Topic Editors

Dr. Renate König
Paul-Ehrlich-Institut, Langen, Germany
Clinic for Gastroenterology, Hepatology and Infectiology, Medical Faculty, Heinrich-Heine-University Düsseldorf, 40225 Düsseldorf, Germany

Novel Biomolecules Modulating Innate Immune Responses against Virus Infection

Abstract submission deadline
closed (31 March 2022)
Manuscript submission deadline
closed (30 June 2022)
Viewed by
21364

Topic Information

Dear Colleagues,

The innate immune response against viruses is fundamental for the host to survive infections.  Foreign viral pathogens are sensed by a set of germline-encoded pattern-recognition receptors triggering a rapid response, including a variety of defense mechanisms, such as DNA damage response, cellular stress response pathways, inflammasome pathways or regulated cell death responses. Central to the innate host defense is the type I interferon pathway inducing antiviral proteins to control infection and alert other cells.  These innate responses are observed at the intra-cellular, tissue and systemic level. The responses not only include the activity of proteins, positive and negative regulators of the innate signaling cascades, but are also regulated by lipids, polysaccharides, nucleic acids and other metabolites.

This Special Issue aims to highlight novel involvement of all kinds of biomolecules in the innate response to mammalian virus infections, including, but not limited to, second messengers, miRNAs, nucleotides and novel cellular factors. These biomolecules may modulate intracellular innate signaling, affect cell–cell communication or change the biology of the host cell. The biomolecules could interfere with cellular signaling responding to viruses, could directly target or repress viruses at any stage or indirectly regulate dependency or restricting proteins or protein complexes.

We encourage the submission of reviews but also welcome original research papers.

Keywords

  • constitutive and induced expression of antiviral factors
  • mediators of cell resistance
  • biomolecules mediating system- or tissue-wide innate response
  • biomolecules regulating the innate response

Participating Journals

Journal Name Impact Factor CiteScore Launched Year First Decision (median) APC
Biomolecules
biomolecules
5.5 8.3 2011 16.9 Days CHF 2700
Pathogens
pathogens
3.7 5.1 2012 16.4 Days CHF 2700
Non-Coding RNA
ncrna
4.3 9.6 2015 16.6 Days CHF 1800

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Published Papers (7 papers)

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16 pages, 3673 KiB  
Article
A Novel Antiviral Protein Derived from Oenanthe javanica: Type I Interferon-Dependent Antiviral Signaling and Its Pharmacological Potential
by Bo-Ram Jo, Hyun-Soo Kim, Jeong-Won Ahn, Eui-Young Jeoung, Su-Kil Jang, Yeong-Min Yoo and Seong-Soo Joo
Biomolecules 2022, 12(6), 835; https://doi.org/10.3390/biom12060835 - 16 Jun 2022
Cited by 3 | Viewed by 1846
Abstract
Pathogenesis-related (PR) proteins produced in plants play a crucial role in self-defense against microbial attacks. Previously, we have identified a novel PR-1-like protein (OPRP) from Oenanthe javanica and examined its pharmacologic relevance and cell signaling in mammalian cells. Purified full-length OPRP protein significantly [...] Read more.
Pathogenesis-related (PR) proteins produced in plants play a crucial role in self-defense against microbial attacks. Previously, we have identified a novel PR-1-like protein (OPRP) from Oenanthe javanica and examined its pharmacologic relevance and cell signaling in mammalian cells. Purified full-length OPRP protein significantly increased toll-like receptor 4 (TLR4)-dependent expression levels of genes such as inducible nitric oxide synthase (iNOS), tumor necrosis factor α (TNF-α), interleukin 6 (IL-6), and CD80. We also found that small peptides (OPRP2 and OPRP3) designed from OPRP remarkably upregulated myxovirus resistance (Mx1), 2′-5′ oligoadenylate sythetase (OAS), and interferon (IFN) α/β genes in mouse splenocytes as well as human epithelial cells. Notably, OPRP protein distinctively activated STAT1 phosphorylation and ISGF-3γ. Interestingly, OPRP2 and OPRP3 were internalized to the cytoplasm and triggered dimerization of STAT1/STAT2, followed by upregulation of type I IFN-dependent antiviral cytokines. Moreover, OPRP1 successfully inhibited viral (Pseudo SARS-CoV-2) entry into host cells. Taken together, we conclude that OPRP and its small peptides (OPRP1 to 3) present a new therapeutic intervention for modulating innate immune activity through type I IFN-dependent antiviral signaling and a new therapeutic approach that drives an antiviral state in non-immune cells by producing antiviral cytokines. Full article
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12 pages, 2370 KiB  
Article
PD-L1 Silencing in Liver Using siRNAs Enhances Efficacy of Therapeutic Vaccination for Chronic Hepatitis B
by Till Bunse, Anna D. Kosinska, Thomas Michler and Ulrike Protzer
Biomolecules 2022, 12(3), 470; https://doi.org/10.3390/biom12030470 - 18 Mar 2022
Cited by 10 | Viewed by 3769
Abstract
In chronic hepatitis B virus (HBV) infection, virus-specific T cells are scarce and partially dysfunctional. Therapeutic vaccination is a promising strategy to induce and activate new virus-specific T cells. In long-term or high-level HBV carriers, however, therapeutic vaccination by itself may not suffice [...] Read more.
In chronic hepatitis B virus (HBV) infection, virus-specific T cells are scarce and partially dysfunctional. Therapeutic vaccination is a promising strategy to induce and activate new virus-specific T cells. In long-term or high-level HBV carriers, however, therapeutic vaccination by itself may not suffice to cure HBV. One reason is the impairment of antiviral T cells by immune checkpoints. In this study, we used small-interfering RNA (siRNA) in combination with a heterologous prime-boost therapeutic vaccination scheme (TherVacB) to interfere with a major immune checkpoint, the interaction of programmed death protein-1 (PD-1) and its ligand (PDL-1). In mice persistently replicating HBV after infection with an adeno-associated virus harboring the HBV genome, siRNA targeting PD-L1 resulted in a higher functionality of HBV-specific CD8+ T cells after therapeutic vaccination, and allowed for a more sustained antiviral effect and control of HBV in peripheral blood and in the liver. The antiviral effect was more pronounced if PD-L1 was down-regulated during prime than during boost vaccination. Thus, targeting PD-L1 using siRNA is a promising approach to enhance the efficacy of therapeutic vaccination and finally cure HBV. Full article
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19 pages, 3112 KiB  
Article
Upregulated Proteasome Subunits in COVID-19 Patients: A Link with Hypoxemia, Lymphopenia and Inflammation
by Enrique Alfaro, Elena Díaz-García, Sara García-Tovar, Ester Zamarrón, Alberto Mangas, Raúl Galera, Eduardo López-Collazo, Francisco García-Rio and Carolina Cubillos-Zapata
Biomolecules 2022, 12(3), 442; https://doi.org/10.3390/biom12030442 - 13 Mar 2022
Cited by 11 | Viewed by 2690
Abstract
Severe COVID-19 disease leads to hypoxemia, inflammation and lymphopenia. Viral infection induces cellular stress and causes the activation of the innate immune response. The ubiquitin-proteasome system (UPS) is highly implicated in viral immune response regulation. The main function of the proteasome is protein [...] Read more.
Severe COVID-19 disease leads to hypoxemia, inflammation and lymphopenia. Viral infection induces cellular stress and causes the activation of the innate immune response. The ubiquitin-proteasome system (UPS) is highly implicated in viral immune response regulation. The main function of the proteasome is protein degradation in its active form, which recognises and binds to ubiquitylated proteins. Some proteasome subunits have been reported to be upregulated under hypoxic and hyperinflammatory conditions. Here, we conducted a prospective cohort study of COVID-19 patients (n = 44) and age-and sex-matched controls (n = 20). In this study, we suggested that hypoxia could induce the overexpression of certain genes encoding for subunits from the α and β core of the 20S proteasome and from regulatory particles (19S and 11S) in COVID-19 patients. Furthermore, the gene expression of proteasome subunits was associated with lymphocyte count reduction and positively correlated with inflammatory molecular and clinical markers. Given the importance of the proteasome in maintaining cellular homeostasis, including the regulation of the apoptotic and pyroptotic pathways, these results provide a potential link between COVID-19 complications and proteasome gene expression. Full article
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14 pages, 1020 KiB  
Review
The Role of Anti-Viral Effector Molecules in Mollusc Hemolymph
by Angus Watson, Jacinta Agius, Danielle Ackerly, Travis Beddoe and Karla Helbig
Biomolecules 2022, 12(3), 345; https://doi.org/10.3390/biom12030345 - 23 Feb 2022
Cited by 5 | Viewed by 3095
Abstract
Molluscs are major contributors to the international and Australian aquaculture industries, however, their immune systems remain poorly understood due to limited access to draft genomes and evidence of divergences from model organisms. As invertebrates, molluscs lack adaptive immune systems or ‘memory’, and rely [...] Read more.
Molluscs are major contributors to the international and Australian aquaculture industries, however, their immune systems remain poorly understood due to limited access to draft genomes and evidence of divergences from model organisms. As invertebrates, molluscs lack adaptive immune systems or ‘memory’, and rely solely on innate immunity for antimicrobial defence. Hemolymph, the circulatory fluid of invertebrates, contains hemocytes which secrete effector molecules with immune regulatory functions. Interactions between mollusc effector molecules and bacterial and fungal pathogens have been well documented, however, there is limited knowledge of their roles against viruses, which cause high mortality and significant production losses in these species. Of the major effector molecules, only the direct acting protein dicer-2 and the antimicrobial peptides (AMPs) hemocyanin and myticin-C have shown antiviral activity. A better understanding of these effector molecules may allow for the manipulation of mollusc proteomes to enhance antiviral and overall antimicrobial defence to prevent future outbreaks and minimize economic outbreaks. Moreover, effector molecule research may yield the description and production of novel antimicrobial treatments for a broad host range of animal species. Full article
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17 pages, 1646 KiB  
Article
HIV-1 Trans Infection via TNTs Is Impeded by Targeting C5aR
by Giulia Bertacchi, Wilfried Posch and Doris Wilflingseder
Biomolecules 2022, 12(2), 313; https://doi.org/10.3390/biom12020313 - 15 Feb 2022
Cited by 4 | Viewed by 2338
Abstract
Nonadjacent immune cells communicate through a complex network of tunneling nanotubes (TNTs). TNTs can be hijacked by HIV-1, allowing it to spread between connected cells. Dendritic cells (DCs) are among the first cells to encounter HIV-1 at mucosal sites, but they are usually [...] Read more.
Nonadjacent immune cells communicate through a complex network of tunneling nanotubes (TNTs). TNTs can be hijacked by HIV-1, allowing it to spread between connected cells. Dendritic cells (DCs) are among the first cells to encounter HIV-1 at mucosal sites, but they are usually efficiently infected only at low levels. However, HIV-1 was demonstrated to productively infect DCs when the virus was complement-opsonized (HIV-C). Such HIV-C-exposed DCs mediated an improved antiviral and T-cell stimulatory capacity. The role of TNTs in combination with complement in enhancing DC infection with HIV-C remains to be addressed. To this aim, we evaluated TNT formation on the surface of DCs or DC/CD4+ T-cell co-cultures incubated with non- or complement-opsonized HIV-1 (HIV, HIV-C) and the role of TNTs or locally produced complement in the infection process using either two different TNT or anaphylatoxin receptor antagonists. We found that HIV-C significantly increased the formation of TNTs between DCs or DC/CD4+ T-cell co-cultures compared to HIV-exposed DCs or co-cultures. While augmented TNT formation in DCs promoted productive infection, as was previously observed, a significant reduction in productive infection was observed in DC/CD4+ T-cell co-cultures, indicating antiviral activity in this setting. As expected, TNT inhibitors significantly decreased infection of HIV-C-loaded-DCs as well as HIV- and HIV-C-infected-DC/CD4+ T-cell co-cultures. Moreover, antagonizing C5aR significantly inhibited TNT formation in DCs as well as DC/CD4+ T-cell co-cultures and lowered the already decreased productive infection in co-cultures. Thus, local complement mobilization via DC stimulation of complement receptors plays a pivotal role in TNT formation, and our findings herein might offer an exciting opportunity for novel therapeutic approaches to inhibit trans infection via C5aR targeting. Full article
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16 pages, 2882 KiB  
Article
Glycan Epitopes and Potential Glycoside Antagonists of DC-SIGN Involved in COVID-19: In Silico Study
by Meina Gao, Hui Li, Chenghao Ye, Kaixian Chen, Hualiang Jiang and Kunqian Yu
Biomolecules 2021, 11(11), 1586; https://doi.org/10.3390/biom11111586 - 27 Oct 2021
Cited by 4 | Viewed by 2845
Abstract
Glycosylation is an important post-translational modification that affects a wide variety of physiological functions. DC-SIGN (Dendritic Cell-Specific Intercellular adhesion molecule-3-Grabbing Non-integrin) is a protein expressed in antigen-presenting cells that recognizes a variety of glycan epitopes. Until now, the binding of DC-SIGN to SARS-CoV-2 [...] Read more.
Glycosylation is an important post-translational modification that affects a wide variety of physiological functions. DC-SIGN (Dendritic Cell-Specific Intercellular adhesion molecule-3-Grabbing Non-integrin) is a protein expressed in antigen-presenting cells that recognizes a variety of glycan epitopes. Until now, the binding of DC-SIGN to SARS-CoV-2 Spike glycoprotein has been reported in various articles and is regarded to be a factor in systemic infection and cytokine storm. The mechanism of DC-SIGN recognition offers an alternative method for discovering new medication for COVID-19 treatment. Here, we discovered three potential pockets that hold different glycan epitopes by performing molecular dynamics simulations of previously reported oligosaccharides. The “EPN” motif, “NDD” motif, and Glu354 form the most critical pocket, which is known as the Core site. We proposed that the type of glycan epitopes, rather than the precise amino acid sequence, determines the recognition. Furthermore, we deduced that oligosaccharides could occupy an additional site, which adds to their higher affinity than monosaccharides. Based on our findings and previously described glycoforms on the SARS-CoV-2 Spike, we predicted the potential glycan epitopes for DC-SIGN. It suggested that glycan epitopes could be recognized at multiple sites, not just Asn234, Asn149 and Asn343. Subsequently, we found that Saikosaponin A and Liquiritin, two plant glycosides, were promising DC-SIGN antagonists in silico. Full article
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13 pages, 2261 KiB  
Article
Variations in the Abortive HIV-1 RNA Hairpin Do Not Impede Viral Sensing and Innate Immune Responses
by Melissa Stunnenberg, John L. van Hamme, Atze T. Das, Ben Berkhout and Teunis B. H. Geijtenbeek
Pathogens 2021, 10(7), 897; https://doi.org/10.3390/pathogens10070897 - 15 Jul 2021
Cited by 1 | Viewed by 2452
Abstract
The highly conserved trans-acting response element (TAR) present in the RNA genome of human immunodeficiency virus 1 (HIV-1) is a stably folded hairpin structure involved in viral replication. However, TAR is also sensed by viral sensors, leading to antiviral immunity. While high variation [...] Read more.
The highly conserved trans-acting response element (TAR) present in the RNA genome of human immunodeficiency virus 1 (HIV-1) is a stably folded hairpin structure involved in viral replication. However, TAR is also sensed by viral sensors, leading to antiviral immunity. While high variation in the TAR RNA structure renders the virus replication-incompetent, effects on viral sensing remain unclear. Here, we investigated the role of TAR RNA structure and stability on viral sensing. TAR mutants with deletions in the TAR hairpin that enhanced thermodynamic stability increased antiviral responses. Strikingly, TAR mutants with lower stability due to destabilization of the TAR hairpin also increased antiviral responses without affecting pro-inflammatory responses. Moreover, mutations that affected the TAR RNA sequence also enhanced specific antiviral responses. Our data suggest that mutations in TAR of replication-incompetent viruses can still induce immune responses via viral sensors, hereby underscoring the robustness of HIV-1 RNA sensing mechanisms. Full article
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Planned Papers

The below list represents only planned manuscripts. Some of these manuscripts have not been received by the Editorial Office yet. Papers submitted to MDPI journals are subject to peer-review.

Title: Variations in the abortive HIV-1 RNA hairpin do not impede viral sensing and innate immune responses
Abstract: The highly conserved trans-acting response element (TAR) present in the RNA genome of human immunodeficiency virus 1 (HIV-1) is a stably folded hairpin structure involved in viral replication. However, TAR is also sensed by viral sensors, leading to antiviral immunity. While high variation in the TAR RNA structure renders the virus replication incompetent, effects on viral sensing remain unclear. Here, we investigated the role of TAR RNA structure and stability on viral sensing. TAR mutants with deletions in the TAR hairpin that enhanced thermodynamic stability increased antiviral responses. Strikingly, TAR mutants with lower stability due to destabilization of the TAR hairpin also increased antiviral responses without affecting pro-inflammatory responses. Moreover, mutations that affected the TAR RNA sequence also enhanced specific antiviral responses. Our data suggest that mutations in TAR of replication-incompetent viruses can still induce immune responses via viral sensors, hereby underscoring the robustness of HIV-1 RNA sensing mechanisms.
Authorship/affiliation
Melissa Stunnenberg1, John L. van Hamme1, Atze T. Das2, Ben Berkhout2 and Teunis B.H. Geijtenbeek1

1Amsterdam UMC, University of Amsterdam, Department of Experimental Immunology, Amsterdam Institute for Infection & Immunity, Meibergdreef 9, Amsterdam, Netherlands.
2Amsterdam UMC, University of Amsterdam, Laboratory of Experimental Virology, Department of Medical Microbiology, Meibergdreef 9, Amsterdam, Netherlands.
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