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Signaling Pathways in Viral Infection and Antiviral Immunity

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A special issue of Viruses (ISSN 1999-4915). This special issue belongs to the section "Viral Immunology, Vaccines, and Antivirals".

Deadline for manuscript submissions: closed (31 March 2023) | Viewed by 17747

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Special Issue Editors

Dr. Holly Ramage

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Guest Editor

Department of Microbiology and Immunology, Thomas Jefferson University, Philadelphia, PA 19107, USA
Interests: virus-host interactions; innate immune signaling; innate immune evasion; RNA viruses

Dr. Jonathan Miner

E-Mail Website
Guest Editor

Department of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
Interests: antiviral immunity; innate immunity; innate immune signaling; DNA/RNA sensing pathways; autoimmunity

Special Issue Information

Dear Colleagues,

Upon the introduction of a virus to a host cell, interactions between viral and host components precipitate changes in host signaling pathways that ultimately dictate infection outcomes. To successfully infect a cell and produce new virions, viruses have evolved mechanisms to alter host cell metabolism and various cellular processes to promote viral replication. In response to infection, host cells employ various mechanisms to sense the presence of viruses and respond to limit infection. Early control of infection with many viruses is mediated by the innate immune system upon recognition of viral pathogen-associated molecular patterns (PAMPs). There are a diverse array of viral PAMPs, and they are primarily sensed through three canonical pathways: the cytoplasmic RIG-I-like receptors (RLRs), the cytoplasmic cGAS/STING pathway and the Toll-like receptors (TLRs), which are present on cellular and endosomal membranes. Activation of these innate immune pathways leads to the expression of interferon regulatory factors, Type I interferon, interferon-stimulated genes and inflammatory cytokines to induce an antiviral state in the host cell. As an added layer of complexity, viruses have further evolved strategies for innate immune evasion, including disruption of the sensing of viral components and downstream signaling pathways.

For this Special Issue, we invite the submission of original research papers and review articles pertaining to signaling pathways in viral infection and antiviral immunity to offer an updated perspective on these topic areas.

Dr. Holly Ramage
Dr. Jonathan Miner
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Viruses is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

cellular signaling in viral infection
innate immune signaling
antiviral immunity
innate immune evasion
virus-host interactions

Published Papers (7 papers)

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Research

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15 pages, 3267 KiB

Open AccessArticle

A Chemical Proteomics Approach to Discover Regulators of Innate Immune Signaling

by Andrew P. Kurland, Boris Bonaventure and Jeffrey R. Johnson

Viruses 2023, 15(5), 1112; https://doi.org/10.3390/v15051112 - 3 May 2023

Viewed by 1471

Abstract

Innate immune pathways are tightly regulated to balance an appropriate response to infectious agents and tolerable levels of inflammation. Dysregulation of innate immune pathways can lead to severe autoinflammatory disorders or susceptibility to infections. Here, we aimed to identify kinases in common cellular pathways that regulate innate immune pathways by combining small-scale kinase inhibitor screening with quantitative proteomics. We found that inhibitors of kinases ATM, ATR, AMPK, and PLK1 reduced the induction of interferon-stimulated gene expression in response to innate immune pathway activation by poly(I:C) transfection. However, siRNA depletion of these kinases did not validate findings with kinase inhibitors, suggesting that off-target effects may explain their activities. We mapped the effects of kinase inhibitors to various stages in innate immune pathways. Determining the mechanisms by which kinase inhibitors antagonize these pathways may illuminate novel mechanisms of innate immune pathway control. Full article

(This article belongs to the Special Issue Signaling Pathways in Viral Infection and Antiviral Immunity)

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17 pages, 2286 KiB

Open AccessArticle

Role of Caspases and Gasdermin A during HSV-1 Infection in Mice

by Lupeng Li, Stephen B. Kovacs, Ine Jørgensen, Heather N. Larson, Helen M. Lazear and Edward A. Miao

Viruses 2022, 14(9), 2034; https://doi.org/10.3390/v14092034 - 13 Sep 2022

Cited by 3 | Viewed by 2621

Abstract

Herpes simplex virus type 1 (HSV-1) infection can manifest locally as mucocutaneous lesions or keratitis and can also spread to the central nervous system to cause encephalitis. HSV-1 establishes a lifelong latent infection and neither cure nor vaccine is currently available. The innate immune response is the first line of defense against infection. Caspases and gasdermins are important components of innate immunity. Caspases are a family of cysteine proteases, most of which mediate regulated cell death. Gasdermins are a family of pore-forming proteins that trigger lytic cell death. To determine whether caspases or gasdermins contribute to innate immune defenses against HSV-1, we screened mice deficient in specific cell death genes. Our results indicate a modest role for caspase-6 in defense against HSV-1. Further, Asc^–/–Casp1/11^–/– mice also had a modest increased susceptibility to HSV-1 infection. Caspase-7, -8, and -14 did not have a notable role in controlling HSV-1 infection. We generated Gsdma1-Gsdma2-Gsdma3 triple knockout mice, which also had normal susceptibility to HSV-1. We confirmed that the previously published importance of RIPK3 during systemic HSV-1 infection also holds true during skin infection. Overall, our data highlight that as a successful pathogen, HSV-1 has multiple ways to evade host innate immune responses. Full article

(This article belongs to the Special Issue Signaling Pathways in Viral Infection and Antiviral Immunity)

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Review

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14 pages, 2895 KiB

Open AccessReview

The Archer and the Prey: The Duality of PAF1C in Antiviral Immunity

by Matthew W. Kenaston and Priya S. Shah

Viruses 2023, 15(5), 1032; https://doi.org/10.3390/v15051032 - 22 Apr 2023

Cited by 1 | Viewed by 1799

Abstract

In the ongoing arms race between virus and host, fine-tuned gene expression plays a critical role in antiviral signaling. However, viruses have evolved to disrupt this process and promote their own replication by targeting host restriction factors. Polymerase-associated factor 1 complex (PAF1C) is a key player in this relationship, recruiting other host factors to regulate transcription and modulate innate immune gene expression. Consequently, PAF1C is consistently targeted by a diverse range of viruses, either to suppress its antiviral functions or co-opt them for their own benefit. In this review, we delve into the current mechanisms through which PAF1C restricts viruses by activating interferon and inflammatory responses at the transcriptional level. We also highlight how the ubiquity of these mechanisms makes PAF1C especially vulnerable to viral hijacking and antagonism. Indeed, as often as PAF1C is revealed to be a restriction factor, viruses are found to have targeted the complex in reply. Full article

(This article belongs to the Special Issue Signaling Pathways in Viral Infection and Antiviral Immunity)

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19 pages, 2384 KiB

Open AccessReview

New Insights into the Crosstalk among the Interferon and Inflammatory Signaling Pathways in Response to Viral Infections: Defense or Homeostasis

by Jingwen Dai, Pingping Zhou, Su Li and Hua-Ji Qiu

Viruses 2022, 14(12), 2798; https://doi.org/10.3390/v14122798 - 15 Dec 2022

Cited by 4 | Viewed by 2378

Abstract

Innate immunity plays critical roles in eliminating viral infections, healing an injury, and restoring tissue homeostasis. The signaling pathways of innate immunity, including interferons (IFNs), nuclear factor kappa B (NF-κB), and inflammasome responses, are activated upon viral infections. Crosstalk and interplay among signaling pathways are involved in the complex regulation of antiviral activity and homeostasis. To date, accumulating evidence has demonstrated that NF-κB or inflammasome signaling exhibits regulatory effects on IFN signaling. In addition, several adaptors participate in the crosstalk between IFNs and the inflammatory response. Furthermore, the key adaptors in innate immune signaling pathways or the downstream cytokines can modulate the activation of other signaling pathways, leading to excessive inflammatory responses or insufficient antiviral effects, which further results in tissue injury. This review focuses on the crosstalk between IFN and inflammatory signaling to regulate defense and homeostasis. A deeper understanding of the functional aspects of the crosstalk of innate immunity facilitates the development of targeted treatments for imbalanced homeostasis. Full article

(This article belongs to the Special Issue Signaling Pathways in Viral Infection and Antiviral Immunity)

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13 pages, 545 KiB

Open AccessReview

In Vivo and In Vitro Studies of Cigarette Smoke Effects on Innate Responses to Influenza Virus: A Matter of Models?

by Wenxin Wu, Jeremy S. Alexander and Jordan P. Metcalf

Viruses 2022, 14(8), 1824; https://doi.org/10.3390/v14081824 - 20 Aug 2022

Cited by 2 | Viewed by 2541

Abstract

Cigarette smoke (CS) is a significant public health problem and a leading risk factor for the development of chronic obstructive pulmonary disease (COPD) in the developed world. Respiratory viral infections, such as the influenza A virus (IAV), are associated with acute exacerbations of COPD and are more severe in cigarette smokers. To fight against viral infection, the host has developed an innate immune system, which has complicated mechanisms regulating the expression and activation of cytokines and chemokines to maximize the innate and adaptive antiviral response, as well as limiting the immunopathology that leads to exaggerated lung damage. In the case of IAV, responders include airway and alveolar epithelia, lung macrophages and dendritic cells. To achieve a successful infection, IAV must overcome these defenses. In this review, we summarize the detrimental role of CS in influenza infections. This includes both immunosuppressive and proinflammatory effects on innate immune responses during IAV infection. Some of the results, with respect to CS effects in mouse models, appear to have discordant results, which could be at least partially addressed by standardization of animal viral infection models to evaluate the effect of CS exposure in this context. Full article

(This article belongs to the Special Issue Signaling Pathways in Viral Infection and Antiviral Immunity)

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39 pages, 605 KiB

Open AccessReview

Flaviviridae Nonstructural Proteins: The Role in Molecular Mechanisms of Triggering Inflammation

by Anastasia Latanova, Elizaveta Starodubova and Vadim Karpov

Viruses 2022, 14(8), 1808; https://doi.org/10.3390/v14081808 - 18 Aug 2022

Cited by 16 | Viewed by 2582

Abstract

Members of the Flaviviridae family are posing a significant threat to human health worldwide. Many flaviviruses are capable of inducing severe inflammation in humans. Flaviviridae nonstructural proteins, apart from their canonical roles in viral replication, have noncanonical functions strongly affecting antiviral innate immunity. Among these functions, antagonism of type I IFN is the most investigated; meanwhile, more data are accumulated on their role in the other pathways of innate response. This review systematizes the last known data on the role of Flaviviridae nonstructural proteins in molecular mechanisms of triggering inflammation, with an emphasis on their interactions with TLRs and RLRs, interference with NF-κB and cGAS-STING signaling, and activation of inflammasomes. Full article

(This article belongs to the Special Issue Signaling Pathways in Viral Infection and Antiviral Immunity)

16 pages, 1003 KiB

Open AccessReview

Shiftless, a Critical Piece of the Innate Immune Response to Viral Infection

by William Rodriguez and Mandy Muller

Viruses 2022, 14(6), 1338; https://doi.org/10.3390/v14061338 - 20 Jun 2022

Cited by 9 | Viewed by 2862

Abstract

Since its initial characterization in 2016, the interferon stimulated gene Shiftless (SHFL) has proven to be a critical piece of the innate immune response to viral infection. SHFL expression stringently restricts the replication of multiple DNA, RNA, and retroviruses with an extraordinary diversity of mechanisms that differ from one virus to the next. These inhibitory strategies include the negative regulation of viral RNA stability, translation, and even the manipulation of RNA granule formation during viral infection. Even more surprisingly, SHFL is the first human protein found to directly inhibit the activity of the -1 programmed ribosomal frameshift, a translation recoding strategy utilized across nearly all domains of life and several human viruses. Recent literature has shown that SHFL expression also significantly impacts viral pathogenesis in mouse models, highlighting its in vivo efficacy. To help reconcile the many mechanisms by which SHFL restricts viral replication, we provide here a comprehensive review of this complex ISG, its influence over viral RNA fate, and the implications of its functions on the virus-host arms race for control of the cell. Full article

(This article belongs to the Special Issue Signaling Pathways in Viral Infection and Antiviral Immunity)

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