scholarly journals B.1.1.7 and B.1.351 SARS-CoV-2 variants display enhanced Spike-mediated fusion

2021 ◽  
Author(s):  
Maaran Michael Rajah ◽  
Mathieu Hubert ◽  
Elodie Bishop ◽  
Nell Saunders ◽  
Rémy Robinot ◽  
...  
Keyword(s):  
Innate Immunity ◽  
Monoclonal Antibodies ◽  
Reference Strain ◽  
Type I Interferon ◽  
Transmembrane Proteins ◽  
Viral Proteins ◽  
Type I ◽  
Cytopathic Effects ◽  
Lung Abnormalities ◽  
Infected Cells

SARS-CoV-2 B.1.1.7 (variant Alpha) and B.1.351 (variant Beta) have supplanted pre-existing strains in many countries. Severe COVID-19 is characterized by lung abnormalities, including the presence of syncytial pneumocytes. Syncytia form when infected cells fuse with adjacent cells. The fitness, cytopathic effects and type-I interferon (IFN) sensitivity of the variants remain poorly characterized. Here, we assessed B.1.1.7 and B.1.351 spread and fusion in cell cultures. B.1.1.7 and B.1.351 replicated similarly to D614G reference strain in Vero, Caco-2, Calu-3 and primary airway cells and were similarly sensitive to IFN. The variants formed larger and more numerous syncytia. Variant Spikes, in the absence of any other viral proteins, resulted in faster fusion relative to D614G. B.1.1.7 and B.1.351 fusion was similarly inhibited by interferon induced transmembrane proteins (IFITMs). Individual mutations present in the variant Spikes modified fusogenicity, binding to ACE2 and recognition by monoclonal antibodies. Also, B.1.1.7 and B.1.351 variants remain sensitive to innate immunity components. The mutations present in the two variants globally enhance viral fusogenicity and allow for antibody evasion.

scholarly journals The Regulatory Network of Cyclic GMP-AMP Synthase-Stimulator of Interferon Genes Pathway in Viral Evasion

2021 ◽  
Vol 12 ◽  
Author(s):  
Tongyu Hu ◽  
Mingyu Pan ◽  
Yue Yin ◽  
Chen Wang ◽  
Ye Cui ◽  
...  
Keyword(s):  
Innate Immunity ◽  
Cyclic Gmp ◽  
Mammalian Cells ◽  
Type I Interferon ◽  
Viral Proteins ◽  
Current Status ◽  
Type I ◽  
Non Coding Rnas ◽  
Sting Pathway ◽  
Viral Evasion

Virus infection has been consistently threatening public health. The cyclic GMP-AMP synthase (cGAS)-Stimulator of Interferon Genes (STING) pathway is a critical defender to sense various pathogens and trigger innate immunity of mammalian cells. cGAS recognizes the pathogenic DNA in the cytosol and then synthesizes 2′3′-cyclic GMP-AMP (2′3′cGAMP). As the second messenger, cGAMP activates STING and induces the following cascade to produce type I interferon (IFN-I) to protect against infections. However, viruses have evolved numerous strategies to hinder the cGAS-STING signal transduction, promoting their immune evasion. Here we outline the current status of the viral evasion mechanism underlying the regulation of the cGAS-STING pathway, focusing on how post-transcriptional modifications, viral proteins, and non-coding RNAs involve innate immunity during viral infection, attempting to inspire new targets discovery and uncover potential clinical antiviral treatments.

scholarly journals IFITMs Inhibit Cell Fusion Mediated by Trophoblast Syncytins

2019 ◽  
Author(s):  
Ashley Zani ◽  
Lizhi Zhang ◽  
Adam Kenney ◽  
Temet M. McMichael ◽  
Jesse J. Kwiek ◽  
...  
Keyword(s):  
Virus Infection ◽  
Fetal Development ◽  
Type I Interferon ◽  
Cell Structure ◽  
Transmembrane Proteins ◽  
Type I ◽  
Multinucleated Cell ◽  
Virus Infections ◽  
Infected Cells ◽  
Inhibit Cell Fusion

AbstractType I interferon (IFN) induced by virus infections during pregnancy causes placental damage, though the mechanisms and identities of IFN-stimulated genes that are involved remain under investigation. The IFN-induced transmembrane proteins (IFITMs) inhibit virus infections by preventing virus membrane fusion with cells and by inhibiting fusion of infected cells (syncytialization). Fusion of placental trophoblasts via expression of endogenous retroviral fusogens known as Syncytins forms the syncytiotrophoblast, a multinucleated cell structure essential for fetal development. We found that IFN blocks fusion of BeWo human placental trophoblasts. Stably-expressed IFITMs 1, 2, and 3 also blocked fusion of these trophoblasts, while making them more resistant to virus infections. Conversely, stable knockdown of IFITMs in BeWo trophoblasts increased their spontaneous fusion and allowed fusion in the presence of IFN, while also making the cells more susceptible to virus infection. Overall, our data demonstrate that IFITMs are anti-viral and anti-fusogenic in trophoblasts.

scholarly journals Atlastin Endoplasmic Reticulum-Shaping Proteins Facilitate Zika Virus Replication

2019 ◽  
Vol 93 (23) ◽  
Author(s):  
Blandine Monel ◽  
Maaran Michael Rajah ◽  
Mohamed Lamine Hafirassou ◽  
Samy Sid Ahmed ◽  
Julien Burlaud-Gaillard ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Viral Replication ◽  
Zika Virus ◽  
Antiviral Treatment ◽  
Viral Proteins ◽  
Neurological Complications ◽  
Cytopathic Effects ◽  
Replication Sites ◽  
Infected Cells ◽  
Er Membrane

ABSTRACT The endoplasmic reticulum (ER) is the site for Zika virus (ZIKV) replication and is central to the cytopathic effects observed in infected cells. ZIKV induces the formation of ER-derived large cytoplasmic vacuoles followed by “implosive” cell death. Little is known about the nature of the ER factors that regulate flavivirus replication. Atlastins (ATL1, -2, and -3) are dynamin-related GTPases that control the structure and the dynamics of the ER membrane. We show here that ZIKV replication is significantly decreased in the absence of ATL proteins. The appearance of infected cells is delayed, the levels of intracellular viral proteins and released virus are reduced, and the cytopathic effects are strongly impaired. We further show that ATL3 is recruited to viral replication sites and interacts with the nonstructural viral proteins NS2A and NS2B3. Thus, proteins that shape and maintain the ER tubular network ensure efficient ZIKV replication. IMPORTANCE Zika virus (ZIKV) is an emerging virus associated with Guillain-Barré syndrome, and fetal microcephaly as well as other neurological complications. There is no vaccine or specific antiviral treatment against ZIKV. We found that endoplasmic reticulum (ER)-shaping atlastin proteins (ATL1, -2, and -3), which induce ER membrane fusion, facilitate ZIKV replication. We show that ATL3 is recruited to the viral replication site and colocalize with the viral proteins NS2A and NS2B3. The results provide insights into host factors used by ZIKV to enhance its replication.

scholarly journals Efficient dengue virus (DENV) infection of human muscle satellite cells upregulates type I interferon response genes and differentially modulates MHC I expression on bystander and DENV-infected cells

2008 ◽  
Vol 89 (7) ◽  
pp. 1605-1615 ◽  
Author(s):  
Rajas V. Warke ◽  
Aniuska Becerra ◽  
Agatha Zawadzka ◽  
Diane J. Schmidt ◽  
Katherine J. Martin ◽  
...  
Keyword(s):  
Cell Surface ◽  
Satellite Cells ◽  
Culture Medium ◽  
Type I Interferon ◽  
Denv Infection ◽  
Human Muscle ◽  
Type I ◽  
Mhc I ◽  
Muscle Satellite Cells ◽  
Infected Cells

Dengue virus (DENV) is a mosquito-borne flavivirus that causes an acute febrile disease in humans, characterized by musculoskeletal pain, headache, rash and leukopenia. The cause of myalgia during DENV infection is still unknown. To determine whether DENV can infect primary muscle cells, human muscle satellite cells were exposed to DENV in vitro. The results demonstrated for the first time high-efficiency infection and replication of DENV in human primary muscle satellite cells. Changes in global gene expression were also examined in these cells following DENV infection using Affymetrix GeneChip analysis. The differentially regulated genes belonged to two main functional categories: cell growth and development, and antiviral type I interferon (IFN) response genes. Increased expression of the type I IFN response genes for tumour necrosis factor-related apoptosis-inducing ligand (TRAIL), melanoma-derived antigen 5 (MDA-5), IFN-γ-inducible protein 10 (IP-10), galectin 3 soluble binding protein (LGals3BP) and IFN response factor 7 (IRF7) was confirmed by quantitative RT-PCR. Furthermore, higher levels of cell-surface-bound intracellular adhesion molecule-1 (ICAM-1) and soluble ICAM-1 in the cell-culture medium were detected following DENV infection. However, DENV infection impaired the ability of the infected cells in the culture medium to upregulate cell-surface expression of MHC I molecules, suggesting a possible mechanism of immune evasion by DENV. The findings of this study warrant further clinical research to identify whether muscle cells are targets for DENV infection during the acute stage of the disease in vivo.

Transcriptome analysis of senecavirus A-infected cells: Type I interferon is a critical anti-viral factor

2020 ◽  
Vol 147 ◽  
pp. 104432
Author(s):  
Jing Wang ◽  
Chunxiao Mou ◽  
Minmin Wang ◽  
Shuonan Pan ◽  
Zhenhai Chen
Keyword(s):  
Transcriptome Analysis ◽  
Type I Interferon ◽  
Type I ◽  
Viral Factor ◽  
Infected Cells

scholarly journals Epstein-Barr Virus (EBV) Tegument Protein BGLF2 Suppresses Type I Interferon Signaling To Promote EBV Reactivation

2020 ◽  
Vol 94 (11) ◽  
Author(s):  
XueQiao Liu ◽  
Tomohiko Sadaoka ◽  
Tammy Krogmann ◽  
Jeffrey I. Cohen
Keyword(s):  
Virus Infection ◽  
Type I Interferon ◽  
Tegument Protein ◽  
Type I ◽  
Type I Ifn ◽  
Virus Reactivation ◽  
Ebv Infection ◽  
Ebv Reactivation ◽  
Stat3 Phosphorylation ◽  
Infected Cells

ABSTRACT Interferon alpha (IFN-α) and IFN-β are type I IFNs that are induced by virus infection and are important in the host’s innate antiviral response. EBV infection activates multiple cell signaling pathways, resulting in the production of type I IFN which inhibits EBV infection and virus-induced B-cell transformation. We reported previously that EBV tegument protein BGLF2 activates p38 and enhances EBV reactivation. To further understand the role of BGLF2 in EBV infection, we used mass spectrometry to identify cellular proteins that interact with BGLF2. We found that BGLF2 binds to Tyk2 and confirmed this interaction by coimmunoprecipitation. BGLF2 blocked type I IFN-induced Tyk2, STAT1, and STAT3 phosphorylation and the expression of IFN-stimulated genes (ISGs) IRF1, IRF7, and MxA. In contrast, BGLF2 did not inhibit STAT1 phosphorylation induced by IFN-γ. Deletion of the carboxyl-terminal 66 amino acids of BGLF2 reduced the ability of the protein to repress type I IFN signaling. Treatment of gastric carcinoma and Raji cells with IFN-α blocked BZLF1 expression and EBV reactivation; however, expression of BGLF2 reduced the ability of IFN-α to inhibit BZLF1 expression and enhanced EBV reactivation. In summary, EBV BGLF2 interacts with Tyk2, inhibiting Tyk2, STAT1, and STAT3 phosphorylation and impairs type I IFN signaling; BGLF2 also counteracts the ability of IFN-α to suppress EBV reactivation. IMPORTANCE Type I interferons are important for controlling virus infection. We have found that the Epstein-Barr virus (EBV) BGLF2 tegument protein binds to a protein in the type I interferon signaling pathway Tyk2 and inhibits the expression of genes induced by type I interferons. Treatment of EBV-infected cells with type I interferon inhibits reactivation of the virus, while expression of EBV BGLF2 reduces the ability of type I interferon to inhibit virus reactivation. Thus, a tegument protein delivered to cells during virus infection inhibits the host’s antiviral response and promotes virus reactivation of latently infected cells. Therefore, EBV BGLF2 might protect virus-infected cells from the type I interferon response in cells undergoing lytic virus replication.

scholarly journals Comprehensive Mutagenesis of Herpes Simplex Virus 1 Genome Identifies UL42 as an Inhibitor of Type I Interferon Induction

2019 ◽  
Vol 93 (23) ◽  
Author(s):  
Maxime Chapon ◽  
Kislay Parvatiyar ◽  
Saba Roghiyh Aliyari ◽  
Jeffrey S. Zhao ◽  
Genhong Cheng
Keyword(s):  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
High Throughput ◽  
Type I Interferon ◽  
Viral Proteins ◽  
Interferon Response ◽  
Type I ◽  
Herpes Simplex Virus 1 ◽  
Simplex Virus ◽  
Hsv 1

ABSTRACT In spite of several decades of research focused on understanding the biology of human herpes simplex virus 1 (HSV-1), no tool has been developed to study its genome in a high-throughput fashion. Here, we describe the creation of a transposon insertion mutant library of the HSV-1 genome. Using this tool, we aimed to identify novel viral regulators of type I interferon (IFN-I). HSV-1 evades the host immune system by encoding viral proteins that inhibit the type I interferon response. Applying differential selective pressure, we identified the three strongest viral IFN-I regulators in HSV-1. We report that the viral polymerase processivity factor UL42 interacts with the host transcription factor IFN regulatory factor 3 (IRF-3), inhibiting its phosphorylation and downstream beta interferon (IFN-β) gene transcription. This study represents a proof of concept for the use of high-throughput screening of the HSV-1 genome in investigating viral biology and offers new targets both for antiviral therapy and for oncolytic vector design. IMPORTANCE This work is the first to report the use of a high-throughput mutagenesis method to study the genome of HSV-1. We report three novel viral proteins potentially involved in regulating the host type I interferon response. We describe a novel mechanism by which the viral protein UL42 is able to suppress the production of beta interferon. The tool we introduce in this study can be used to study the HSV-1 genome in great detail to better understand viral gene functions.

Sign in / Sign up

Export Citation Format

Share Document