scholarly journals Of Keeping and Tipping the Balance: Host Regulation and Viral Modulation of IRF3-Dependent IFNB1 Expression

Viruses ◽  
2020 ◽  
Vol 12 (7) ◽  
pp. 733
Author(s):  
Hella Schwanke ◽  
Markus Stempel ◽  
Melanie M. Brinkmann
Keyword(s):  
Transcription Factors ◽  
Viral Entry ◽  
Principal Component ◽  
Host Cells ◽  
Productive Infection ◽  
Type I ◽  
Gene Encoding ◽  
Irf3 Activation ◽  
Signalling Cascade ◽  
Host Regulation

The type I interferon (IFN) response is a principal component of our immune system that allows to counter a viral attack immediately upon viral entry into host cells. Upon engagement of aberrantly localised nucleic acids, germline-encoded pattern recognition receptors convey their find via a signalling cascade to prompt kinase-mediated activation of a specific set of five transcription factors. Within the nucleus, the coordinated interaction of these dimeric transcription factors with coactivators and the basal RNA transcription machinery is required to access the gene encoding the type I IFN IFNβ (IFNB1). Virus-induced release of IFNβ then induces the antiviral state of the system and mediates further mechanisms for defence. Due to its key role during the induction of the initial IFN response, the activity of the transcription factor interferon regulatory factor 3 (IRF3) is tightly regulated by the host and fiercely targeted by viral proteins at all conceivable levels. In this review, we will revisit the steps enabling the trans-activating potential of IRF3 after its activation and the subsequent assembly of the multi-protein complex at the IFNβ enhancer that controls gene expression. Further, we will inspect the regulatory mechanisms of these steps imposed by the host cell and present the manifold strategies viruses have evolved to intervene with IFNβ transcription downstream of IRF3 activation in order to secure establishment of a productive infection.

scholarly journals The Level of CD81 Cell Surface Expression Is a Key Determinant for Productive Entry of Hepatitis C Virus into Host Cells

2006 ◽  
Vol 81 (2) ◽  
pp. 588-598 ◽  
Author(s):  
George Koutsoudakis ◽  
Eva Herrmann ◽  
Stephanie Kallis ◽  
Ralf Bartenschlager ◽  
Thomas Pietschmann
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Cell Surface ◽  
Surface Expression ◽  
Hcv Infection ◽  
Host Cells ◽  
Productive Infection ◽  
Cell Surface Expression ◽  
Type I ◽  
Cell Clones

ABSTRACT Recently a cell culture model supporting the complete life cycle of the hepatitis C virus (HCV) was developed. Searching for host cell determinants involved in the HCV replication cycle, we evaluated the efficiency of virus propagation in different Huh-7-derived cell clones. We found that Huh-7.5 cells and Huh7-Lunet cells, two former replicon cell clones that had been generated by removal of an HCV replicon by inhibitor treatment, supported comparable levels of RNA replication and particle production, whereas virus spread was severely impaired in the latter cells. Analysis of cell surface expression of CD81 and scavenger receptor class B type I (SR-BI), two molecules previously implicated in HCV entry, revealed similar expression levels for SR-BI, while CD81 surface expression was much higher on Huh-7.5 cells than on Huh7-Lunet cells. Ectopic expression of CD81 in Huh7-Lunet cells conferred permissiveness for HCV infection to a level comparable to that for Huh-7.5 cells. Modulation of CD81 cell surface density in Huh-7.5 cells by RNA interference indicated that a certain amount of this molecule (∼7 × 104 molecules per cell) is required for productive infection with a low dose of HCV. Consistent with this, we show that susceptibility to HCV infection depends on a critical quantity of CD81 molecules. While infection is restricted in cells expressing very small amounts of CD81, susceptibility rapidly rises within a narrow range of CD81 levels, reaching a plateau where higher expression does not further increase the efficiency of infection. Together these data indicate that a high density of cell surface-exposed CD81 is a key determinant for productive HCV entry into host cells.

scholarly journals Therapeutic Modalities for Sars-Cov-2 (Covid-19): Current Status and Role of Protease Inhibitors to Block Viral Entry Into Host Cells

2020 ◽  
Vol 14 (3) ◽  
pp. 1695-1703
Author(s):  
Sarmad Ahmad Qamar ◽  
Kanta Basharat ◽  
Muhammad Bilal ◽  
Hafiz M.N. Iqbal
Keyword(s):  
Protease Inhibitors ◽  
Viral Entry ◽  
Host Cells ◽  
Type I Interferons ◽  
World Health ◽  
Current Status ◽  
Type I ◽  
Respiratory Pathway ◽  
Therapeutic Modalities ◽  
Health Organization

An acute respiratory disease (SARS-CoV-2, also recognized as COVID-19/2019-nCoV), caused by nCoV created a worldwide emergency. The World Health Organization declared the SARS-CoV-2 as epidemic of international concern on January 2020. After SARS-CoV in 2002 and MERS-CoV in 2012, the emergence of SARS-CoV-2 is marked as third highly pathogenic coronavirus of 21st century. Till now, various researches have been conducted, highlighting SARS-CoV-2 as β-coronavirus with high phylogenetic and genomic similarity with bat-CoV, indicating bats as natural reservoir of coronaviruses. It has also been confirmed that SARS-CoV-2 uses the same (ACE2) receptor for host cellular entry as of SARS-CoV, and primarily spread through respiratory pathway. Evidences shows continuous human-to-human viral transfer, with numerous worldwide exported cases. Currently, there is no specific approved drug available for the treatment of SARS-CoV-2, but various anti-parasitic and anti-viral drugs are being investigated. In this review, we have described several possible therapeutic modalities for SARS-CoV-2 infection based on (i) host protease inhibitors to block viral entry into the cell; (ii) gene silencing using siRNA-based RNAi and (iii) type I interferons (IFN1)-based therapeutics have been discussed in detail. Background knowledge on these strategies highlight them as potential therapeutic targets, which could be evaluated on urgent basis to combat COVID-19 epidemic.

scholarly journals TMPRSS2 and TMPRSS4 mediate SARS-CoV-2 infection of human small intestinal enterocytes

2020 ◽  
Author(s):  
Ruochen Zang ◽  
Maria F.G. Castro ◽  
Broc T. McCune ◽  
Qiru Zeng ◽  
Paul W. Rothlauf ◽  
...  
Keyword(s):  
Viral Entry ◽  
Gastrointestinal Symptoms ◽  
Host Cells ◽  
Productive Infection ◽  
Intestinal Lumen ◽  
Fecal Shedding ◽  
Oral Transmission ◽  
Stool Specimens ◽  
Small Intestinal ◽  
Intestinal Enterocytes

AbstractBoth gastrointestinal symptoms and fecal shedding of SARS-CoV-2 RNA have been frequently observed in COVID-19 patients. However, whether SARS-CoV-2 replicate in the human intestine and its clinical relevance to potential fecal-oral transmission remain unclear. Here, we demonstrate productive infection of SARS-CoV-2 in ACE2+ mature enterocytes in human small intestinal enteroids. In addition to TMPRSS2, another mucosa-specific serine protease, TMPRSS4, also enhanced SARS-CoV-2 spike fusogenic activity and mediated viral entry into host cells. However, newly synthesized viruses released into the intestinal lumen were rapidly inactivated by human colonic fluids and no infectious virus was recovered from the stool specimens of COVID-19 patients. Our results highlight the intestine as a potential site of SARS-CoV-2 replication, which may contribute to local and systemic illness and overall disease progression.

scholarly journals Lack of Functional Receptors Is the Only Barrier That Prevents Caprine Arthritis-Encephalitis Virus from Infecting Human Cells

2000 ◽  
Vol 74 (18) ◽  
pp. 8343-8348 ◽  
Author(s):  
Laila Mselli-Lakhal ◽  
Colette Favier ◽  
Kevin Leung ◽  
Francois Guiguen ◽  
Delphine Grezel ◽  
...  
Keyword(s):  
Host Cell ◽  
Viral Entry ◽  
Human Cells ◽  
Encephalitis Virus ◽  
Host Cells ◽  
Productive Infection ◽  
Caprine Arthritis Encephalitis Virus ◽  
Successful Infection ◽  
Host Cell Surface ◽  
Vesicular Stomatitis

ABSTRACT Barriers to replication of viruses in potential host cells may occur at several levels. Lack of suitable and functional receptors on the host cell surface, thereby precluding entry of the virus, is a frequent reason for noninfectivity, as long as no alternative way of entry (e.g., pinocytosis, antibody-dependent adsorption) can be exploited by the virus. Other barriers can intervene at later stages of the virus life cycle, with restrictions on transcription of the viral genome, incorrect translation and posttranslational processing of viral proteins, inefficient viral assembly, and release or efficient early induction of apoptosis in the infected cell. The data we present here demonstrate that replication of caprine arthritis-encephalitis virus (CAEV) is restricted in a variety of human cell lines and primary tissue cultures. This barrier was efficiently overcome by transfection of a novel infectious complete-proviral CAEV construct into the same cells. The successful infection of human cells with a vesicular stomatitis virus (VSV) G-pseudotyped Env-defective CAEV confirmed that viral entry is the major obstacle to CAEV infection of human cells. The fully efficient productive infection obtained with the VSV-G-protein-pseudotyped infectious CAEV strengthened the evidence that lack of viral entry is the only practical barrier to CAEV replication in human cells. The virus thus produced retained its original host cell specificity and acquired no propensity to propagate further in human cultures.

scholarly journals Poxviral Targeting of Interferon Regulatory Factor Activation

Viruses ◽  
2020 ◽  
Vol 12 (10) ◽  
pp. 1191 ◽  
Author(s):  
Clara Lawler ◽  
Gareth Brady
Keyword(s):  
Gene Expression ◽  
Transcription Factors ◽  
Nucleic Acids ◽  
Viral Gene Expression ◽  
Host Cells ◽  
Viral Gene ◽  
Type I ◽  
Adaptive Responses ◽  
Regulatory Factor ◽  
Wide Range

As viruses have a capacity to rapidly evolve and continually alter the coding of their protein repertoires, host cells have evolved pathways to sense viruses through the one invariable feature common to all these pathogens—their nucleic acids. These genomic and transcriptional pathogen-associated molecular patterns (PAMPs) trigger the activation of germline-encoded anti-viral pattern recognition receptors (PRRs) that can distinguish viral nucleic acids from host forms by their localization and subtle differences in their chemistry. A wide range of transmembrane and cytosolic PRRs continually probe the intracellular environment for these viral PAMPs, activating pathways leading to the activation of anti-viral gene expression. The activation of Nuclear Factor Kappa B (NFκB) and Interferon (IFN) Regulatory Factor (IRF) family transcription factors are of central importance in driving pro-inflammatory and type-I interferon (TI-IFN) gene expression required to effectively restrict spread and trigger adaptive responses leading to clearance. Poxviruses evolve complex arrays of inhibitors which target these pathways at a variety of levels. This review will focus on how poxviruses target and inhibit PRR pathways leading to the activation of IRF family transcription factors.

scholarly journals JC Polyomavirus Entry by Clathrin-Mediated Endocytosis Is Driven by β-Arrestin

2019 ◽  
Vol 93 (8) ◽  
Author(s):  
Colleen L. Mayberry ◽  
Ashley N. Soucy ◽  
Conner R. Lajoie ◽  
Jeanne K. DuShane ◽  
Melissa S. Maginnis
Keyword(s):  
Progressive Multifocal Leukoencephalopathy ◽  
Viral Entry ◽  
Demyelinating Disease ◽  
Simian Virus 40 ◽  
Host Cells ◽  
Productive Infection ◽  
Host Immune System ◽  
Jc Polyomavirus ◽  
Viral Attachment ◽  
Cellular Factors

ABSTRACTJC polyomavirus (JCPyV) establishes a persistent, lifelong, asymptomatic infection within the kidney of the majority of the human population. Under conditions of severe immunosuppression or immune modulation, JCPyV can reactivate in the central nervous system (CNS) and cause progressive multifocal leukoencephalopathy (PML), a fatal demyelinating disease. Initiation of infection is mediated through viral attachment to α2,6-sialic acid-containing lactoseries tetrasaccharide c (LSTc) on the surface of host cells. JCPyV internalization is dependent on serotonin 5-hydroxytryptamine subfamily 2 receptors (5-HT2Rs), and entry is thought to occur by clathrin-mediated endocytosis (CME). However, the JCPyV entry process and the cellular factors involved in viral internalization remain poorly understood. Treatment of cells with small-molecule chemical inhibitors and RNA interference of 5-HT2R endocytic machinery, including β-arrestin, clathrin, AP2, and dynamin, significantly reduced JCPyV infection. However, infectivity of the polyomavirus simian virus 40 (SV40) was not affected by CME-specific treatments. Inhibition of clathrin or β-arrestin specifically reduced JCPyV internalization but did not affect viral attachment. Furthermore, mutagenesis of a β-arrestin binding domain (Ala-Ser-Lys) within the intracellular C terminus of 5-HT2AR severely diminished internalization and infection, suggesting that β-arrestin interactions with 5-HT2AR are critical for JCPyV infection and entry. These conclusions illuminate key host factors that regulate clathrin-mediated endocytosis of JCPyV, which is necessary for viral internalization and productive infection.IMPORTANCEViruses usurp cellular factors to invade host cells. Activation and utilization of these proteins upon initiation of viral infection are therefore required for productive infection and resultant viral disease. The majority of healthy individuals are asymptomatically infected by JC polyomavirus (JCPyV), but if the host immune system is compromised, JCPyV can cause progressive multifocal leukoencephalopathy (PML), a rare, fatal, demyelinating disease. Individuals infected with HIV or taking prolonged immunomodulatory therapies have a heightened risk for developing PML. The cellular proteins and pathways utilized by JCPyV to mediate viral entry are poorly understood. Our findings further characterize how JCPyV utilizes the clathrin-mediated endocytosis pathway to invade host cells. We have identified specific components of this pathway that are necessary for the viral entry process and infection. Collectively, the conclusions increase our understanding of JCPyV infection and pathogenesis and may contribute to the future development of novel therapeutic strategies for PML.

scholarly journals Bub1 Facilitates Virus Entry through Endocytosis in a Model ofDrosophilaPathogenesis

2018 ◽  
Vol 92 (18) ◽  
Author(s):  
Shuo Yang ◽  
Junjing Yu ◽  
Zhiqin Fan ◽  
Si-tang Gong ◽  
Hong Tang ◽  
...  
Keyword(s):  
Cell Membrane ◽  
Cell Line ◽  
Viral Entry ◽  
Unknown Function ◽  
Virus Entry ◽  
Survival Rates ◽  
Host Cells ◽  
Productive Infection ◽  
Content Type ◽  
Chromosome Congression

ABSTRACTIn order to establish productive infection and dissemination, viruses usually evolve a number of strategies to hijack and/or subvert the host defense systems. However, host factors utilized by the virus to facilitate infection remain poorly characterized. In this work, we found thatDrosophila melanogasterdeficient inbudding uninhibited by benzimidazoles 1(bub1), a highly conserved subunit of the kinetochore complex regulating chromosome congression (1), became resistant toDrosophila C virus(DCV) infection, evidenced in increased survival rates and reduced viral loads, compared to the wild-type control. Mechanistic analysis further showed that Bub1 also functioned in the cytoplasm and was essentially involved in clathrin-dependent endocytosis of DCV and other pathogens, thus limiting pathogen entry. DCV infection potentially had strengthened the interaction between Bub1 and the clathrin adaptor on the cell membrane. Furthermore, the conserved function of Bub1 was also verified in a mammalian cell line. Thus, our data demonstrated a previously unknown function of Bub1 that could be hijacked by pathogens to facilitate their infection and spread.IMPORTANCEIn this work, we identify for the first time that the nuclear protein Bub1 (budding uninhibited by benzimidazoles 1), a highly conserved subunit of the kinetochore complex regulating chromosome congression, has a novel and important function on the cell membrane to facilitate the virus to enter host cells. Bub1 deficiency empowers the host to have the ability to resist viral infection inDrosophilaand a human cell line. Bub1 is involved in the virus entry step through regulating endocytosis. The DCV capsid protein can recruit Bub1, and DCV infection can strengthen the interaction between Bub1 and a clathrin-dependent endocytosis component. The restricted entry of vesicular stomatitis virus (VSV) andListeria monocytogenesinbub1-deficient flies and cell lines was also observed. Therefore, our data implicate a previously unknown function of Bub1 that can be hijacked by pathogens to facilitate their entry, and Bub1 may serve as a potential antiviral therapy target for limiting viral entry.

Identification of a single-copy gene encoding a Type I chlorophyll a/b-binding polypeptide of photosystem I in Arabidopsis thaliana

1992 ◽  
Vol 84 (4) ◽  
pp. 561-567 ◽  
Author(s):  
Poul E. Jensen ◽  
Michael Kristensen ◽  
Tine Hoff ◽  
Jan Lehmbeck ◽  
Bjarne M. Stummann ◽  
...  
Keyword(s):  
Arabidopsis Thaliana ◽  
Chlorophyll A ◽  
Photosystem I ◽  
Single Copy ◽  
Type I ◽  
Single Copy Gene ◽  
Gene Encoding ◽  
Copy Gene

SARS-CoV-2 Biology Insights, Part IV.Antibody-Dependent Enhancement (ADE) and the tricky “Herd Immunity”: narrative review (Preprint)

2020 ◽  
Author(s):  
Laura Lafon-Hughes
Keyword(s):  
Viral Infection ◽  
Viral Entry ◽  
Neutralizing Antibodies ◽  
Vaccine Development ◽  
Whooping Cough ◽  
Common Knowledge ◽  
Herd Immunity ◽  
Life Quality ◽  
Host Cells ◽  
System P

BACKGROUND It is common knowledge that vaccination has improved our life quality and expectancy since it succeeded in achieving almost eradication of several diseases including chickenpox (varicella), diphtheria, hepatitis A and B, measles, meningococcal, mumps, pneumococcal, polio, rotavirus, rubella, tetanus and whooping cough (pertussis) Vaccination success is based on vaccine induction of neutralizing antibodies that help fight the infection (e.g. by a virus), preventing the disease. Conversely, Antibody-dependent enhancement (ADE) of a viral infection occurs when anti-viral antibodies facilitate viral entry into host cells and enhance viral infection in these cells. ADE has been previously studied in Dengue and HIV viruses and explains why a second infection with Dengue can be lethal. As already reviewed in Part I and Part II, SARS-Cov-2 shares with HIV not only 4 sequences in the Spike protein but also the capacity to attack the immune system. OBJECTIVE As HIV presents ADE, we wondered whether this was also the case regarding SARS-CoV-2. METHODS A literature review was done through Google. RESULTS SARS-CoV-2 presents ADE. As SARS, which does not have the 4 HIV-like inserts, has the same property, ADE would not be driven by the HIV-like spike sequences. CONCLUSIONS ADE can explain the failure of herd immunity-based strategies and will also probably hamper anti-SARS-CoV-2 vaccine development. As reviewed in Part I, there fortunately are promising therapeutic strategies for COVID-19, which should be further developed. In the meantime, complementary countermeasures to protect mainly the youth from this infection are presented to be discussed in Part V Viewpoint.

scholarly journals SARS-CoV-2 Is Not Detected in the Cerebrospinal Fluid of Encephalopathic COVID-19 Patients

2020 ◽  
Vol 11 ◽  
Author(s):  
Dimitris G. Placantonakis ◽  
Maria Aguero-Rosenfeld ◽  
Abdallah Flaifel ◽  
John Colavito ◽  
Kenneth Inglima ◽  
...  
Keyword(s):  
Cerebrospinal Fluid ◽  
Viral Entry ◽  
Cell Types ◽  
Host Cells ◽  
Nasopharyngeal Swab ◽  
Rt Pcr ◽  
Neurologic Sequelae ◽  
Show Evidence ◽  
Novel Coronavirus ◽  
Transmembrane Serine Protease

Neurologic manifestations of the novel coronavirus SARS-CoV-2 infection have received wide attention, but the mechanisms remain uncertain. Here, we describe computational data from public domain RNA-seq datasets and cerebrospinal fluid data from adult patients with severe COVID-19 pneumonia that suggest that SARS-CoV-2 infection of the central nervous system is unlikely. We found that the mRNAs encoding the ACE2 receptor and the TMPRSS2 transmembrane serine protease, both of which are required for viral entry into host cells, are minimally expressed in the major cell types of the brain. In addition, CSF samples from 13 adult encephalopathic COVID-19 patients diagnosed with the viral infection via nasopharyngeal swab RT-PCR did not show evidence for the virus. This particular finding is robust for two reasons. First, the RT-PCR diagnostic was validated for CSF studies using stringent criteria; and second, 61% of these patients had CSF testing within 1 week of a positive nasopharyngeal diagnostic test. We propose that neurologic sequelae of COVID-19 are not due to SARS-CoV-2 meningoencephalitis and that other etiologies are more likely mechanisms.

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