scholarly journals System-Based Approaches to Delineate the Antiviral Innate Immune Landscape

Viruses ◽  
2020 ◽  
Vol 12 (10) ◽  
pp. 1196
Author(s):  
Karsten Krey ◽  
Aleksandra W. Babnis ◽  
Andreas Pichlmair
Keyword(s):  
Large Scale ◽  
Innate Immune ◽  
Host Interactions ◽  
Interferon Stimulated Genes ◽  
Cellular Processes ◽  
Virus Inhibition ◽  
Cellular Factors ◽  
Functional Factors ◽  
Infected Cells ◽  
Screening Approaches

Viruses pose substantial challenges for society, economy, healthcare systems, and research. Their distinctive pathologies are based on specific interactions with cellular factors. In order to develop new antiviral treatments, it is of central importance to understand how viruses interact with their host and how infected cells react to the virus on a molecular level. Invading viruses are commonly sensed by components of the innate immune system, which is composed of a highly effective yet complex network of proteins that, in most cases, mediate efficient virus inhibition. Central to this process is the activity of interferons and other cytokines that coordinate the antiviral response. So far, numerous methods have been used to identify how viruses interact with cellular processes and revealed that the innate immune response is highly complex and involves interferon-stimulated genes and their binding partners as functional factors. Novel approaches and careful experimental design, combined with large-scale, high-throughput methods and cutting-edge analysis pipelines, have to be utilized to delineate the antiviral innate immune landscape at a global level. In this review, we describe different currently used screening approaches, how they contributed to our knowledge on virus–host interactions, and essential considerations that have to be taken into account when planning such experiments.

scholarly journals A virus-encoded microRNA contributes to evade innate immune response during SARS-CoV-2 infection

2021 ◽  
Author(s):  
Meetali Singh ◽  
Maxime Chazal ◽  
Piergiuseppe Quarato ◽  
Loan Bourdon ◽  
Christophe Malabat ◽  
...  
Keyword(s):  
Immune Response ◽  
Innate Immune Response ◽  
Small Rnas ◽  
Viral Genome ◽  
Innate Immune ◽  
Micro Rna ◽  
Interferon Response ◽  
Interferon Stimulated Genes ◽  
Argonaute Proteins ◽  
Infected Cells

SARS-CoV-2 infection results in impaired interferon response in severe COVID-19 patients. However, how SARS-CoV-2 interferes with host immune response is incompletely understood. Here, we sequenced small RNAs from SARS-CoV-2-infected human cells and identified a micro-RNA (miRNA) encoded in a recently evolved region of the viral genome. We show that the virus-encoded miRNA produces two miRNA isoforms in infected cells by the enzyme Dicer and they are loaded into Argonaute proteins. Moreover, the predominant miRNA isoform targets the 3’UTR of interferon-stimulated genes and represses their expression in a miRNA-like fashion. Finally, the two viral miRNA isoforms were detected in nasopharyngeal swabs from COVID-19 patients. We propose that SARS-CoV-2 employs a virus-encoded miRNA to hijack the host miRNA machinery and evade the interferon-mediated immune response.

scholarly journals Innate Immune Activity Correlates with CD4 T Cell-Associated HIV-1 DNA Decline during Latency-Reversing Treatment with Panobinostat

2015 ◽  
Vol 89 (20) ◽  
pp. 10176-10189 ◽  
Author(s):  
Rikke Olesen ◽  
Selena Vigano ◽  
Thomas A. Rasmussen ◽  
Ole S. Søgaard ◽  
Zhengyu Ouyang ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Nk Cells ◽  
Expression Patterns ◽  
Innate Immune ◽  
Viral Reservoir ◽  
Immune Activity ◽  
Interferon Stimulated Genes ◽  
Infected Cells ◽  
Hiv 1 ◽  
Reversing Agents

ABSTRACTThe pharmaceutical reactivation of dormant HIV-1 proviruses by histone deacetylase inhibitors (HDACi) represents a possible strategy to reduce the reservoir of HIV-1-infected cells in individuals treated with suppressive combination antiretroviral therapy (cART). However, the effects of such latency-reversing agents on the viral reservoir size are likely to be influenced by host immune responses. Here, we analyzed the immune factors associated with changes in proviral HIV-1 DNA levels during treatment with the potent HDACi panobinostat in a human clinical trial involving 15 cART-treated HIV-1-infected patients. We observed that the magnitude, breadth, and cytokine secretion profile of HIV-1-specific CD8 T cell responses were unrelated to changes in HIV-1 DNA levels in CD4 T cells during panobinostat treatment. In contrast, the proportions of CD3−CD56+total NK cells and CD16+CD56dimNK cells were inversely correlated with HIV-1 DNA levels throughout the study, and changes in HIV-1 DNA levels during panobinostat treatment were negatively associated with the corresponding changes in CD69+NK cells. Decreasing levels of HIV-1 DNA during latency-reversing treatment were also related to the proportions of plasmacytoid dendritic cells, to distinct expression patterns of interferon-stimulated genes, and to the expression of theIL28BCC genotype. Together, these data suggest that innate immune activity can critically modulate the effects of latency-reversing agents on the viral reservoir and may represent a target for future immunotherapeutic interventions in HIV-1 eradication studies.IMPORTANCECurrently available antiretroviral drugs are highly effective in suppressing HIV-1 replication, but the virus persists, despite treatment, in a latent form that does not actively express HIV-1 gene products. One approach to eliminate these cells, colloquially termed the “shock-and-kill” strategy, focuses on the use of latency-reversing agents that induce active viral gene expression in latently infected cells, followed by immune-mediated killing. Panobinostat, a histone deacetylase inhibitor, demonstrated potent activities in reversing HIV-1 latency in a recent pilot clinical trial and reduced HIV-1 DNA levels in a subset of patients. Interestingly, we found that innate immune factors, such as natural killer cells, plasmacytoid dendritic cells, and the expression patterns of interferon-stimulated genes, were most closely linked to a decline in the HIV-1 DNA level during treatment with panobinostat. These data suggest that innate immune activity may play an important role in reducing the residual reservoir of HIV-1-infected cells.

scholarly journals Host Cell Restriction Factors of Bunyaviruses and Viral Countermeasures

Viruses ◽  
2021 ◽  
Vol 13 (5) ◽  
pp. 784
Author(s):  
Solène Lerolle ◽  
Natalia Freitas ◽  
François-Loïc Cosset ◽  
Vincent Legros
Keyword(s):  
Host Cell ◽  
Viral Entry ◽  
Current Knowledge ◽  
Restriction Factors ◽  
Antiviral State ◽  
Cellular Factors ◽  
Pathogenic Viruses ◽  
Genome Transcription ◽  
Infected Cells ◽  
Molecular Patterns

The Bunyavirales order comprises more than 500 viruses (generally defined as bunyaviruses) classified into 12 families. Some of these are highly pathogenic viruses infecting different hosts, including humans, mammals, reptiles, arthropods, birds, and/or plants. Host cell sensing of infection activates the innate immune system that aims at inhibiting viral replication and propagation. Upon recognition of pathogen-associated molecular patterns (PAMPs) by cellular pattern recognition receptors (PRRs), numerous signaling cascades are activated, leading to the production of interferons (IFNs). IFNs act in an autocrine and paracrine manner to establish an antiviral state by inducing the expression of hundreds of IFN-stimulated genes (ISGs). Some of these ISGs are known to restrict bunyavirus infection. Along with other constitutively expressed host cellular factors with antiviral activity, these proteins (hereafter referred to as “restriction factors”) target different steps of the viral cycle, including viral entry, genome transcription and replication, and virion egress. In reaction to this, bunyaviruses have developed strategies to circumvent this antiviral response, by avoiding cellular recognition of PAMPs, inhibiting IFN production or interfering with the IFN-mediated response. Herein, we review the current knowledge on host cellular factors that were shown to restrict infections by bunyaviruses. Moreover, we focus on the strategies developed by bunyaviruses in order to escape the antiviral state developed by the infected cells.

scholarly journals Role of Virally-Encoded Deubiquitinating Enzymes in Regulation of the Virus Life Cycle

2021 ◽  
Vol 22 (9) ◽  
pp. 4438
Author(s):  
Jessica Proulx ◽  
Kathleen Borgmann ◽  
In-Woo Park
Keyword(s):  
Immune Response ◽  
Life Cycle ◽  
Deubiquitinating Enzyme ◽  
Deubiquitinating Enzymes ◽  
Antiviral Immune Response ◽  
Cellular Processes ◽  
Virus Life Cycle ◽  
Infected Cells ◽  
Dependent Processes

The ubiquitin (Ub) proteasome system (UPS) plays a pivotal role in regulation of numerous cellular processes, including innate and adaptive immune responses that are essential for restriction of the virus life cycle in the infected cells. Deubiquitination by the deubiquitinating enzyme, deubiquitinase (DUB), is a reversible molecular process to remove Ub or Ub chains from the target proteins. Deubiquitination is an integral strategy within the UPS in regulating survival and proliferation of the infecting virus and the virus-invaded cells. Many viruses in the infected cells are reported to encode viral DUB, and these vial DUBs actively disrupt cellular Ub-dependent processes to suppress host antiviral immune response, enhancing virus replication and thus proliferation. This review surveys the types of DUBs encoded by different viruses and their molecular processes for how the infecting viruses take advantage of the DUB system to evade the host immune response and expedite their replication.

scholarly journals Salmonella–Host Interactions – Modulation of the Host Innate Immune System

2014 ◽  
Vol 5 ◽  
Author(s):  
Daniel Hurley ◽  
Matthew P. McCusker ◽  
Séamus Fanning ◽  
Marta Martins
Keyword(s):  
Immune System ◽  
Innate Immune System ◽  
Innate Immune ◽  
Host Interactions

scholarly journals Nonameric Peptide Orchestrates Signal Transduction in the Activating HLA-E/NKG2C/CD94 Immune Complex as Revealed by All-Atom Simulations

2021 ◽  
Vol 22 (13) ◽  
pp. 6670
Author(s):  
Eva Prašnikar ◽  
Andrej Perdih ◽  
Jure Borišek
Keyword(s):  
Signal Transduction ◽  
Cell Activation ◽  
Nk Cell ◽  
Innate Immune ◽  
Target Cells ◽  
Molecular Events ◽  
Activating Receptors ◽  
Molecular Machinery ◽  
Infected Cells ◽  
Bond Network

The innate immune system’s natural killer (NK) cells exert their cytolytic function against a variety of pathological challenges, including tumors and virally infected cells. Their activation depends on net signaling mediated via inhibitory and activating receptors that interact with specific ligands displayed on the surfaces of target cells. The CD94/NKG2C heterodimer is one of the NK activating receptors and performs its function by interacting with the trimeric ligand comprised of the HLA-E/β2m/nonameric peptide complex. Here, simulations of the all-atom multi-microsecond molecular dynamics in five immune complexes provide atomistic insights into the receptor–ligand molecular recognition, as well as the molecular events that facilitate the NK cell activation. We identify NKG2C, the HLA-Eα2 domain, and the nonameric peptide as the key elements involved in the molecular machinery of signal transduction via an intertwined hydrogen bond network. Overall, the study addresses the complex intricacies that are necessary to understand the mechanisms of the innate immune system.

scholarly journals Masking of β(1-3)-Glucan in the Cell Wall of Candida albicans from Detection by Innate Immune Cells Depends on Phosphatidylserine

2014 ◽  
Vol 82 (10) ◽  
pp. 4405-4413 ◽  
Author(s):  
Sarah E. Davis ◽  
Alex Hopke ◽  
Steven C. Minkin ◽  
Anthony E. Montedonico ◽  
Robert T. Wheeler ◽  
...  
Keyword(s):  
Cell Wall ◽  
Candida Albicans ◽  
De Novo ◽  
Invasive Disease ◽  
Innate Immune ◽  
Dependent Manner ◽  
Content Type ◽  
Immune Effector ◽  
Host Interactions ◽  
Innate Immune Effector

ABSTRACTThe virulence ofCandida albicansin a mouse model of invasive candidiasis is dependent on the phospholipids phosphatidylserine (PS) and phosphatidylethanolamine (PE). Disruption of the PS synthase geneCHO1(i.e.,cho1Δ/Δ) eliminates PS and blocks thede novopathway for PE biosynthesis. In addition, thecho1Δ/Δ mutant's ability to cause invasive disease is severely compromised. Thecho1Δ/Δ mutant also exhibits cell wall defects, and in this study, it was determined that loss of PS results in decreased masking of cell wall β(1-3)-glucan from the immune system. In wild-typeC. albicans, the outer mannan layer of the wall masks the inner layer of β(1-3)-glucan from exposure and detection by innate immune effector molecules like the C-type signaling lectin Dectin-1, which is found on macrophages, neutrophils, and dendritic cells. Thecho1Δ/Δ mutant exhibits increases in exposure of β(1-3)-glucan, which leads to greater binding by Dectin-1 in both yeast and hyphal forms. The unmasking of β(1-3)-glucan also results in increased elicitation of TNF-α from macrophages in a Dectin-1-dependent manner. The role of phospholipids in fungal pathogenesis is an emerging field, and this is the first study showing that loss of PS inC. albicansresults in decreased masking of β(1-3)-glucan, which may contribute to our understanding of fungus-host interactions.

scholarly journals Natural Cytotoxicity Receptors: Pattern Recognition and Involvement of Carbohydrates

2005 ◽  
Vol 5 ◽  
pp. 151-154 ◽  
Author(s):  
Angel Porgador
Keyword(s):  
Pattern Recognition ◽  
Cell Membrane ◽  
Cell Surface ◽  
Innate Immune ◽  
Target Cells ◽  
Natural Cytotoxicity ◽  
Tumor Cell Membrane ◽  
Infected Cells ◽  
Natural Cytotoxicity Receptors ◽  
New Evidence

Natural cytotoxicity receptors (NCRs), expressed by natural killer (NK) cells, trigger NK lysis of tumor and virus-infected cells on interaction with cell-surface ligands of these target cells. We have determined that viral hemagglutinins expressed on the surface of virus-infected cells are involved in the recognition by the NCRs, NKp44 and NKp46. Recognition of tumor cells by the NCRs NKp30 and NKp46 involves heparan sulfate epitopes expressed on the tumor cell membrane. Our studies provide new evidence for the identity of the ligands for NCRs and indicate that a broader definition should be applied to pathological patterns recognized by innate immune receptors. Since nonmicrobial endogenous carbohydrate structures contribute significantly to this recognition, there is an imperative need to develop appropriate tools for the facile sequencing of carbohydrate moieties.

Proteomic landscape of Japanese encephalitis virus-infected fibroblasts

2021 ◽  
Vol 102 (9) ◽  
Author(s):  
Kiran Bala Sharma ◽  
Simran Chhabra ◽  
Suruchi Aggarwal ◽  
Aarti Tripathi ◽  
Arup Banerjee ◽  
...  
Keyword(s):  
Japanese Encephalitis Virus ◽  
Japanese Encephalitis ◽  
Protein Composition ◽  
Enrichment Analysis ◽  
Mouse Embryonic Fibroblast ◽  
Encephalitis Virus ◽  
Innate Immune ◽  
Pathway Enrichment Analysis ◽  
Interferon Stimulated Genes ◽  
Immune Sensing

Advances in proteomics have enabled a comprehensive understanding of host–pathogen interactions. Here we have characterized Japanese encephalitis virus (JEV) infection-driven changes in the mouse embryonic fibroblast (MEF) proteome. Through tandem mass tagging (TMT)-based mass spectrometry, we describe changes in 7.85 % of the identified proteome due to JEV infection. Pathway enrichment analysis showed that proteins involved in innate immune sensing, interferon responses and inflammation were the major upregulated group, along with the immunoproteasome and poly ADP-ribosylation proteins. Functional validation of several upregulated anti-viral innate immune proteins, including an active cGAS–STING axis, was performed. Through siRNA depletion, we describe a crucial role of the DNA sensor cGAS in restricting JEV replication. Further, many interferon-stimulated genes (ISGs) were observed to be induced in infected cells. We also observed activation of TLR2 and inhibition of TLR2 signalling using TLR1/2 inhibitor CU-CPT22-blocked production of inflammatory cytokines IL6 and TNF-α from virus-infected N9 microglial cells. The major proteins that were downregulated by infection were involved in cell adhesion (collagens), transport (solute carrier and ATP-binding cassette transporters), sterol and lipid biosynthesis. Several collagens were found to be transcriptionally downregulated in infected MEFs and mouse brain. Collectively, our data provide a bird’s-eye view into how fibroblast protein composition is rewired following JEV infection.

An integrated view of innate immune mechanisms in C. elegans

2021 ◽  
Author(s):  
Benjamin W. Harding ◽  
Jonathan J. Ewbank
Keyword(s):  
Innate Immune ◽  
Innate Immune Responses ◽  
Fully Integrated ◽  
Immune Mechanisms ◽  
C Elegans ◽  
Cellular Processes ◽  
Physiological Processes ◽  
Model Animal ◽  
Molecular Specificity ◽  
Simple Notion

The simple notion ‘infection causes an immune response' is being progressively refined as it becomes clear that immune mechanisms cannot be understood in isolation, but need to be considered in a more global context with other cellular and physiological processes. In part, this reflects the deployment by pathogens of virulence factors that target diverse cellular processes, such as translation or mitochondrial respiration, often with great molecular specificity. It also reflects molecular cross-talk between a broad range of host signalling pathways. Studies with the model animal C. elegans have uncovered a range of examples wherein innate immune responses are intimately connected with different homeostatic mechanisms, and can influence reproduction, ageing and neurodegeneration, as well as various other aspects of its biology. Here we provide a short overview of a number of such connections, highlighting recent discoveries that further the construction of a fully integrated view of innate immunity.

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