scholarly journals The Interferon-Stimulated Gene IFITM3 Restricts Infection and Pathogenesis of Arthritogenic and Encephalitic Alphaviruses

2016 ◽  
Vol 90 (19) ◽  
pp. 8780-8794 ◽  
Author(s):  
Subhajit Poddar ◽  
Jennifer L. Hyde ◽  
Matthew J. Gorman ◽  
Michael Farzan ◽  
Michael S. Diamond
Keyword(s):  
Viral Infections ◽  
Transmembrane Protein ◽  
Flow Cytometric Analysis ◽  
Antiviral Effect ◽  
Host Cells ◽  
Type I ◽  
Targeted Gene Deletion ◽  
Multiple Organs ◽  
Viral Burden ◽  
Alphavirus Infection

ABSTRACTHost cells respond to viral infections by producing type I interferon (IFN), which induces the expression of hundreds of interferon-stimulated genes (ISGs). Although ISGs mediate a protective state against many pathogens, the antiviral functions of the majority of these genes have not been identified. IFITM3 is a small transmembrane ISG that restricts a broad range of viruses, including orthomyxoviruses, flaviviruses, filoviruses, and coronaviruses. Here, we show that alphavirus infection is increased inIfitm3−/−andIfitmlocus deletion (Ifitm-del) fibroblasts and, reciprocally, reduced in fibroblasts transcomplemented with Ifitm3. Mechanistic studies showed that Ifitm3 did not affect viral binding or entry but inhibited pH-dependent fusion. In a murine model of chikungunya virus arthritis,Ifitm3−/−mice sustained greater joint swelling in the ipsilateral ankle at days 3 and 7 postinfection, and this correlated with higher levels of proinflammatory cytokines and viral burden. Flow cytometric analysis suggested thatIfitm3−/−macrophages from the spleen were infected at greater levels than observed in wild-type (WT) mice, results that were supported by experiments withIfitm3−/−bone marrow-derived macrophages.Ifitm3−/−mice also were more susceptible than WT mice to lethal alphavirus infection with Venezuelan equine encephalitis virus, and this was associated with greater viral burden in multiple organs. Collectively, our data define an antiviral role for Ifitm3 in restricting infection of multiple alphaviruses.IMPORTANCEThe interferon-induced transmembrane protein 3 (IFITM3) inhibits infection of multiple families of viruses in cell culture. Compared to other viruses, much less is known about the antiviral effect of IFITM3 on alphaviruses. In this study, we characterized the antiviral activity of mouse Ifitm3 against arthritogenic and encephalitic alphaviruses using cells and animals with a targeted gene deletion ofIfitm3as well as deficient cells transcomplemented with Ifitm3. Based on extensive virological analysis, we demonstrate greater levels of alphavirus infection and disease pathogenesis when Ifitm3 expression is absent. Our data establish an inhibitory role for Ifitm3 in controlling infection of alphaviruses.

scholarly journals Immunological Aspects Related to Viral Infections in Severe Asthma and the Role of Omalizumab

Biomedicines ◽  
2021 ◽  
Vol 9 (4) ◽  
pp. 348
Author(s):  
Francesco Menzella ◽  
Giulia Ghidoni ◽  
Carla Galeone ◽  
Silvia Capobelli ◽  
Chiara Scelfo ◽  
...  
Keyword(s):  
Innate Immunity ◽  
Severe Asthma ◽  
Viral Infections ◽  
Respiratory Infections ◽  
Antiviral Effect ◽  
Point Of View ◽  
Type I ◽  
Effector Cells ◽  
Viral Spread ◽  
Increased Risk

Viral respiratory infections are recognized risk factors for the loss of control of allergic asthma and the induction of exacerbations, both in adults and children. Severe asthma is more susceptible to virus-induced asthma exacerbations, especially in the presence of high IgE levels. In the course of immune responses to viruses, an initial activation of innate immunity typically occurs and the production of type I and III interferons is essential in the control of viral spread. However, the Th2 inflammatory environment still appears to be protective against viral infections in general and in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections as well. As for now, literature data, although extremely limited and preliminary, show that severe asthma patients treated with biologics don’t have an increased risk of SARS-CoV-2 infection or progression to severe forms compared to the non-asthmatic population. Omalizumab, an anti-IgE monoclonal antibody, exerts a profound cellular effect, which can stabilize the effector cells, and is becoming much more efficient from the point of view of innate immunity in contrasting respiratory viral infections. In addition to the antiviral effect, clinical efficacy and safety of this biological allow a great improvement in the management of asthma.

scholarly journals Interferon-Induced Transmembrane Protein 3 Is a Virus-Associated Protein Which Suppresses Porcine Reproductive and Respiratory Syndrome Virus Replication by Blocking Viral Membrane Fusion

2020 ◽  
Vol 94 (24) ◽  
Author(s):  
Angke Zhang ◽  
Hong Duan ◽  
Huijun Zhao ◽  
Huancheng Liao ◽  
Yongkun Du ◽  
...  
Keyword(s):  
Membrane Fusion ◽  
Transmembrane Protein ◽  
Fluorescent Labeling ◽  
Host Cells ◽  
Respiratory Syndrome Virus ◽  
Type I ◽  
Antiviral Immune Response ◽  
Viral Membrane ◽  
Viral Membrane Fusion

ABSTRACT Porcine reproductive and respiratory syndrome virus (PRRSV) infection eliminates production of type I interferons (IFNs) in host cells, which triggers an antiviral immune response through the induction of downstream IFN-stimulated genes (ISGs), thus escaping the fate of host-mediated clearance. The IFN-induced transmembrane 3 (IFITM3) has recently been identified as an ISG and plays a pivotal role against enveloped RNA viruses by restricting cell entry. However, the role of IFITM3 in PRRSV replication is unknown. The present study demonstrated that overexpression of IFITM3 suppresses PRRSV replication, while silencing of endogenous IFITM3 prominently promoted PRRSV replication. Additionally, it was shown that IFITM3 undergoes S-palmitoylation and ubiquitination modification, and both posttranslational modifications contribute to the anti-PRRSV activity of IFITM3. Further study showed that PRRSV particles are transported into endosomes and then into lysosomes during the early stages of infection, and confocal microscopy results revealed that PRRSV particles are transported to IFITM3-positive cellular vesicles. By using a single virus particle fluorescent labeling technique, we confirmed that IFITM3 can restrict PRRSV membrane fusion by inducing accumulation of cholesterol in cellular vesicles. Additionally, we found that both endogenous and exogenous IFITM3 are incorporated into newly producing PRRS virions and diminish viral intrinsic infectivity. By using cell coculture systems, we found that IFITM3 effectively restricted PRRSV intercellular transmission, which may have been caused by disrupted membrane fusion and reduced viral infectivity. In conclusion, our results demonstrate, for the first time, that swine IFITM3 interferes with the life cycle of PRRSV, and possibly other enveloped arteritis viruses, at multiple steps. IMPORTANCE Porcine reproductive and respiratory syndrome (PRRS), which is caused by PRRS virus (PRRSV), is of great economic significance to the swine industry. Due to the complicated immune escape mechanisms of PRRSV, there are no effective vaccines or therapeutic drugs currently available against PRRS. Identification of cellular factors and underlying mechanisms that establish an effective antiviral state against PRRSV can provide unique strategies for developing antiviral vaccines or drugs. As an interferon (IFN)-stimulated gene, the role of IFN-induced transmembrane 3 (IFITM3) in PRRSV infection has not been reported as of yet. In the present study, it was shown that IFITM3 can exert a potent anti-PRRSV effect, and PRRS virions are trafficked to IFITM3-containing cell vesicles, where viral membrane fusion is impaired by cholesterol accumulation that is induced by IFITM3. Additionally, both endogenous and exogenous IFITM3 are incorporated into newly assembled progeny virions, and this decreased their intrinsic infectivity.

scholarly journals ABCE1 Regulates RNase L-Induced Autophagy during Viral Infections

Viruses ◽  
2021 ◽  
Vol 13 (2) ◽  
pp. 315
Author(s):  
Barkha Ramnani ◽  
Praveen Manivannan ◽  
Sarah Jaggernauth ◽  
Krishnamurthy Malathi
Keyword(s):  
Cellular Proliferation ◽  
Viral Infections ◽  
Antiviral Effect ◽  
Host Protein ◽  
Type I ◽  
Rnase L ◽  
Oligoadenylate Synthetase ◽  
Interferon Stimulated Genes ◽  
Antiviral Effects ◽  
Increased Activity

Host response to a viral infection includes the production of type I interferon (IFN) and the induction of interferon-stimulated genes that have broad antiviral effects. One of the key antiviral effectors is the IFN-inducible oligoadenylate synthetase/ribonuclease L (OAS/RNase L) pathway, which is activated by double-stranded RNA to synthesize unique oligoadenylates, 2-5A, to activate RNase L. RNase L exerts an antiviral effect by cleaving diverse RNA substrates, limiting viral replication; many viruses have evolved mechanisms to counteract the OAS/RNase L pathway. Here, we show that the ATP-binding cassette E1 (ABCE1) transporter, identified as an inhibitor of RNase L, regulates RNase L activity and RNase L-induced autophagy during viral infections. ABCE1 knockdown cells show increased RNase L activity when activated by 2-5A. Compared to parental cells, the autophagy-inducing activity of RNase L in ABCE1-depleted cells is enhanced with early onset. RNase L activation in ABCE1-depleted cells inhibits cellular proliferation and sensitizes cells to apoptosis. Increased activity of caspase-3 causes premature cleavage of autophagy protein, Beclin-1, promoting a switch from autophagy to apoptosis. ABCE1 regulates autophagy during EMCV infection, and enhanced autophagy in ABCE1 knockdown cells promotes EMCV replication. We identify ABCE1 as a host protein that inhibits the OAS/RNase L pathway by regulating RNase L activity, potentially affecting antiviral effects.

scholarly journals Collision between Two Pandemics: Obesity and COVID-19 Viral Infection

2021 ◽  
pp. 27-37
Author(s):  
Jehan Saad Alrahimi
Keyword(s):  
Immune System ◽  
Chronic Inflammation ◽  
Complex Disease ◽  
Viral Infections ◽  
Host Cells ◽  
Organ Injury ◽  
Primary Immune Response ◽  
Type I ◽  
Novel Coronavirus ◽  
The Impact

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes the novel coronavirus disease 2019 (COVID-19). The principal risk factor for the development of serious forms of COVID-19 was found to be the precarious metabolic health. There are several mechanisms that are implicated in the seriousness of COVID-19 ranging from attenuation of immune system function to chronic inflammation. It is important to keep in mind that obesity is a complex disease when discussing the relation between obesity and the severity of COVID-19. An increasing body of proof links obesity to COVID-19. Obesity has an obvious role in the high incidence, symptoms severity and mortality rates of viral infections seen in obese patients. Adipose tissue shows a high expression of the angiotensin-converting enzyme 2 (ACE2), the receptor for entry of SARS-CoV-2 into host cells, so obese population exhibit higher vulnerability to COVID-19. The primary immune response is offered mainly by type-I interferon (IFN-I) that is suppressed in COVID-19. The pro-inflammatory state associated with obesity produces imbalance of the inflammatory response to COVID-19, as the cytokine storm found in subjects with serious disease form. Obesity is considered as chronic inflammation of low degree, so it shows a capacity for pathogenic immune amplification. In this review, the effect of obesity on the immune system is described. The authors described the dysfunctional immune responses caused by obesity that lead to organ injury in COVID-19 infection and impair the ability of patient to combat the virus. Further research is required to assess the impact of obesity control, immunonutrition and physical exercise in SARS-CoV-2 infection.

scholarly journals How Do Enveloped Viruses Exploit the Secretory Proprotein Convertases to Regulate Infectivity and Spread?

2021 ◽  
Author(s):  
Nabil G Seidah ◽  
Antonella Pasquato ◽  
Ursula Andreo
Keyword(s):  
Plasma Membranes ◽  
Viral Infections ◽  
Limited Proteolysis ◽  
Viral Envelope ◽  
Host Cells ◽  
Surface Glycoprotein ◽  
Type I ◽  
Proprotein Convertases ◽  
Enveloped Viruses ◽  
Surface Glycoproteins

Inhibition of the binding of enveloped viruses surface glycoproteins to host cell receptor(s) is a major target of vaccines and constitutes an efficient strategy to block viral entry and infection of various host cells and tissues. Cellular entry usually requires fusion of the viral envelope with host plasma membranes. Such entry mechanism is often preceded by “priming” and/or “activation” steps requiring limited proteolysis of the viral surface glycoprotein to expose a fusiogenic domain for efficient membrane juxtapositions. The 9-membered family of Proprotein Convertases related to Subtilisin/Kexin (PCSK) serine proteases (PC1, PC2, Furin, PC4, PC5, PACE4, PC7, SKI-1/S1P and PCSK9) participate in post-translational cleavages and/or regulation of multiple secretory proteins. The type-I membrane-bound Furin and SKI-1/S1P are the major convertases responsible for the processing of surface glycoproteins of enveloped viruses. Stefan Kunz has considerably contributed to define the role of SKI-1/S1P in the activation of arenaviruses causing hemorrhagic fever. Furin was recently implicated in the activation of the spike S-protein of SARS-CoV-2 and Furin-inhibitors are being tested as antivirals in COVID-19. Other members of the PCSK-family are also implicated in some viral infections such as PCSK9 in Dengue. Herein, we summarize the various functions of the PCSKs and present arguments whereby their inhibition could represent a powerful arsenal to limit viral infections causing the present and future pandemics.

scholarly journals Immunological Aspects Related to Viral Infections in Severe Asthma and the Role of Omalizumab

2021 ◽  
Author(s):  
Francesco Menzella ◽  
Giulia Ghidoni ◽  
Carla Galeone ◽  
Silvia Capobelli ◽  
Chiara Scelfo ◽  
...  
Keyword(s):  
Innate Immunity ◽  
Severe Asthma ◽  
Viral Infections ◽  
Respiratory Infections ◽  
Antiviral Effect ◽  
Point Of View ◽  
Type I ◽  
Effector Cells ◽  
Viral Spread ◽  
Increased Risk

Viral respiratory infections are recognized risk factors for the loss of control of allergic asthma and the induction of exacerbations, both in adults and children. Severe asthma is more susceptible to virus-induced asthma exacerbations, especially in the presence of high IgE levels. In the course of immune responses to viruses, an initial activation of innate immunity typically occurs and the production of type I and III interferons is essential in the control of viral spread. However, the Th2 inflammatory environment still appears to be protective against viral infections in general and in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections as well. As for now, literature data, although very limited and preliminary, show that severe asthma patients treated with biologics don’t have an increased risk of SARS-CoV-2 infection or progression to severe forms compared to the non-asthmatic population. Omalizumab, an anti-IgE monoclonal antibody, exerts a profound cellular effect, which is able to stabilize the effector cells becoming much more efficient from the point of view of innate immunity in contrasting respiratory viral infections. In addition to the antiviral effect, clinical efficacy and safety of this biological allows a great improvement in the management of asthma.

scholarly journals Meglumine acridone acetate, the ionic salt of CMA and N-methylglucamine, induces apoptosis in human PBMCs via the mitochondrial pathway

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Marina A. Plotnikova ◽  
Sergey A. Klotchenko ◽  
Artem A. Kiselev ◽  
Andrey N. Gorshkov ◽  
Anna-Polina S. Shurygina ◽  
...  
Keyword(s):  
Mononuclear Cells ◽  
Viral Infections ◽  
Human Peripheral Blood ◽  
Antiviral Effect ◽  
Response To Treatment ◽  
Type I ◽  
Sequencing Analysis ◽  
Human Pbmcs ◽  
Peripheral Blood Mononuclear ◽  
Docking Simulations

AbstractMeglumine acridone acetate (MA) is used in Russia for the treatment of influenza and other acute respiratory viral infections. It was assumed, until recently, that its antiviral effect was associated with its potential ability to induce type I interferon. Advanced studies, however, have shown the failure of 10-carboxymethyl-9-acridanone (CMA) to activate human STING. As such, MA’s antiviral properties are still undergoing clarification. To gain insight into MA’s mechanisms of action, we carried out RNA-sequencing analysis of global transcriptomes in MA-treated (MA+) human peripheral blood mononuclear cells (PBMCs). In response to treatment, approximately 1,223 genes were found to be differentially expressed, among which 464 and 759 were identified as either up- or down-regulated, respectively. To clarify the cellular and molecular processes taking place in MA+ cells, we performed a functional analysis of those genes. We have shown that evident MA subcellular localizations are: at the nuclear envelope; inside the nucleus; and diffusely in perinuclear cytoplasm. Postulating that MA may be a nuclear receptor agonist, we carried out docking simulations with PPARα and RORα ligand binding domains including prediction and molecular dynamics-based analysis of potential MA binding poses. Finally, we confirmed that MA treatment enhanced nuclear apoptosis in human PBMCs. The research presented here, in our view, indicates that: (i) MA activity is mediated by nuclear receptors; (ii) MA is a possible PPARα and/or RORα agonist; (iii) MA has an immunosuppressive effect; and (iv) MA induces apoptosis through the mitochondrial signaling pathway.

Inactivation of Herpes Simplex Virus by Photosensitizing Anthraquinones Isolated from Heterophyllaea pustulata

Planta Medica ◽  
2021 ◽  
Author(s):  
M. Laura Mugas ◽  
Juliana Marioni ◽  
Florencia Martinez ◽  
Juan J. Aguilar ◽  
José L. Cabrera ◽  
...  
Keyword(s):  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Antiviral Activity ◽  
Antiviral Effect ◽  
Neutral Red ◽  
Host Cells ◽  
Type I ◽  
Antiherpetic Activity ◽  
Simplex Virus

Abstract Heterophyllaea pustulata is a phototoxic plant from Argentina. Aerial parts extracts, high in photosensitizing anthraquinones, have shown in vitro antiviral activity. The purpose of this study was to study the antiherpetic activity of the main purified anthraquinones, even evaluating their competence as photodynamic sensitizers to photo-stimulate the antiviral effect. In vitro antiviral activity against Herpes Simplex virus type I and the photo-inactivation of viral particle were studied by the Neutral Red uptake test and observation of the cytopathic effect. Rubiadin 1-methyl ether and 5,5′-bisoranjidiol produced a significant effect (≥ 80% inhibition) with minimal damage to host cells (subtoxic concentration). Anthraquinones with poor antiherpetic activity at its maximum noncytotoxic concentration showed an important photo-stimulated effect, such is the case of soranjidiol and 5,5′-bisoranjidiol (28.0 ± 6.3 vs. 81.8 ± 2.1% and 15.5 ± 0.3 vs. 89.8 ± 1.7%, respectively). The study also proved the decrease of viral particles, necessary to reduce infection. Therefore, photosensitizing anthraquinones from natural resources could be proposed to develop new treatments for localized viral lesions with antimicrobial photodynamic therapy.

scholarly journals How Do Enveloped Viruses Exploit the Secretory Proprotein Convertases to Regulate Infectivity and Spread?

Viruses ◽  
2021 ◽  
Vol 13 (7) ◽  
pp. 1229
Author(s):  
Nabil G. Seidah ◽  
Antonella Pasquato ◽  
Ursula Andréo
Keyword(s):  
Plasma Membranes ◽  
Viral Infections ◽  
Limited Proteolysis ◽  
Viral Envelope ◽  
Host Cells ◽  
Surface Glycoprotein ◽  
Type I ◽  
Proprotein Convertases ◽  
Enveloped Viruses ◽  
Surface Glycoproteins

Inhibition of the binding of enveloped viruses surface glycoproteins to host cell receptor(s) is a major target of vaccines and constitutes an efficient strategy to block viral entry and infection of various host cells and tissues. Cellular entry usually requires the fusion of the viral envelope with host plasma membranes. Such entry mechanism is often preceded by “priming” and/or “activation” steps requiring limited proteolysis of the viral surface glycoprotein to expose a fusogenic domain for efficient membrane juxtapositions. The 9-membered family of Proprotein Convertases related to Subtilisin/Kexin (PCSK) serine proteases (PC1, PC2, Furin, PC4, PC5, PACE4, PC7, SKI-1/S1P, and PCSK9) participate in post-translational cleavages and/or regulation of multiple secretory proteins. The type-I membrane-bound Furin and SKI-1/S1P are the major convertases responsible for the processing of surface glycoproteins of enveloped viruses. Stefan Kunz has considerably contributed to define the role of SKI-1/S1P in the activation of arenaviruses causing hemorrhagic fever. Furin was recently implicated in the activation of the spike S-protein of SARS-CoV-2 and Furin-inhibitors are being tested as antivirals in COVID-19. Other members of the PCSK-family are also implicated in some viral infections, such as PCSK9 in Dengue. Herein, we summarize the various functions of the PCSKs and present arguments whereby their inhibition could represent a powerful arsenal to limit viral infections causing the present and future pandemics.

scholarly journals Effects of Type I Interferons on Friend Retrovirus Infection

2006 ◽  
Vol 80 (7) ◽  
pp. 3438-3444 ◽  
Author(s):  
Nicole Gerlach ◽  
Simone Schimmer ◽  
Siegfried Weiss ◽  
Ulrich Kalinke ◽  
Ulf Dittmer
Keyword(s):  
Viral Infections ◽  
Antiviral Effect ◽  
Immune Defense ◽  
Type I Interferons ◽  
Type I ◽  
Type I Ifn ◽  
Viral Loads ◽  
Friend Retrovirus ◽  
Retroviral Infections ◽  
Retrovirus Infection

ABSTRACT The type I interferon (IFN) response plays an important role in the control of many viral infections. However, since there is no rodent animal model for human immunodeficiency virus, the antiviral effect of IFN-α and IFN-β in retroviral infections is not well characterized. In the current study we have used the Friend virus (FV) model to determine the activity of type I interferons against a murine retrovirus. After FV infection of mice, IFN-α and IFN-β could be measured between 12 and 48 h in the serum. The important role of type I IFN in the early immune defense against FV became evident when mice deficient in IFN type I receptor (IFNAR−/−) or IFN-β (IFN-β−/−) were infected. The levels of FV infection in plasma and in spleen were higher in both strains of knockout mice than in C57BL/6 wild-type mice. This difference was induced by an antiviral effect of IFN-α and IFN-β and was most likely mediated by antiviral enzymes as well as by an effect of these IFNs on T-cell responses. Interestingly, the lack of IFNAR and IFN-β enhanced viral loads during acute and chronic FV infection. Exogenous IFN-α could be used therapeutically to reduce FV replication during acute but not chronic infection. These findings indicate that type I IFN plays an important role in the immediate antiviral defense against Friend retrovirus infection.

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