought to be mediated through viral structural and nonstructural proteins N, ORF3b, ORF6, nsp1, and papain-like protease (6 -12).The signaling pathways through which viruses induce the production of type I interferons have been well characterized (13)(14)(15). In response to double-stranded RNA (dsRNA) produced during viral replication, endosomal Toll-like receptor 3 (TLR3) and cytoplasmic retinoic acid-inducible gene I (RIG-I) trigger the activation of two different pathways adapted to downstream kinases through TRIF (TLR adaptor inducing interferon ␤) and VISA, respectively. These pathways converge on the formation of TRAF3⅐TANK⅐TBK1/IKK⑀ complex, which catalyzes the phosphorylation of IRF3 and IRF7 transcription factors, leading to the activation of type I interferon promoters (15-17).SARS coronaviral proteins counteract the production of type I interferons at multiple steps. Although IRF3 phosphorylation was inhibited in cells expressing ORF3b, ORF6, or N protein (7), papain-like protease could physically interact with IRF3 and prevent its phosphorylation and nuclear translocation in a protease-independent manner (11). In addition, nsp1 suppressed the synthesis of host proteins including interferons by inducing mRNA degradation (6, 12). Meanwhile, viral proteins such as nsp1 and ORF6 were multifunctional (10,18,19) and could also inhibit interferon signaling. For example, both nsp1 and ORF6 inhibited the activity of STAT1, a key regulator of interferon-responsive genes (8, 9). Whereas nsp1 attenuated phosphorylati...

show abstract

mentioning

confidence: 99%

Severe Acute Respiratory Syndrome Coronavirus M Protein Inhibits Type I Interferon Production by Impeding the Formation of TRAF3·TANK·TBK1/IKKϵ Complex

Siu¹,

Kok²,

Ng³

et al. 2009

Journal of Biological Chemistry

262

311

View full text Add to dashboard Cite

show abstract

“…The coronaviruses genome encodes structural proteins: membrane (M), spike (S), envelope (E) and nucleocapsid (N); two replicase polyproteins: ORF1a and ORF1b and between one and eight accessory proteins that perform important functions in coronavirus replication and pathogenesis in vivo , such as blocking innate immune signaling pathways (Frieman and Baric, 2008). In the case of MERS-CoV, there are 5 accessory proteins (van Boheemen et al, 2012), for which mechanisms of action are starting to be characterized (Matthews et al, 2014; Niemeyer et al, 2013; Siu et al, 2014; Yang et al, 2013).…”

Section: Basic Protocol 4: Quantification Of Mers-cov Rna Products Ofmentioning

confidence: 99%

Growth and Quantification of MERS‐CoV Infection

Coleman

Frieman

2015

CP Microbiology

View full text Add to dashboard Cite

Middle East respiratory syndrome coronavirus (MERS‐CoV) is an emerging highly pathogenic respiratory virus. Although MERS‐CoV only emerged in 2012, we and others have developed assays to grow and quantify infectious MERS‐CoV and RNA products of replication in vitro. MERS‐CoV is able to infect a range of cell types, but replicates to high titers in Vero E6 cells. Protocols for the propagation and quantification of MERS‐CoV are presented. © 2015 by John Wiley & Sons, Inc.

show abstract

“…A careful reading of these reviews shows that the humoral and cellular components of the adaptive immune system of those who succumbed were deficient on presentation and deteriorated thereafter. There is controversy about whether adequate antiviral interferons were generated during the innate response, but there is common agreement that the switch from innate to adaptive immunity was defective [10][11][12][13][14][15][16][17][18][19][20][21][22][23].…”

Section: Sars Medical Issuesmentioning

confidence: 99%

Literature-related discovery: Potential treatments and preventatives for SARS

Kostoff

2011

Technological Forecasting and Social Change

View full text Add to dashboard Cite

Literature-related discovery (LRD) is the linking of two or more previously disjoint concepts in order to produce novel, interesting, plausible, and intelligible connections (i.e., potential discovery). LRD has been used to identify potential treatments or preventative actions for challenging medical problems, among myriad other applications. Severe acute respiratory syndrome (SARS) was the first pandemic of the 21st century. SARS was eventually controlled through increased hygienic measures (e.g., face mask protection, frequent hand washing, living quarter disinfection), travel restrictions, and quarantine. According to recent reviews of SARS, none of the drugs that were used during the pandemic worked. For the present paper, SARS was selected as the first application of LRD to an infectious disease. The main goal of this research was to identify non-drug non-surgical treatments that would 1) prevent the occurrence, or 2) reduce the progression rate, or 3) stop/reverse the progression of SARS. The MeSH taxonomy of Medline was used to restrict potential discoveries to selected semantic classes, and to identify potential discoveries efficiently. To enhance the volume of potential discovery, databases were used in addition to Medline. These included the Science Citation Index (SCI) and, in contrast to previous work, a full text database. Because of the richness of the full text, 'surgical' queries were developed that targeted the exact types of potential discovery of interest while eliminating clutter more efficiently.

show abstract

Mechanisms of Severe Acute Respiratory Syndrome Pathogenesis and Innate Immunomodulation

Cited by 106 publications

References 170 publications

Severe Acute Respiratory Syndrome Coronavirus M Protein Inhibits Type I Interferon Production by Impeding the Formation of TRAF3·TANK·TBK1/IKKϵ Complex

Severe Acute Respiratory Syndrome Coronavirus M Protein Inhibits Type I Interferon Production by Impeding the Formation of TRAF3·TANK·TBK1/IKKϵ Complex

Growth and Quantification of MERS‐CoV Infection

Literature-related discovery: Potential treatments and preventatives for SARS

Contact Info

Product

Resources

About