scholarly journals Interferon Regulatory Factor 3-Mediated Signaling Limits Middle-East Respiratory Syndrome (MERS) Coronavirus Propagation in Cells from an Insectivorous Bat

Viruses ◽  
2019 ◽  
Vol 11 (2) ◽  
pp. 152 ◽  
Author(s):  
Arinjay Banerjee ◽  
Darryl Falzarano ◽  
Noreen Rapin ◽  
Jocelyne Lew ◽  
Vikram Misra
Keyword(s):  
Middle East ◽  
Nuclear Translocation ◽  
Human Cells ◽  
Middle East Respiratory Syndrome ◽  
Poly I:C ◽  
Interferon Response ◽  
Synthetic Analogue ◽  
Post Translational Modifications ◽  
Antiviral Responses ◽  
Interfering Rna

Insectivorous bats are speculated to be ancestral hosts of Middle-East respiratory syndrome (MERS) coronavirus (CoV). MERS-CoV causes disease in humans with thirty-five percent fatality, and has evolved proteins that counteract human antiviral responses. Since bats experimentally infected with MERS-CoV do not develop signs of disease, we tested the hypothesis that MERS-CoV would replicate less efficiently in bat cells than in human cells because of its inability to subvert antiviral responses in bat cells. We infected human and bat (Eptesicus fuscus) cells with MERS-CoV and observed that the virus grew to higher titers in human cells. MERS-CoV also effectively suppressed the antiviral interferon beta (IFNβ) response in human cells, unlike in bat cells. To determine if IRF3, a critical mediator of the interferon response, also regulated the response in bats, we examined the response of IRF3 to poly(I:C), a synthetic analogue of viral double-stranded RNA. We observed that bat IRF3 responded to poly(I:C) by nuclear translocation and post-translational modifications, hallmarks of IRF3 activation. Suppression of IRF3 by small-interfering RNA (siRNA) demonstrated that IRF3 was critical for poly(I:C) and MERS-CoV induced induction of IFNβ in bat cells. Our study demonstrates that innate antiviral signaling in E. fuscus bat cells is resistant to MERS-CoV-mediated subversion.

scholarly journals Regulatory effects of chicken TRIM25 on the replication of ALV-A and the MDA5-mediated type I interferon response

2020 ◽  
Vol 51 (1) ◽  
Author(s):  
Jin-run Zhou ◽  
Jun-hong Liu ◽  
Hong-mei Li ◽  
Yue Zhao ◽  
Ziqiang Cheng ◽  
...  
Keyword(s):  
Type I Interferon ◽  
Poly I:C ◽  
Interferon Response ◽  
Type I ◽  
Relative Expression ◽  
Time Points ◽  
Antiviral Responses ◽  
Antiviral Activities ◽  
Regulatory Effects ◽  
Interfering Rna

AbstractThis study focuses on the immunoregulatory effects of chicken TRIM25 on the replication of subgroup A of avian leukosis virus (ALV-A) and the MDA5-mediated type I interferon response. The ALV-A-SDAU09C1 strain was inoculated into DF1 cells and 1-day-old SPF chickens, and the expression of TRIM25 was detected at different time points after inoculation. A recombinant overexpression plasmid containing the chicken TRIM25 gene (TRIM25-GFP) was constructed and transfected into DF1 cells to analyse the effects of the overexpression of chicken TRIM25 on the replication of ALV-A and the expression of MDA5, MAVS and IFN-β. A small interfering RNA targeting chicken TRIM25 (TRIM25-siRNA) was prepared and transfected into DF1 cells to assess the effects of the knockdown of chicken TRIM25 on the replication of ALV-A and the expression of MDA5, MAVS and IFN-β. The results showed that chicken TRIM25 was significantly upregulated at all time points both in ALV-A-infected cells and in ALV-A-infected chickens. Overexpression of chicken TRIM25 in DF1 cells dramatically decreased the antigenic titres of ALV-A in the cell supernatant and upregulated the relative expression of MDA5, MAVS and IFN-β induced by ALV-A or by poly(I:C); in contrast, knockdown of chicken TRIM25 significantly increased the antigenic titres of ALV-A and downregulated the relative expression of MDA5, MAVS and IFN-β. It can be concluded that chicken TRIM25 can inhibit the replication of ALV-A and upregulate the MDA5 receptor-mediated type I interferon response in chickens. This study can help improve the understanding of the antiviral activities of chicken TRIM25 and enrich the knowledge of antiviral responses in chickens.

scholarly journals PRV UL13 inhibits cGAS–STING-mediated IFN-β production by phosphorylating IRF3

2020 ◽  
Vol 51 (1) ◽  
Author(s):  
Zongyi Bo ◽  
Yurun Miao ◽  
Rui Xi ◽  
Qiuping Zhong ◽  
Chenyi Bao ◽  
...  
Keyword(s):  
Transcriptional Activation ◽  
Pseudorabies Virus ◽  
Nuclear Translocation ◽  
Economic Loss ◽  
Inhibitory Effect ◽  
Poly I:C ◽  
Interferon Response ◽  
Type I ◽  
Creb Binding Protein ◽  
Swine Industry

Abstract Cyclic GMP-AMP (cGAMP) synthase (cGAS) is an intracellular sensor of cytoplasmic viral DNA created during virus infection, which subsequently activates the stimulator of interferon gene (STING)-dependent type I interferon response to eliminate pathogens. In contrast, viruses have developed different strategies to modulate this signalling pathway. Pseudorabies virus (PRV), an alphaherpesvirus, is the causative agent of Aujeszky’s disease (AD), a notable disease that causes substantial economic loss to the swine industry globally. Previous reports have shown that PRV infection induces cGAS-dependent IFN-β production, conversely hydrolysing cGAMP, a second messenger synthesized by cGAS, and attenuates PRV-induced IRF3 activation and IFN-β secretion. However, it is not clear whether PRV open reading frames (ORFs) modulate the cGAS–STING-IRF3 pathway. Here, 50 PRV ORFs were screened, showing that PRV UL13 serine/threonine kinase blocks the cGAS–STING-IRF3-, poly(I:C)- or VSV-mediated transcriptional activation of the IFN-β gene. Importantly, it was discovered that UL13 phosphorylates IRF3, and its kinase activity is indispensable for such an inhibitory effect. Moreover, UL13 does not affect IRF3 dimerization, nuclear translocation or association with CREB-binding protein (CBP) but attenuates the binding of IRF3 to the IRF3-responsive promoter. Consistent with this, it was discovered that UL13 inhibits the expression of multiple interferon-stimulated genes (ISGs) induced by cGAS–STING or poly(I:C). Finally, it was determined that PRV infection can activate IRF3 by recruiting it to the nucleus, and PRVΔUL13 mutants enhance the transactivation level of the IFN-β gene. Taken together, the data from the present study demonstrated that PRV UL13 inhibits cGAS–STING-mediated IFN-β production by phosphorylating IRF3.

scholarly journals SARS-CoV-2 Nucleocapsid Protein Targets RIG-I-Like Receptor Pathways to Inhibit the Induction of Interferon Response

Cells ◽  
2021 ◽  
Vol 10 (3) ◽  
pp. 530
Author(s):  
Soo Jin Oh ◽  
Ok Sarah Shin
Keyword(s):  
Nucleocapsid Protein ◽  
Nuclear Translocation ◽  
Nonstructural Protein ◽  
Poly I:C ◽  
Interferon Response ◽  
Type I ◽  
Antiviral Immune Response ◽  
N Protein ◽  
Nonstructural Protein 1 ◽  
Polycytidylic Acid

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of the coronavirus disease 2019 (COVID-19) that has resulted in the current pandemic. The lack of highly efficacious antiviral drugs that can manage this ongoing global emergency gives urgency to establishing a comprehensive understanding of the molecular pathogenesis of SARS-CoV-2. We characterized the role of the nucleocapsid protein (N) of SARS-CoV-2 in modulating antiviral immunity. Overexpression of SARS-CoV-2 N resulted in the attenuation of retinoic acid inducible gene-I (RIG-I)-like receptor-mediated interferon (IFN) production and IFN-induced gene expression. Similar to the SARS-CoV-1 N protein, SARS-CoV-2 N suppressed the interaction between tripartate motif protein 25 (TRIM25) and RIG-I. Furthermore, SARS-CoV-2 N inhibited polyinosinic: polycytidylic acid [poly(I:C)]-mediated IFN signaling at the level of Tank-binding kinase 1 (TBK1) and interfered with the association between TBK1 and interferon regulatory factor 3 (IRF3), subsequently preventing the nuclear translocation of IRF3. We further found that both type I and III IFN production induced by either the influenza virus lacking the nonstructural protein 1 or the Zika virus were suppressed by the SARS-CoV-2 N protein. Our findings provide insights into the molecular function of the SARS-CoV-2 N protein with respect to counteracting the host antiviral immune response.

scholarly journals An Observational, Laboratory-Based Study of Outbreaks of Middle East Respiratory Syndrome Coronavirus in Jeddah and Riyadh, Kingdom of Saudi Arabia, 2014

2014 ◽  
Vol 60 (3) ◽  
pp. 369-377 ◽  
Author(s):  
Christian Drosten ◽  
Doreen Muth ◽  
Victor M. Corman ◽  
Raheela Hussain ◽  
Malaki Al Masri ◽  
...  
Keyword(s):  
Saudi Arabia ◽  
Middle East ◽  
Middle East Respiratory Syndrome ◽  
Nosocomial Transmission ◽  
Interferon Response ◽  
Nucleotide Polymorphisms ◽  
Diagnostic Laboratory ◽  
Virus Shedding ◽  
Negative Results ◽  
Sudden Rise

Abstract Background.  In spring 2014, a sudden rise in the number of notified Middle East respiratory syndrome coronavirus (MERS-CoV) infections occurred across Saudi Arabia with a focus in Jeddah. Hypotheses to explain the outbreak pattern include increased surveillance, increased zoonotic transmission, nosocomial transmission, and changes in viral transmissibility, as well as diagnostic laboratory artifacts. Methods.  Diagnostic results from Jeddah Regional Laboratory were analyzed. Viruses from the Jeddah outbreak and viruses occurring during the same time in Riyadh, Al-Kharj, and Madinah were fully or partially sequenced. A set of 4 single-nucleotide polymorphisms distinctive to the Jeddah outbreak were determined from additional viruses. Viruses from Riyadh and Jeddah were isolated and studied in cell culture. Results.  Up to 481 samples were received per day for reverse transcription polymerase chain reaction (RT-PCR) testing. A laboratory proficiency assessment suggested positive and negative results to be reliable. Forty-nine percent of 168 positive-testing samples during the Jeddah outbreak stemmed from King Fahd Hospital. All viruses from Jeddah were monophyletic and similar, whereas viruses from Riyadh were paraphyletic and diverse. A hospital-associated transmission cluster, to which cases in Indiana (United States) and the Netherlands belonged, was discovered in Riyadh. One Jeddah-type virus was found in Riyadh, with matching travel history to Jeddah. Virus isolates representing outbreaks in Jeddah and Riyadh were not different from MERS-CoV EMC/2012 in replication, escape of interferon response, or serum neutralization. Conclusions.  Virus shedding and virus functions did not change significantly during the outbreak in Jeddah. These results suggest the outbreaks to have been caused by biologically unchanged viruses in connection with nosocomial transmission.

scholarly journals Two Mutations Were Critical for Bat-to-Human Transmission of Middle East Respiratory Syndrome Coronavirus

2015 ◽  
Vol 89 (17) ◽  
pp. 9119-9123 ◽  
Author(s):  
Yang Yang ◽  
Chang Liu ◽  
Lanying Du ◽  
Shibo Jiang ◽  
Zhengli Shi ◽  
...  
Keyword(s):  
Middle East ◽  
Viral Entry ◽  
Human Cells ◽  
Middle East Respiratory Syndrome ◽  
Intermediate Hosts ◽  
Virus Surface ◽  
Bat Coronavirus ◽  
Do So

To understand how Middle East respiratory syndrome coronavirus (MERS-CoV) transmitted from bats to humans, we compared the virus surface spikes of MERS-CoV and a related bat coronavirus, HKU4. Although HKU4 spike cannot mediate viral entry into human cells, two mutations enabled it to do so by allowing it to be activated by human proteases. These mutations are present in MERS-CoV spike, explaining why MERS-CoV infects human cells. These mutations therefore played critical roles in the bat-to-human transmission of MERS-CoV, either directly or through intermediate hosts.

scholarly journals Proteolytic processing, deubiquitinase and interferon antagonist activities of Middle East respiratory syndrome coronavirus papain-like protease

2014 ◽  
Vol 95 (3) ◽  
pp. 614-626 ◽  
Author(s):  
Xingxing Yang ◽  
Xiaojuan Chen ◽  
Guangxing Bian ◽  
Jian Tu ◽  
Yaling Xing ◽  
...  
Keyword(s):  
Middle East ◽  
Nuclear Translocation ◽  
Proteolytic Processing ◽  
Middle East Respiratory Syndrome ◽  
Effective Control ◽  
Cleavage Sites ◽  
Viral Proteases ◽  
N Terminus ◽  
Genomic Studies

The emerging Middle East respiratory syndrome coronavirus (MERS-CoV) causes severe pulmonary disease in humans and represents the second example of a highly pathogenic coronavirus (CoV) following severe acute respiratory syndrome coronavirus (SARS-CoV). Genomic studies revealed that two viral proteases, papain-like protease (PLpro) and 3C-like protease (3CLpro), process the polyproteins encoded by the MERS-CoV genomic RNA. We previously reported that SARS-CoV PLpro acts as both deubiquitinase (DUB) and IFN antagonist, but the function of the MERS-CoV PLpro was poorly understood. In this study, we characterized MERS-CoV PLpro, which is a protease and can recognize and process the cleavage sites (CS) of nsp1-2, nsp2-3 and nsp3-4. The LXGG consensus cleavage sites in the N terminus of pp1a/1ab, which is generally essential for CoV PLpro-mediated processing, were also characterized in MERS-CoV. MERS-CoV PLpro, like human SARS-CoV PLpro and NL63-CoV PLP2, is a viral deubiquitinating enzyme. It acts on both K48- and K63-linked ubiquitination and ISG15-linked ISGylation. We confirmed that MERS-CoV PLpro acts as an IFN antagonist through blocking the phosphorylation and nuclear translocation of IFN regulatory factor 3 (IRF3). These findings indicate that MERS-CoV PLpro acts as a viral DUB and suppresses production of IFN-β by an interfering IRF3-mediated signalling pathway, in addition to recognizing and processing the CS at the N terminus of replicase polyprotein to release the non-structural proteins. The characterization of proteolytic processing, DUB and IFN antagonist activities of MERS-CoV PLpro would reveal the interactions between MERS-CoV and its host, and be applicable to develop strategies targeting PLpro for the effective control of MERS-CoV infection.

Massive Infektion und alveolare Schädigung der humanen Lunge durch das Middle East Respiratory Syndrome Coronavirus (MERS-CoV)

Pneumologie ◽  
2015 ◽  
Vol 69 (04) ◽  
Author(s):  
A Becher ◽  
J von Recum ◽  
K Schierhorn ◽  
T Wolff ◽  
M Tönnies ◽  
...  
Keyword(s):  
Middle East ◽  
Middle East Respiratory Syndrome

Aerogen übertragene Infektionskrankheiten bei Kindern auf Reisen

2018 ◽  
Vol 18 (06) ◽  
pp. 422-426
Author(s):  
C. Rau ◽  
J. Lindert ◽  
S. Kotsias-Konopelska ◽  
R. Kobbe
Keyword(s):  
Middle East ◽  
Middle East Respiratory Syndrome ◽  
Bakterielle Infektionen ◽  
Saisonale Influenza

ZusammenfassungErkrankungen der Atemwege gehören zu den häufigsten Gesundheitsproblemen von Kindern und treten regelhaft auch während und nach Reisen auf. Virale Atemwegsinfektionen können die Reisefähigkeit von Kindern – und damit auch ihren Angehörigen – ungünstig beeinflussen, beispielsweise durch Fieber, bronchiale Obstruktion und Schwierigkeiten beim Druckausgleich während des Fliegens durch Schwellungen und Sekretionen der Schleimhäute und der eustachi‘schen Röhre. Zu den reisemedizinisch relevanten aerogen übertragenen Krankheiten zählen neben banalen, viralen Erkältungen auch potenziell schwer verlaufende Viruserkrankungen, allen voran die saisonale Influenza und die Masern, sowie bakterielle Infektionen durch Meningokokken und die Tuberkulose. Gegen einige dieser Erkrankungen stehen effektive Impfstoffe zur Verfügung. Auch seltene, schwer verlaufende Atemwegsinfektionen, die unter bestimmten epidemiologischen Umständen außerhalb Europas erworben werden können, sollen im Folgenden exemplarisch an den Erkrankungen Middle East respiratory syndrome (MERS) und der Histoplasmose dargestellt werden.

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