scholarly journals Interferon-Independent Restriction of RNA Virus Entry and Replication by a Class of Damage-Associated Molecular Patterns

mBio ◽  
2021 ◽  
Vol 12 (2) ◽  
Author(s):  
Michael J. Ernandes ◽  
Jonathan C. Kagan
Keyword(s):  
Virus Infection ◽  
Viral Replication ◽  
Mammalian Cells ◽  
Rna Virus ◽  
Interferon Response ◽  
Oxidized Lipids ◽  
Defensive Responses ◽  
Molecular Patterns ◽  
Interferon Responses ◽  
Damage Associated Molecular Patterns

ABSTRACT Mammalian cells detect microbial molecules known as pathogen-associated molecular patterns (PAMPs) as indicators of potential infection. Upon PAMP detection, diverse defensive responses are induced by the host, including those that promote inflammation and cell-intrinsic antimicrobial activities. Host-encoded molecules released from dying or damaged cells, known as damage-associated molecular patterns (DAMPs), also induce defensive responses. Both DAMPs and PAMPs are recognized for their inflammatory potential, but only the latter are well established to stimulate cell-intrinsic host defense. Here, we report a class of DAMPs that engender an antiviral state in human epithelial cells. These DAMPs include oxPAPC (oxidized 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine), PGPC (1-palmitoyl-2-glutaryl phosphatidylcholine), and POVPC [1-palmitoyl-2-(5-oxovaleroyl)-sn-glycero-3-phosphatidylcholine], oxidized lipids that are naturally released from dead or dying cells. Exposing cells to these DAMPs prior to vesicular stomatitis virus (VSV) infection limits viral replication. Mechanistically, these DAMPs prevent viral entry, thereby limiting the percentage of cells that are productively infected and consequently restricting viral load. We found that the antiviral actions of oxidized lipids are distinct from those mediated by the PAMP Poly I:C, in that the former induces a more rapid antiviral response without the induction of the interferon response. These data support a model whereby interferon-independent defensive activities can be induced by DAMPs, which may limit viral replication before PAMP-mediated interferon responses are induced. This antiviral activity may impact viruses that disrupt interferon responses in the oxygenated environment of the lung, such as influenza virus and SARS-CoV-2. IMPORTANCE In this work, we explored how a class of oxidized lipids, spontaneously created during tissue damage and unprogrammed cell lysis, block the earliest events in RNA virus infection in the human epithelium. This gives us novel insight into the ways that we view infection models, unveiling a built-in mechanism to slow viral growth that neither engages the interferon response nor is subject to known viral antagonism. These oxidized phospholipids act prior to infection, allowing time for other, better-known innate immune mechanisms to take effect. This discovery broadens our understanding of host defenses, introducing a soluble factor that alters the cellular environment to protect from RNA virus infection.

scholarly journals Sequence-Specific Modifications Enhance the Broad-Spectrum Antiviral Response Activated by RIG-I Agonists

2015 ◽  
Vol 89 (15) ◽  
pp. 8011-8025 ◽  
Author(s):  
Cindy Chiang ◽  
Vladimir Beljanski ◽  
Kevin Yin ◽  
David Olagnier ◽  
Fethia Ben Yebdri ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Virus Infection ◽  
Inflammatory Responses ◽  
Rna Viruses ◽  
Rna Virus ◽  
A549 Cells ◽  
Antiviral Response ◽  
Interferon Response

ABSTRACTThe cytosolic RIG-I (retinoic acid-inducible gene I) receptor plays a pivotal role in the initiation of the immune response against RNA virus infection by recognizing short 5′-triphosphate (5′ppp)-containing viral RNA and activating the host antiviral innate response. In the present study, we generated novel 5′ppp RIG-I agonists of varieous lengths, structures, and sequences and evaluated the generation of the antiviral and inflammatory responses in human epithelial A549 cells, human innate immune primary cells, and murine models of influenza and chikungunya viral pathogenesis. A 99-nucleotide, uridine-rich hairpin 5′pppRNA termed M8 stimulated an extensive and robust interferon response compared to other modified 5′pppRNA structures, RIG-I aptamers, or poly(I·C). Interestingly, manipulation of the primary RNA sequence alone was sufficient to modulate antiviral activity and inflammatory response, in a manner dependent exclusively on RIG-I and independent of MDA5 and TLR3. Both prophylactic and therapeutic administration of M8 effectively inhibited influenza virus and dengue virus replicationin vitro. Furthermore, multiple strains of influenza virus that were resistant to oseltamivir, an FDA-approved therapeutic treatment for influenza, were highly sensitive to inhibition by M8. Finally, prophylactic M8 treatmentin vivoprolonged survival and reduced lung viral titers of mice challenged with influenza virus, as well as reducing chikungunya virus-associated foot swelling and viral load. Altogether, these results demonstrate that 5′pppRNA can be rationally designed to achieve a maximal RIG-I-mediated protective antiviral response against human-pathogenic RNA viruses.IMPORTANCEThe development of novel therapeutics to treat human-pathogenic RNA viral infections is an important goal to reduce spread of infection and to improve human health and safety. This study investigated the design of an RNA agonist with enhanced antiviral and inflammatory properties against influenza, dengue, and chikungunya viruses. A novel, sequence-dependent, uridine-rich RIG-I agonist generated a protective antiviral responsein vitroandin vivoand was effective at concentrations 100-fold lower than prototype sequences or other RNA agonists, highlighting the robust activity and potential clinical use of the 5′pppRNA against RNA virus infection. Altogether, the results identify a novel, sequence-specific RIG-I agonist as an attractive therapeutic candidate for the treatment of a broad range of RNA viruses, a pressing issue in which a need for new and more effective options persists.

scholarly journals A simple model of COVID-19 explains disease severity and the effect of treatments

2021 ◽  
Author(s):  
Steven Sanche ◽  
Tyler Cassidy ◽  
Pinghan Chu ◽  
Alan S. Perelson ◽  
Ruy M. Ribeiro ◽  
...  
Keyword(s):  
Disease Severity ◽  
Treatment Strategies ◽  
Clinical Findings ◽  
Interferon Response ◽  
Type I ◽  
Infected Cells ◽  
New Treatment ◽  
High Level ◽  
Molecular Patterns ◽  
Damage Associated Molecular Patterns

ABSTRACTConsiderable effort was made to better understand why some people suffer from severe COVID-19 while others remain asymptomatic. This has led to important clinical findings; people with severe COVID-19 generally experience persistently high levels of inflammation, slower viral load decay, display a dysregulated type-I interferon response, have less active natural killer cells and increased levels of neutrophil extracellular traps. How these findings are connected to the pathogenesis of COVID-19 remains unclear. We propose a mathematical model that sheds light on this issue. The model focuses on cells that trigger inflammation through molecular patterns: infected cells carrying pathogen-associated molecular patterns (PAMPs) and damaged cells producing damage-associated molecular patterns (DAMPs). The former signals the presence of pathogens while the latter signals danger such as hypoxia or the lack of nutrients. Analyses show that SARS-CoV-2 infections can lead to a self-perpetuating feedback loop between DAMP expressing cells and inflammation. It identifies the inability to quickly clear PAMPs and DAMPs as the main contributor to hyperinflammation. The model explains clinical findings and the conditional impact of treatments on disease severity. The simplicity of the model and its high level of consistency with clinical findings motivate its use for the formulation of new treatment strategies.

scholarly journals Itaconate and derivatives reduce interferon responses and inflammation in influenza A virus infection

2021 ◽  
Author(s):  
Aaqib Sohail ◽  
Azeem A. Iqbal ◽  
Nishika Sahini ◽  
Mohamed Tantawy ◽  
Moritz Winterhoff ◽  
...  
Keyword(s):  
Virus Infection ◽  
Viral Replication ◽  
Influenza A Virus ◽  
Influenza A ◽  
Pulmonary Inflammation ◽  
Transcriptome Profiling ◽  
Host Responses ◽  
Monocytes And Macrophages ◽  
Influenza A Virus Infection ◽  
Interferon Responses

AbstractItaconate has recently emerged as a metabolite with immunomodulatory properties. We evaluated effects of endogenous itaconate and exogenous itaconate, dimethyl-, and 4-octyl-itaconate on host responses to influenza A virus infection. Infection induced ACOD1 (the enzyme catalyzing itaconate synthesis) mRNA in monocytes and macrophages, which correlated with viral replication and was abrogated by itaconate treatment. Pulmonary inflammation and weight loss were greater in Acod1-/- than wild-type mice, and ectopic synthesis of itaconate in human epithelial cells reduced infection-induced inflammation. The compounds induced different recruitment programs in infected human macrophages, and transcriptome profiling revealed that they reversed infection-triggered interferon responses and modulated inflammation in cell lines, PBMC, and lung tissue. Single-cell RNA sequencing of PBMC revealed that infection induced ACOD1 exclusively in monocytes, whereas treatment silenced IFN-responses in monocytes, lymphocytes, and NK cells. Viral replication did not increase under treatment despite the dramatically repressed IFN responses, but 4-octyl itaconate inhibited viral transcription in PBMC. The results reveal dramatic reprogramming of host responses by itaconate and derivatives and their potential as adjunct treatments for hyperinflammation in viral infection.

scholarly journals MAPK Phosphatase 5 Expression Induced by Influenza and Other RNA Virus Infection Negatively Regulates IRF3 Activation and Type I Interferon Response

Cell Reports ◽  
2015 ◽  
Vol 10 (10) ◽  
pp. 1722-1734 ◽  
Author(s):  
Sharmy J. James ◽  
Huipeng Jiao ◽  
Hong-Ying Teh ◽  
Hirotaka Takahashi ◽  
Chin Wen Png ◽  
...  
Keyword(s):  
Virus Infection ◽  
Type I Interferon ◽  
Rna Virus ◽  
Interferon Response ◽  
Type I ◽  
Mapk Phosphatase ◽  
Irf3 Activation

scholarly journals Potent programmable antiviral against dengue virus in primary human cells by Cas13b RNP with short spacer and delivery by virus-like particle

2020 ◽  
Author(s):  
Ekapot Singsuksawat ◽  
Suppachoke Onnome ◽  
Pratsaneeyaporn Posiri ◽  
Amporn Suphatrakul ◽  
Nittaya Srisuk ◽  
...  
Keyword(s):  
Virus Infection ◽  
Dengue Virus ◽  
Mammalian Cells ◽  
Sequence Data ◽  
Rna Virus ◽  
Genetic Material ◽  
Target Cells ◽  
Emerging Viruses ◽  
Spacer Length ◽  
Virus Like Particle

SummaryWith sequencing as a standard frontline protocol to identify emerging viruses such zika virus and SARS-CoV2, direct utilization of sequence data to program antivirals against the viruses could accelerate drug development to treat their infections. CRISPR-Cas effectors are promising candidates that could be programmed to inactivate viral genetic material based on sequence data but several challenges such as delivery and design of effective crRNA need to be addressed to realize practical use. Here, we showed that virus-like particle (VLP) could deliver PspCas13b-crRNA ribonucleoprotein (RNP) in nanomolar range to efficiently suppress dengue virus infection in primary human target cells. Shortening spacer length could significantly enhance RNA-targeting efficiency of PspCas13b in mammalian cells compared to the natural length of 30 nucleotides without compromising multiplex targeting by a crRNA array. Our results demonstrate the potentials of applying PspCas13b RNP to suppress RNA virus infection, with implications in targeting host RNA as well.

scholarly journals FAS-associated factor-1 positively regulates type I interferon response to RNA virus infection by targeting NLRX1

2017 ◽  
Vol 13 (5) ◽  
pp. e1006398 ◽  
Author(s):  
Jae-Hoon Kim ◽  
Min-Eun Park ◽  
Chamilani Nikapitiya ◽  
Tae-Hwan Kim ◽  
Md Bashir Uddin ◽  
...  
Keyword(s):  
Virus Infection ◽  
Type I Interferon ◽  
Rna Virus ◽  
Interferon Response ◽  
Type I ◽  
Associated Factor

scholarly journals STING-dependent translation inhibition restricts RNA virus replication

2018 ◽  
Vol 115 (9) ◽  
pp. E2058-E2067 ◽  
Author(s):  
Kate M. Franz ◽  
William J. Neidermyer ◽  
Yee-Joo Tan ◽  
Sean P. J. Whelan ◽  
Jonathan C. Kagan
Keyword(s):  
Virus Infection ◽  
Mammalian Cells ◽  
Viral Infections ◽  
Rna Virus ◽  
Virus Infections ◽  
Dna Viruses ◽  
Translation Inhibition ◽  
Basal Expression ◽  
Antiviral Activities ◽  
Mitochondrial Antiviral Signaling

In mammalian cells, IFN responses that occur during RNA and DNA virus infections are activated by distinct signaling pathways. The RIG-I–like-receptors (RLRs) bind viral RNA and engage the adaptor MAVS (mitochondrial antiviral signaling) to promote IFN expression, whereas cGAS (cGMP–AMP synthase) binds viral DNA and activates an analogous pathway via the protein STING (stimulator of IFN genes). In this study, we confirm that STING is not necessary to induce IFN expression during RNA virus infection but also find that STING is required to restrict the replication of diverse RNA viruses. The antiviral activities of STING were not linked to its ability to regulate basal expression of IFN-stimulated genes, activate transcription, or autophagy. Using vesicular stomatitis virus as a model, we identified a requirement of STING to inhibit translation during infection and upon transfection of synthetic RLR ligands. This inhibition occurs at the level of translation initiation and restricts the production of viral and host proteins. The inability to restrict translation rendered STING-deficient cells 100 times more likely to support productive viral infections than wild-type counterparts. Genetic analysis linked RNA sensing by RLRs to STING-dependent translation inhibition, independent of MAVS. Thus, STING has dual functions in host defense, regulating protein synthesis to prevent RNA virus infection and regulating IFN expression to restrict DNA viruses.

scholarly journals Pattern recognition receptors in GtoPdb v.2021.3

2021 ◽  
Vol 2021 (3) ◽  
Author(s):  
Clare Bryant ◽  
Tom P. Monie
Keyword(s):  
Pattern Recognition ◽  
Cell Attachment ◽  
Pattern Recognition Receptors ◽  
Interferon Response ◽  
Type I ◽  
Intracellular Proteins ◽  
Molecular Patterns ◽  
Damage Associated Molecular Patterns ◽  
Microbial Agents ◽  
Oligomerization Domain

Pattern Recognition Receptors (PRRs, [104]) (nomenclature as agreed by NC-IUPHAR sub-committee on Pattern Recognition Receptors, [18]) participate in the innate immune response to microbial agents, the stimulation of which leads to activation of intracellular enzymes and regulation of gene transcription. PRRs express multiple leucine-rich regions to bind a range of microbially-derived ligands, termed PAMPs or pathogen-associated molecular patterns or endogenous ligands, termed DAMPS or damage-associated molecular patterns. These include peptides, carbohydrates, peptidoglycans, lipoproteins, lipopolysaccharides, and nucleic acids. PRRs include both cell-surface and intracellular proteins. PRRs may be divided into signalling-associated members, identified here, and endocytic members, the function of which appears to be to recognise particular microbial motifs for subsequent cell attachment, internalisation and destruction. Some are involved in inflammasome formation, and modulation of IL-1β cleavage and secretion, and others in the initiation of the type I interferon response. PRRs included in the Guide To PHARMACOLOGY are:Catalytic PRRs (see links below this overview)Toll-like receptors (TLRs)Nucleotide-binding oligomerization domain, leucine-rich repeat containing receptors (NLRs, also known as NOD (Nucleotide oligomerisation domain)-like receptors)RIG-I-like receptors (RLRs)Caspase 4 and caspase 5 Non-catalytic PRRsAbsent in melanoma (AIM)-like receptors (ALRs)C-type lectin-like receptors (CLRs)Other pattern recognition receptorsAdvanced glycosylation end-product specific receptor (RAGE)

scholarly journals Pattern recognition receptors (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database

2019 ◽  
Vol 2019 (4) ◽  
Author(s):  
Clare Bryant ◽  
Tom P. Monie
Keyword(s):  
Pattern Recognition ◽  
Cell Attachment ◽  
Pattern Recognition Receptors ◽  
Interferon Response ◽  
Type I ◽  
Intracellular Proteins ◽  
Molecular Patterns ◽  
Damage Associated Molecular Patterns ◽  
Microbial Agents ◽  
Oligomerization Domain

Pattern Recognition Receptors (PRRs, [83]) (nomenclature as agreed by NC-IUPHAR sub-committee on Pattern Recognition Receptors, [15]) participate in the innate immune response to microbial agents, the stimulation of which leads to activation of intracellular enzymes and regulation of gene transcription. PRRs express multiple leucine-rich regions to bind a range of microbially-derived ligands, termed PAMPs or pathogen-associated molecular patterns or endogenous ligands, termed DAMPS or damage-associated molecular patterns. These include peptides, carbohydrates, peptidoglycans, lipoproteins, lipopolysaccharides, and nucleic acids. PRRs include both cell-surface and intracellular proteins. PRRs may be divided into signalling-associated members, identified here, and endocytic members, the function of which appears to be to recognise particular microbial motifs for subsequent cell attachment, internalisation and destruction. Some are involved in inflammasome formation, and modulation of IL-1β cleavage and secretion, and others in the initiation of the type I interferon response. PRRs included in the Guide To PHARMACOLOGY are:Catalytic PRRs (see links below this overview)Toll-like receptors (TLRs)Nucleotide-binding oligomerization domain, leucine-rich repeat containing receptors (NLRs, also known as NOD (Nucleotide oligomerisation domain)-like receptors)RIG-I-like receptors (RLRs)Caspase 4 and caspase 5 Non-catalytic PRRsAbsent in melanoma (AIM)-like receptors (ALRs)C-type lectin-like receptors (CLRs)Other pattern recognition receptorsAdvanced glycosylation end-product specific receptor (RAGE)

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