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Viruses
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Toll-Like Receptors in Antiviral Immunity
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Toll-Like Receptors in Antiviral Immunity

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 December 2021) | Viewed by 17248

Special Issue Editor

Prof. Dr. William M. Mitchell

E-Mail Website
Guest Editor
Department of Pathology, Microbiology & Immunology, Vanderbilt University, Nashville, TN, USA
Interests: innate immunity initiated by Activation of Toll-Like Receptor 3 (TLR3); next generation sequencing (NGS) applications (cancer diagnostics, intracellular pathogen discovery and analysis); pathogenesis of intracellular microbes (Chlamydia/HIV)

Special Issue Information

Dear Colleagues,

Pathogen Associated Molecular Patterns (PAMP) expressed by all replicating microorganisms bind to cellular Toll Like Receptors (TLR) with remarkable homologies from Drosophila to humans. PAMPs of replicating animal viruses bind to four distinct TLRs, dependent on nucleic acid structural patterns. TLR3 detects double stranded RNA (dsRNA), TLR7 and TLR8 detect single stranded RNAs (ssRNA), and TLR9 detects DNA with sequences containing unmethylated GC motifs. TLR4 agonists have been clinically employed as next generation adjuvants. B-cell TLR2 activation has been linked recently with HBV infection resolution. Nucleic acid binding by TLRs initiates two distinct intracellular cascades culminating in the activation of hundreds or less frequently deactivation of transitory cellular regulatory activities. Up regulation of TLRs by pathogens is necessary for the induction of the innate immune response as well as subsequent initiation of adaptive immunity through cytokine signaling. The differential expression of cytokine signaling has prompted the investigation of a variety of TLR agonists which include inhibition of viral pathogen replication as well as next generation vaccine adjuvants as potent immune enhancers. TLR genomic polymorphisms have been implicated in susceptibility to microorganism pathogenesis. Sustained TLR expression has been implicated in autoimmune responses with the development of TLR antagonists. Basic research on TLR structure and function has provided the foundation for numerous translational studies and clinical trials of a variety of agonists.

This special edition which focuses on mammalian TLRs welcomes full article and communication manuscripts of original research and clinical trials as well as reviews and can be highly focused or broadly based.

Prof. Dr. William M. Mitchell
Guest Editor

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

  • molecular structure and function
  • agonists
  • antagonists
  • differential activity of MAMPs
  • cytokine/chemokine responses to gene activation
  • TLR polymorphisms/SNPs
  • vaccines
  • differential PAMP specific toxicity
  • cancer
  • SARS-CoV-2 (COVID-19)
  • clinical trials

Published Papers (5 papers)

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Research

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17 pages, 9206 KiB  
Article
Antiviral Toll-like Receptor Signaling in Non-Parenchymal Liver Cells Is Restricted to TLR3
by Melanie Werner, Stefan Schefczyk, Martin Trippler, Juergen W. Treckmann, Hideo A. Baba, Guido Gerken, Joerg F. Schlaak and Ruth Broering
Viruses 2022, 14(2), 218; https://doi.org/10.3390/v14020218 - 24 Jan 2022
Cited by 3 | Viewed by 2573
Abstract
The role of non-parenchymal liver cells as part of the hepatic, innate immune system in the defense against hepatotropic viruses is not well understood. Here, primary human Kupffer cells, liver sinusoidal endothelial cells and hepatic stellate cells were isolated from liver tissue obtained [...] Read more.
The role of non-parenchymal liver cells as part of the hepatic, innate immune system in the defense against hepatotropic viruses is not well understood. Here, primary human Kupffer cells, liver sinusoidal endothelial cells and hepatic stellate cells were isolated from liver tissue obtained after tumor resections or liver transplantations. Cells were stimulated with Toll-like receptor 1–9 ligands for 6–24 h. Non-parenchymal liver cells expressed and secreted inflammatory cytokines (IL6, TNF and IL10). Toll-like receptor- and cell type-specific downstream signals included the phosphorylation of NF-κB, AKT, JNK, p38 and ERK1/2. However, only supernatants of TLR3-activated Kupffer cells, liver sinusoidal endothelial cells and hepatic stellate cells contained type I and type III interferons and mediated an antiviral activity in the interferon-sensitive subgenomic hepatitis C virus replicon system. The antiviral effect could not be neutralized by antibodies against IFNA, IFNB nor IFNL, but could be abrogated using an interferon alpha receptor 2-specific neutralization. Interestingly, TLR3 responsiveness was enhanced in liver sinusoidal endothelial cells isolated from hepatitis C virus-positive donors, compared to uninfected controls. In conclusion, non-parenchymal liver cells are potent activators of the hepatic immune system by mediating inflammatory responses. Furthermore, liver sinusoidal endothelial cells were identified to be hyperresponsive to viral stimuli in chronic hepatitis C virus infection. Full article
(This article belongs to the Special Issue Toll-Like Receptors in Antiviral Immunity)
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25 pages, 337 KiB  
Article
Single Nucleotide Polymorphisms of Interleukins and Toll-like Receptors and Neuroimaging Results in Newborns with Congenital HCMV Infection
by Justyna Czech-Kowalska, Dominika Jedlińska-Pijanowska, Agata K. Pleskaczyńska, Anna Niezgoda, Kinga Gradowska, Aleksandra Pietrzyk, Elżbieta Jurkiewicz, Maciej Jaworski and Beata Kasztelewicz
Viruses 2021, 13(9), 1783; https://doi.org/10.3390/v13091783 - 07 Sep 2021
Viewed by 1887
Abstract
Congenital cytomegalovirus infection (cCMV) is the most common intrauterine infection with central nervous system (CNS) involvement. There is limited data on the associations between Single Nucleotide Polymorphisms (SNPs) in genes involving the first-line defense mechanism and the risk of CNS damage during cCMV. [...] Read more.
Congenital cytomegalovirus infection (cCMV) is the most common intrauterine infection with central nervous system (CNS) involvement. There is limited data on the associations between Single Nucleotide Polymorphisms (SNPs) in genes involving the first-line defense mechanism and the risk of CNS damage during cCMV. We investigated the associations between neuroimaging findings and SNPs in genes encoding the following cytokines and cytokine receptors in 92 infants with cCMV: interleukins (IL1B rs16944, IL12B rs3212227, IL28B rs12979860), C-C motif chemokine ligand 2 (CCL2 rs1024611), dendritic cell-specific intercellular adhesion grabbing non-integrin (DC-SIGN rs735240), Toll-like receptors (TLR2 rs5743708, TLR4 rs4986791, TLR9 rs352140). The SNP of IL1B rs16944 (G/A) was associated with a reduced risk of ventriculomegaly on MRI (OR = 0.46, 95% CI, 0.22–0.95; p = 0.03) and cUS (OR = 0.38, 95% CI, 0.0–0.93; p = 0.034). Infants carrying heterozygous (T/C) genotype at IL28B rs12979860 had an increased risk of cystic lesions on cUS (OR = 3.31, 95% CI, 1.37–8.01; p = 0.0064) and MRI (OR = 4.97, 95% CI, 1.84–13.43; p = 0.001), and an increased risk of ventriculomegaly on MRI (OR = 2.46, 95% CI, 1.03–5.90; p = 0.04). No other associations between genotyped SNPs and neuroimaging results were found. This is the first study demonstrating new associations between SNPs of IL1B and IL28B and abnormal neuroimaging in infants with cCMV. Full article
(This article belongs to the Special Issue Toll-Like Receptors in Antiviral Immunity)

Review

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21 pages, 1082 KiB  
Review
Innate Immune Response to Dengue Virus: Toll-like Receptors and Antiviral Response
by Caroline Fernandes-Santos and Elzinandes Leal de Azeredo
Viruses 2022, 14(5), 992; https://doi.org/10.3390/v14050992 - 07 May 2022
Cited by 9 | Viewed by 4536
Abstract
Dengue is a mosquito-borne viral disease caused by the dengue virus (DENV1-4). The clinical manifestations range from asymptomatic to life-threatening dengue hemorrhagic fever (DHF) and/or Dengue Shock Syndrome (DSS). Viral and host factors are related to the clinical outcome of dengue, although the [...] Read more.
Dengue is a mosquito-borne viral disease caused by the dengue virus (DENV1-4). The clinical manifestations range from asymptomatic to life-threatening dengue hemorrhagic fever (DHF) and/or Dengue Shock Syndrome (DSS). Viral and host factors are related to the clinical outcome of dengue, although the disease pathogenesis remains uncertain. The innate antiviral response to DENV is implemented by a variety of immune cells and inflammatory mediators. Blood monocytes, dendritic cells (DCs) and tissue macrophages are the main target cells of DENV infection. These cells recognize pathogen-associated molecular patterns (PAMPs) through pattern recognition receptors (PRRs). Pathogen recognition is a critical step in eliciting the innate immune response. Toll-like receptors (TLRs) are responsible for the innate recognition of pathogens and represent an essential component of the innate and adaptive immune response. Ten different TLRs are described in humans, which are expressed in many different immune cells. The engagement of TLRs with viral PAMPs triggers downstream signaling pathways leading to the production of inflammatory cytokines, interferons (IFNs) and other molecules essential for the prevention of viral replication. Here, we summarize the crucial TLRs’ roles in the antiviral innate immune response to DENV and their association with viral pathogenesis. Full article
(This article belongs to the Special Issue Toll-Like Receptors in Antiviral Immunity)
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11 pages, 1030 KiB  
Review
Current Understanding of the Innate Control of Toll-like Receptors in Response to SARS-CoV-2 Infection
by Hi Eun Jung and Heung Kyu Lee
Viruses 2021, 13(11), 2132; https://doi.org/10.3390/v13112132 - 22 Oct 2021
Cited by 24 | Viewed by 3813
Abstract
The global coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) infection, threatens the entire world. It has affected every aspect of life and increased the burden on both healthcare and socioeconomic systems. Current studies have revealed that excessive inflammatory [...] Read more.
The global coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) infection, threatens the entire world. It has affected every aspect of life and increased the burden on both healthcare and socioeconomic systems. Current studies have revealed that excessive inflammatory immune responses are responsible for the severity of COVID-19, which suggests that anti-inflammatory drugs may be promising therapeutic treatments. However, there are currently a limited number of approved therapeutics for COVID-19. Toll-like receptors (TLRs), which recognize microbial components derived from invading pathogens, are involved in both the initiation of innate responses against SARS-CoV-2 infection and the hyperinflammatory phenotype of COVID-19. In this review, we provide current knowledge on the pivotal role of TLRs in immune responses against SARS-CoV-2 infection and demonstrate the potential effectiveness of TLR-targeting drugs on the control of hyperinflammation in patients with COVID-19. Full article
(This article belongs to the Special Issue Toll-Like Receptors in Antiviral Immunity)
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33 pages, 1493 KiB  
Review
Toll-like Receptors in Viral Encephalitis
by Olivia Luise Gern, Felix Mulenge, Andreas Pavlou, Luca Ghita, Imke Steffen, Martin Stangel and Ulrich Kalinke
Viruses 2021, 13(10), 2065; https://doi.org/10.3390/v13102065 - 14 Oct 2021
Cited by 12 | Viewed by 3665
Abstract
Viral encephalitis is a rare but serious syndrome. In addition to DNA-encoded herpes viruses, such as herpes simplex virus and varicella zoster virus, RNA-encoded viruses from the families of Flaviviridae, Rhabdoviridae and Paramyxoviridae are important neurotropic viruses. Whereas in the periphery, the role [...] Read more.
Viral encephalitis is a rare but serious syndrome. In addition to DNA-encoded herpes viruses, such as herpes simplex virus and varicella zoster virus, RNA-encoded viruses from the families of Flaviviridae, Rhabdoviridae and Paramyxoviridae are important neurotropic viruses. Whereas in the periphery, the role of Toll-like receptors (TLR) during immune stimulation is well understood, TLR functions within the CNS are less clear. On one hand, TLRs can affect the physiology of neurons during neuronal progenitor cell differentiation and neurite outgrowth, whereas under conditions of infection, the complex interplay between TLR stimulated neurons, astrocytes and microglia is just on the verge of being understood. In this review, we summarize the current knowledge about which TLRs are expressed by cell subsets of the CNS. Furthermore, we specifically highlight functional implications of TLR stimulation in neurons, astrocytes and microglia. After briefly illuminating some examples of viral evasion strategies from TLR signaling, we report on the current knowledge of primary immunodeficiencies in TLR signaling and their consequences for viral encephalitis. Finally, we provide an outlook with examples of TLR agonist mediated intervention strategies and potentiation of vaccine responses against neurotropic virus infections. Full article
(This article belongs to the Special Issue Toll-Like Receptors in Antiviral Immunity)
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