scholarly journals Evolutionary conflicts and adverse effects of antiviral factors

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Daniel Sauter ◽  
Frank Kirchhoff
Keyword(s):  
Cell Death ◽  
Adverse Effects ◽  
Antiviral Activity ◽  
Host Cell ◽  
Molecular Mechanisms ◽  
Viral Infections ◽  
Restriction Factors ◽  
Viral Pathogens ◽  
Trade Off ◽  
Viral Spread

Human cells are equipped with a plethora of antiviral proteins protecting them against invading viral pathogens. In contrast to apoptotic or pyroptotic cell death, which serves as ultima ratio to combat viral infections, these cell-intrinsic restriction factors may prevent or at least slow down viral spread while allowing the host cell to survive. Nevertheless, their antiviral activity may also have detrimental effects on the host. While the molecular mechanisms underlying the antiviral activity of restriction factors are frequently well investigated, potential undesired effects of their antiviral functions on the host cell are hardly explored. With a focus on antiretroviral proteins, we summarize in this review how individual restriction factors may exert adverse effects as trade-off for efficient defense against attacking pathogens.

scholarly journals At the crossroads of homoeostasis and disease: roles of the PACS proteins in membrane traffic and apoptosis

2009 ◽  
Vol 421 (1) ◽  
pp. 1-15 ◽  
Author(s):  
Robert T. Youker ◽  
Ujwal Shinde ◽  
Robert Day ◽  
Gary Thomas
Keyword(s):  
Cell Death ◽  
Mammalian Cells ◽  
Current Knowledge ◽  
Virus Assembly ◽  
Membrane Traffic ◽  
Endocytic Pathway ◽  
Viral Pathogens ◽  
Viral Spread ◽  
Disease States ◽  
Organ Systems

The endomembrane system in mammalian cells has evolved over the past two billion years from a simple endocytic pathway in a single-celled primordial ancestor to complex networks supporting multicellular structures that form metazoan tissue and organ systems. The increased organellar complexity of metazoan cells requires additional trafficking machinery absent in yeast or other unicellular organisms to maintain organ homoeostasis and to process the signals that control proliferation, differentiation or the execution of cell death programmes. The PACS (phosphofurin acidic cluster sorting) proteins are one such family of multifunctional membrane traffic regulators that mediate organ homoeostasis and have important roles in diverse pathologies and disease states. This review summarizes our current knowledge of the PACS proteins, including their structure and regulation in cargo binding, their genetics, their roles in secretory and endocytic pathway traffic, interorganellar communication and how cell-death signals reprogramme the PACS proteins to regulate apoptosis. We also summarize our current understanding of how PACS genes are dysregulated in cancer and how viral pathogens ranging from HIV-1 to herpesviruses have evolved to usurp the PACS sorting machinery to promote virus assembly, viral spread and immunoevasion.

scholarly journals Nutraceuticals in Viral Infections: An Overview of the Immunomodulating Properties

Nutrients ◽  
2021 ◽  
Vol 13 (7) ◽  
pp. 2410
Author(s):  
Giorgio Costagliola ◽  
Giulia Nuzzi ◽  
Erika Spada ◽  
Pasquale Comberiati ◽  
Elvira Verduci ◽  
...  
Keyword(s):  
Immune Response ◽  
Inflammatory Cytokines ◽  
Molecular Mechanisms ◽  
Viral Infections ◽  
Coenzyme Q ◽  
Antimicrobial Effect ◽  
Common Element ◽  
Viral Pathogens ◽  
Differentiation And Proliferation ◽  
Pro Inflammatory Cytokines

Nutraceuticals, including vitamin D, vitamin A, zinc, lactoferrin, polyphenols coenzyme Q, magnesium, and selenium, are implicated in the modulation of the complex molecular pathways involved in the immune response against viral pathogens. A common element of the activity of nutraceuticals is their ability to enhance the innate immune response against pathogens by acting on the major cellular subsets and inducing the release of pro-inflammatory cytokines and antimicrobial peptides. In some cases, this action is accompanied by a direct antimicrobial effect, as evidenced in the specific case of lactoferrin. Furthermore, nutraceuticals act through complex molecular mechanisms to minimize the damage caused by the activation of the immune system against pathogens, reducing the oxidative damage, influencing the antigen presentation, enhancing the differentiation and proliferation of regulatory T cells, driving the differentiation of lymphocyte subsets, and modulating the production of pro-inflammatory cytokines. In this paper, we review the main molecular mechanisms responsible for the immunomodulatory function of nutraceuticals, focusing on the most relevant aspects for the prevention and treatment of viral infections.

scholarly journals Expression of Ifnlr1 on Intestinal Epithelial Cells Is Critical to the Antiviral Effects of Interferon Lambda against Norovirus and Reovirus

2017 ◽  
Vol 91 (7) ◽  
Author(s):  
Megan T. Baldridge ◽  
Sanghyun Lee ◽  
Judy J. Brown ◽  
Nicole McAllister ◽  
Kelly Urbanek ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Antiviral Activity ◽  
Viral Infections ◽  
Intestinal Epithelial Cells ◽  
Intestinal Epithelial ◽  
Murine Norovirus ◽  
Intestinal Tissue ◽  
Viral Pathogens ◽  
Fecal Shedding ◽  
Antiviral Effects

ABSTRACT Lambda interferon (IFN-λ) has potent antiviral effects against multiple enteric viral pathogens, including norovirus and rotavirus, in both preventing and curing infection. Because the intestine includes a diverse array of cell types, however, the cell(s) upon which IFN-λ acts to exert its antiviral effects is unclear. Here, we sought to identify IFN-λ-responsive cells by generation of mice with lineage-specific deletion of the receptor for IFN-λ, Ifnlr1. We found that expression of IFNLR1 on intestinal epithelial cells (IECs) in the small intestine and colon is required for enteric IFN-λ antiviral activity. IEC Ifnlr1 expression also determines the efficacy of IFN-λ in resolving persistent murine norovirus (MNoV) infection and regulates fecal shedding and viral titers in tissue. Thus, the expression of Ifnlr1 by IECs is necessary for the response to both endogenous and exogenous IFN-λ. We further demonstrate that IEC Ifnlr1 expression is required for the sterilizing innate immune effects of IFN-λ by extending these findings in Rag1-deficient mice. Finally, we assessed whether our findings pertained to multiple viral pathogens by infecting mice specifically lacking IEC Ifnlr1 expression with reovirus. These mice phenocopied Ifnlr1-null animals, exhibiting increased intestinal tissue titers and enhanced reovirus fecal shedding. Thus, IECs are the critical cell type responding to IFN-λ to control multiple enteric viruses. This is the first genetic evidence that supports an essential role for IECs in IFN-λ-mediated control of enteric viral infection, and these findings provide insight into the mechanism of IFN-λ-mediated antiviral activity. IMPORTANCE Human noroviruses (HNoVs) are the leading cause of epidemic gastroenteritis worldwide. Type III interferons (IFN-λ) control enteric viral infections in the gut and have been shown to cure mouse norovirus, a small-animal model for HNoVs. Using a genetic approach with conditional knockout mice, we identified IECs as the dominant IFN-λ-responsive cells in control of enteric virus infection in vivo. Upon murine norovirus or reovirus infection, Ifnlr1 depletion in IECs largely recapitulated the phenotype seen in Ifnlr1 −/− mice of higher intestinal tissue viral titers and increased viral shedding in the stool. Moreover, IFN-λ-mediated sterilizing immunity against murine norovirus requires the capacity of IECs to respond to IFN-λ. These findings clarify the mechanism of action of this cytokine and emphasize the therapeutic potential of IFN-λ for treating mucosal viral infections.

scholarly journals Unraveling the Molecular Mechanism of Traditional Chinese Medicine: Formulas Against Acute Airway Viral Infections as Examples

Molecules ◽  
2019 ◽  
Vol 24 (19) ◽  
pp. 3505 ◽  
Author(s):  
Yi Shin Eng ◽  
Chien Hsing Lee ◽  
Wei Chang Lee ◽  
Ching Chun Huang ◽  
Jung San Chang
Keyword(s):  
Chinese Medicine ◽  
Herbal Medicine ◽  
Traditional Chinese Medicine ◽  
Adverse Effects ◽  
Drug Interactions ◽  
Clinical Studies ◽  
Molecular Mechanisms ◽  
Viral Infections ◽  
Herbal Medicines ◽  
Clinical Effects

Herbal medicine, including traditional Chinese medicine (TCM), is widely used worldwide. Herbs and TCM formulas contain numerous active molecules. Basically, they are a kind of cocktail therapy. Herb-drug, herb-food, herb-herb, herb-microbiome, and herb-disease interactions are complex. There is potential for both benefit and harm, so only after understanding more of their mechanisms and clinical effects can herbal medicine and TCM be helpful to users. Many pharmacologic studies have been performed to unravel the molecular mechanisms; however, basic and clinical studies of good validity are still not enough to translate experimental results into clinical understanding and to provide tough evidence for better use of herbal medicines. There are still issues regarding the conflicting pharmacologic effects, pharmacokinetics, drug interactions, adverse and clinical effects of herbal medicine and TCM. Understanding study validation, pharmacologic effects, drug interactions, indications and clinical effects, adverse effects and limitations, can all help clinicians in providing adequate suggestions to patients. At present, it would be better to use herbs and TCM formulas according to their traditional indications matching the disease pathophysiology and their molecular mechanisms. To unravel the molecular mechanisms and understand the benefits and harms of herbal medicine and TCM, there is still much work to be done.

scholarly journals Targeting CK2 mediated signaling to impair/tackle SARS-CoV-2 infection: a computational biology approach

2021 ◽  
Vol 27 (1) ◽  
Author(s):  
Jamilet Miranda ◽  
Ricardo Bringas ◽  
Jorge Fernandez-de-Cossio ◽  
Yasser Perera-Negrin
Keyword(s):  
Immune Response ◽  
Antiviral Activity ◽  
Computational Biology ◽  
Rna Splicing ◽  
Molecular Mechanisms ◽  
Kinase Activity ◽  
Viral Infections ◽  
Antagonistic Effect ◽  
Functional Enrichment ◽  
Ck2 Kinase

Abstract Background Similarities in the hijacking mechanisms used by SARS-CoV-2 and several types of cancer, suggest the repurposing of cancer drugs to treat Covid-19. CK2 kinase antagonists have been proposed for cancer treatment. A recent study in cells infected with SARS-CoV-2 found a significant CK2 kinase activity, and the use of a CK2 inhibitor showed antiviral responses. CIGB-300, originally designed as an anticancer peptide, is an antagonist of CK2 kinase activity that binds to the CK2 phospho-acceptor sites. Recent preliminary results show the antiviral activity of CIGB-300 using a surrogate model of coronavirus. Here we present a computational biology study that provides evidence, at the molecular level, of how CIGB-300 may interfere with the SARS-CoV-2 life cycle within infected human cells. Methods Sequence analyses and data from phosphorylation studies were combined to predict infection-induced molecular mechanisms that can be interfered by CIGB-300. Next, we integrated data from multi-omics studies and data focusing on the antagonistic effect on the CK2 kinase activity of CIGB-300. A combination of network and functional enrichment analyses was used. Results Firstly, from the SARS-CoV studies, we inferred the potential incidence of CIGB-300 in SARS-CoV-2 interference on the immune response. Afterwards, from the analysis of multiple omics data, we proposed the action of CIGB-300 from the early stages of viral infections perturbing the virus hijacking of RNA splicing machinery. We also predicted the interference of CIGB-300 in virus-host interactions that are responsible for the high infectivity and the particular immune response to SARS-CoV-2 infection. Furthermore, we provided evidence of how CIGB-300 may participate in the attenuation of phenotypes related to muscle, bleeding, coagulation and respiratory disorders. Conclusions Our computational analysis proposes putative molecular mechanisms that support the antiviral activity of CIGB-300.

scholarly journals Autocrine and paracrine interferon signaling as 'ring vaccination' and 'contact tracing' strategies to suppress virus infection in a host

2020 ◽  
Author(s):  
G. Michael Lavigne ◽  
Hayley Russell ◽  
Barbara Sherry ◽  
Ruian Ke
Keyword(s):  
Molecular Mechanisms ◽  
Viral Infections ◽  
Population Level ◽  
Host Cells ◽  
Contact Tracing ◽  
Interferon Response ◽  
Paracrine Signaling ◽  
Viral Spread ◽  
Ring Vaccination ◽  
Spread Of Infection

The innate immune response, particularly the interferon response, represents a first line of defense against viral infections. The interferon molecules produced from infected cells act through autocrine and paracrine signaling to turn host cells into an antiviral state. Although the molecular mechanisms of IFN signaling have been well characterized, how the interferon response collectively contribute to the regulation of host cells to stop or suppress viral infection during early infection remain unclear. Here, we use mathematical models to delineate the roles of the autocrine and the paracrine signaling, and show that their impacts on viral spread are dependent on how infection proceeds. In particular, we found that when infection is well-mixed, the paracrine signaling is not as effective; in contrast, when infection spreads in a spatial manner, a likely scenario during initial infection in tissue, the paracrine signaling can impede the spread of infection by decreasing the number of susceptible cells close to the site of infection. Furthermore, we argue that the interferon response can be seen as a parallel to population-level epidemic prevention strategies such as contact tracing or ring vaccination. Thus, our results here may have implications for the outbreak control at the population scale more broadly.

scholarly journals Autocrine and paracrine interferon signalling as ‘ring vaccination’ and ‘contact tracing’ strategies to suppress virus infection in a host

2021 ◽  
Vol 288 (1945) ◽  
pp. 20203002
Author(s):  
G. Michael Lavigne ◽  
Hayley Russell ◽  
Barbara Sherry ◽  
Ruian Ke
Keyword(s):  
Molecular Mechanisms ◽  
Viral Infections ◽  
Population Level ◽  
Host Cells ◽  
Contact Tracing ◽  
Interferon Response ◽  
Paracrine Signalling ◽  
Viral Spread ◽  
Ring Vaccination ◽  
Spread Of Infection

The innate immune response, particularly the interferon response, represents a first line of defence against viral infections. The interferon molecules produced from infected cells act through autocrine and paracrine signalling to turn host cells into an antiviral state. Although the molecular mechanisms of IFN signalling have been well characterized, how the interferon response collectively contribute to the regulation of host cells to stop or suppress viral infection during early infection remain unclear. Here, we use mathematical models to delineate the roles of the autocrine and the paracrine signalling, and show that their impacts on viral spread are dependent on how infection proceeds. In particular, we found that when infection is well-mixed, the paracrine signalling is not as effective; by contrast, when infection spreads in a spatial manner, a likely scenario during initial infection in tissue, the paracrine signalling can impede the spread of infection by decreasing the number of susceptible cells close to the site of infection. Furthermore, we argue that the interferon response can be seen as a parallel to population-level epidemic prevention strategies such as ‘contact tracing’ or ‘ring vaccination’. Thus, our results here may have implications for the outbreak control at the population scale more broadly.

scholarly journals The Antagonism of HIV-1 Nef to SERINC5 Particle Infectivity Restriction Involves the Counteraction of Virion-Associated Pools of the Restriction Factor

2016 ◽  
Vol 90 (23) ◽  
pp. 10915-10927 ◽  
Author(s):  
Birthe Trautz ◽  
Virginia Pierini ◽  
Rebecka Wombacher ◽  
Bettina Stolp ◽  
Amanda J. Chase ◽  
...  
Keyword(s):  
Antiviral Activity ◽  
Cell Surface ◽  
Host Cell ◽  
Molecular Mechanisms ◽  
Functional Characterization ◽  
Cell Surface Receptor ◽  
Restriction Factor ◽  
Virion Incorporation ◽  
Hiv 1

ABSTRACTSERINC3 (serine incorporator 3) and SERINC5 are recently identified host cell inhibitors of HIV-1 particle infectivity that are counteracted by the viral pathogenesis factor Nef. Here we confirm that HIV-1 Nef, but not HIV-1 Vpu, antagonizes the particle infectivity restriction of SERINC5. SERINC5 antagonism occurred in parallel with other Nef activities, including cell surface receptor downregulation,trans-Golgi network targeting of Lck, and inhibition of host cell actin dynamics. Interaction motifs with host cell endocytic machinery and the Nef-associated kinase complex, as well as CD4 cytoplasmic tail/HIV-1 protease, were identified as essential Nef determinants for SERINC5 antagonism. Characterization of antagonism-deficient Nef mutants revealed that counteraction of SERINC5 occurs in the absence of retargeting of the restriction factor to intracellular compartments and reduction of SERINC5 cell surface density is insufficient for antagonism. Consistent with virion incorporation of SERINC5 being a prerequisite for its antiviral activity, the infectivity of HIV-1 particles produced in the absence of a SERINC5 antagonist decreased with increasing amounts of virion SERINC5. At low levels of SERINC5 expression, enhancement of virion infectivity by Nef was associated with reduced virion incorporation of SERINC5 and antagonism-defective Nef mutants failed to exclude SERINC5 from virions. However, at elevated levels of SERINC5 expression, Nef maintained infectious HIV particles, despite significant virion incorporation of the restriction factor. These results suggest that in addition to virion exclusion, Nef employs a cryptic mechanism to antagonize virion-associated SERINC5. The involvement of common determinants suggests that the antagonism of Nef to SERINC5 and the downregulation of cell surface CD4 by Nef involve related molecular mechanisms.IMPORTANCEHIV-1 Nef critically determines virus spread and disease progression in infected individuals by incompletely defined mechanisms. SERINC3 and SERINC5 were recently identified as potent inhibitors of HIV particle infectivity whose antiviral activity is antagonized by HIV-1 Nef. To address the mechanism of SERINC5 antagonism, we identified four molecular determinants of Nef antagonism that are all linked to the mechanism by which Nef downregulates cell surface CD4. Functional characterization of these mutants revealed that endosomal targeting and cell surface downregulation of SERINC5 are dispensable and insufficient for antagonism, respectively. In contrast, virion exclusion and antagonism of SERINC5 were correlated; however, Nef was also able to enhance the infectivity of virions that incorporated robust levels of SERINC5. These results suggest that the antagonism of HIV-1 Nef to SERINC5 restriction of virion infectivity is mediated by a dual mechanism that is related to CD4 downregulation.

scholarly journals Epigenetic Regulation Mechanisms in Viral Infections: A Special Focus on COVID-19

2021 ◽  
Author(s):  
Burcu Biterge Süt
Keyword(s):  
Host Cell ◽  
Epigenetic Regulation ◽  
Viral Entry ◽  
Molecular Mechanisms ◽  
Viral Infections ◽  
Health Concern ◽  
Special Focus ◽  
Comprehensive Overview ◽  
Regulation Mechanisms ◽  
Host Metabolism

The outbreak of Coronavirus Disease-2019 (Covid-19), caused by a novel and highly pathogenic coronavirus (severe acute respiratory syndrome coronavirus-2, SARS-CoV-2), is a persisting global health concern. Research so far has successfully identified the molecular mechanisms of viral entry, alterations within the host cell upon infection, and the stimulation of an immune response to fight it. One of the most important cellular regulatory machineries within the host cell to be affected by the SARS-CoV-2 infection is epigenetic regulation, which modulates transcriptional activity by DNA sequence-independent factors such as DNA-methylation, RNA interference and histone modifications. Several studies in the literature have previously reported epigenetic alterations within the host due to infections of the Coronaviridae family viruses including SARS-CoV and MERS-CoV that antagonized immune system activation. Recent studies have also identified epigenetic dysregulation of host metabolism by SARS-CoV-2 infection, linking epigenetic mechanisms with the pathophysiology and illness severity of Covid-19. Therefore, this book chapter aims to provide a comprehensive overview of the epigenetic regulation mechanisms in viral infections with a special focus on SARS-CoV-2 infection.

scholarly journals Emerging Role of PYHIN Proteins as Antiviral Restriction Factors

Viruses ◽  
2020 ◽  
Vol 12 (12) ◽  
pp. 1464
Author(s):  
Matteo Bosso ◽  
Frank Kirchhoff
Keyword(s):  
Viral Infections ◽  
Specific Pattern ◽  
Immune Defense ◽  
Innate Immune ◽  
Cellular Proteins ◽  
Restriction Factors ◽  
First Line ◽  
Viral Pathogens ◽  
Molecular Patterns

Innate immune sensors and restriction factors are cellular proteins that synergize to build an effective first line of defense against viral infections. Innate sensors are usually constitutively expressed and capable of detecting pathogen-associated molecular patterns (PAMPs) via specific pattern recognition receptors (PRRs) to stimulate the immune response. Restriction factors are frequently upregulated by interferons (IFNs) and may inhibit viral pathogens at essentially any stage of their replication cycle. Members of the Pyrin and hematopoietic interferon-inducible nuclear (HIN) domain (PYHIN) family have initially been recognized as important sensors of foreign nucleic acids and activators of the inflammasome and the IFN response. Accumulating evidence shows, however, that at least three of the four members of the human PYHIN family restrict viral pathogens independently of viral sensing and innate immune activation. In this review, we provide an overview on the role of human PYHIN proteins in the innate antiviral immune defense and on viral countermeasures.

Sign in / Sign up

Export Citation Format

Share Document