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Virus–Host Interaction and Cell Restriction Mechanisms 2.0

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Immunology".

Deadline for manuscript submissions: closed (31 March 2024) | Viewed by 16938

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Dr. Greta Forlani

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Laboratory of General Pathology and Immunology “Giovanna Tosi”, Department of Medicine and Surgery, School of Medicine, University of Insubria, Via O.Rossi 9, 21100 Varese, Italy
Interests: tumor immunology and development of tumor vaccines; viral oncology: study of virus-host interaction and molecular mechanisms of viral-associated diseases
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Dr. Maria Grazia Romanelli

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Department of Neurosciences, Biomedicine and Movement Sciences, University of Verona, 37134 Verona, Italy
Interests: cell biology and gene expression regulation focused on biomarkers characterization; the functional interaction between proteins and nucleic acids; viral oncology, development of cell models to study the molecular basis of cardiovascular; cancer and viral diseases
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Special Issue Information

Dear Colleagues,

Viral diseases are becoming a major public health concern and an extended field of research. Deciphering the mechanisms that allow viruses to enter susceptible host cells, hijack cellular pathways, and evade innate immune response is a major requirement for potential treatments and drug discoveries. In this context, HIV-1 infection is considered one of the most aggressive pandemics in the world, causing the death of millions of people; however, it represents a clear example of how progress in research has significantly contributed to understanding the molecular and cellular correlates of this infection, providing effective tools to counteract the virus and contain viral replication in the host. Chronic viral infections account for 15% to 20% of total human cancers. Advances in our understanding of how oncoviruses modulate key host factors and signaling pathways have shed light on the pathogenic mechanisms of cancer-causing viruses, including, among others, human papillomaviruses (HPVs) Epstein–Barr virus (EBV), hepatitis B virus (HBV) and hepatitis C virus (HCV), and human T-cell leukemia virus-1 (HTLV-1). Viral adaptation and cell host tropism play a critical role in the emergence of human coronaviruses: severe acute respiratory syndrome coronavirus (SARS-CoV), Middle East respiratory syndrome coronavirus (MERS-CoV), and the most recent and highly pathogenic SARS-coronavirus 2 (SARS-CoV-2). The evaluation of the similarities or the differences of the novel virus with other coronaviruses that have caused outbreaks of severe respiratory diseases in the past should be critical to understand the nature of infection and pathogenicity of the new virus. Although SARS-CoV-2, responsible for the COVID-19 pandemic, has been successfully isolated and its viral infectivity and pathogenicity has been partially understood, more needs to be revealed of the viral antigenic structure, host-immune response, viral entry in host cells, and infectivity in order to contain infection and develop an effective strategy in the management of viral infection.

In this research topic, we welcome contributions focused on understanding the virus–host interaction involved in (i) viral entry (i), viral infection and replication, (ii) viral persistence (iii), cell restriction mechanisms, (iv) immune response and pathogenesis, and (v) oncovirus pathogenesis.

Dr. Greta Forlani
Dr. Maria Grazia Romanelli
Guest Editors

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Published Papers (8 papers)

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Research

16 pages, 1192 KiB

Open AccessArticle

Restriction of Zika Virus Replication in Human Monocyte-Derived Macrophages by Pro-Inflammatory (M1) Polarization

by Isabel Pagani, Silvia Ghezzi, Giulia Aimola, Paola Podini, Francesca Genova, Elisa Vicenzi and Guido Poli

Int. J. Mol. Sci. 2025, 26(3), 951; https://doi.org/10.3390/ijms26030951 - 23 Jan 2025

Viewed by 1067

Abstract

Zika virus (ZIKV), a member of the Flaviviridae family, is primarily transmitted through mosquito bites, but can also spread via sexual contact and from mother to fetus. While often asymptomatic, ZIKV can lead to severe neurological conditions, including microcephaly in fetuses and Guillain–Barré Syndrome in adults. ZIKV can infect placental macrophages and fetal microglia in vivo as well as human monocytes and monocyte-derived macrophages (MDMs) in vitro. Here, we observed that both human monocytes, and MDM particularly, supported ZIKV replication without evident cytopathicity, with virions accumulating in cytoplasmic vacuoles. We also investigated whether the cytokine-induced polarization of MDMs into M1 or M2 cells affected ZIKV replication. The stimulation of MDMs with pro-inflammatory cytokines (interferon-γ and tumor necrosis factor-α) polarized MDMs into M1 cells, significantly reducing ZIKV replication, akin to previous observations with a human immunodeficiency virus type-1 infection. In contrast, M2 polarization, induced by interleukin-4, did not affect ZIKV replication in MDMs. M1 polarization selectively reduced the expression of MERTK, a TAM family putative entry receptor, and increased the expression of several interferon-stimulated genes (ISGs) previously associated with the containment of ZIKV infection; of interest, ZIKV infection transiently boosted the expression of some ISGs in M1-MDMs. These findings suggest a dual mechanism of ZIKV restriction in M1-MDMs and highlight potential antiviral strategies targeting innate immune responses. Full article

(This article belongs to the Special Issue Virus–Host Interaction and Cell Restriction Mechanisms 2.0)

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15 pages, 1443 KiB

Open AccessArticle

Torque Teno Virus: A Promising Biomarker in Kidney Transplant Recipients

by Sara Dal Lago, Paola Brani, Giuseppe Ietto, Daniela Dalla Gasperina, Francesco Gianfagna, Cristina Giaroni, Annalisa Bosi, Francesca Drago Ferrante, Angelo Genoni, Hafza Zahira Manzoor, Andrea Ambrosini, Marco De Cicco, Corradina Dina Quartarone, Sara Khemara, Giulio Carcano, Fabrizio Maggi and Andreina Baj

Int. J. Mol. Sci. 2024, 25(14), 7744; https://doi.org/10.3390/ijms25147744 - 15 Jul 2024

Cited by 2 | Viewed by 3800

Abstract

Torque Teno Virus (TTV) is a ubiquitous component of the human virome, not associated with any disease. As its load increases when the immune system is compromised, such as in kidney transplant (KT) recipients, TTV load monitoring has been proposed as a method to assess immunosuppression. In this prospective study, TTV load was measured in plasma and urine samples from 42 KT recipients, immediately before KT and in the first 150 days after it. Data obtained suggest that TTV could be a relevant marker for evaluating immune status and could be used as a guide to predict the onset of infectious complications in the follow-up of KT recipients. Since we observed no differences considering distance from transplantation, while we found a changing trend in days before viral infections, we suggest to consider changes over time in the same subjects, irrespective of time distance from transplantation. Full article

(This article belongs to the Special Issue Virus–Host Interaction and Cell Restriction Mechanisms 2.0)

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22 pages, 16957 KiB

Open AccessArticle

Ectromelia Virus Affects the Formation and Spatial Organization of Adhesive Structures in Murine Dendritic Cells In Vitro

by Zuzanna Biernacka, Karolina Gregorczyk-Zboroch, Iwona Lasocka, Agnieszka Ostrowska, Justyna Struzik, Małgorzata Gieryńska, Felix N. Toka and Lidia Szulc-Dąbrowska

Int. J. Mol. Sci. 2024, 25(1), 558; https://doi.org/10.3390/ijms25010558 - 31 Dec 2023

Cited by 1 | Viewed by 1824

Abstract

Ectromelia virus (ECTV) is a causative agent of mousepox. It provides a suitable model for studying the immunobiology of orthopoxviruses, including their interaction with the host cell cytoskeleton. As professional antigen-presenting cells, dendritic cells (DCs) control the pericellular environment, capture antigens, and present them to T lymphocytes after migration to secondary lymphoid organs. Migration of immature DCs is possible due to the presence of specialized adhesion structures, such as podosomes or focal adhesions (FAs). Since assembly and disassembly of adhesive structures are highly associated with DCs’ immunoregulatory and migratory functions, we evaluated how ECTV infection targets podosomes and FAs’ organization and formation in natural-host bone marrow-derived DCs (BMDC). We found that ECTV induces a rapid dissolution of podosomes at the early stages of infection, accompanied by the development of larger and wider FAs than in uninfected control cells. At later stages of infection, FAs were predominantly observed in long cellular extensions, formed extensively by infected cells. Dissolution of podosomes in ECTV-infected BMDCs was not associated with maturation and increased 2D cell migration in a wound healing assay; however, accelerated transwell migration of ECTV-infected cells towards supernatants derived from LPS-conditioned BMDCs was observed. We suggest that ECTV-induced changes in the spatial organization of adhesive structures in DCs may alter the adhesiveness/migration of DCs during some conditions, e.g., inflammation. Full article

(This article belongs to the Special Issue Virus–Host Interaction and Cell Restriction Mechanisms 2.0)

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15 pages, 3924 KiB

Open AccessArticle

BmRRS1 Protein Inhibits the Proliferation of Baculovirus Autographa californica Nucleopolyhedrovirus in Silkworm, Bombyx mori

by Liqin Zhou, Xinyi Ding, Zhisheng Wang, Si Zhou, Sheng Qin, Xia Sun, Xueyang Wang and Muwang Li

Int. J. Mol. Sci. 2024, 25(1), 306; https://doi.org/10.3390/ijms25010306 - 25 Dec 2023

Viewed by 1412

Abstract

The study of functional genes involved in baculovirus infection is vital for its wide application in pest biocontrol. This study utilized the Autographa californica nucleopolyhedrovirus (AcMNPV) and silkworm as models to elucidate the role of BmRRS1, which has been found to exhibit notable differential expression between resistant and susceptible silkworm strains. The results showed that it was evolutionarily conserved in selected species. Among different tissues, it was expressed at the highest level in the gonads, followed by the hemolymph and silk glands; among the different developmental stages, it was the highest in the second instar, followed by the pupae and adults. Moreover, its vital role in suppressing AcMNPV infection was verified by the decreased expression of lef3 and vp39 protein after overexpression of BmRRS1 as well as by the increased expression of the viral gene lef3 and the viral protein vp39 after siRNA treatment against BmRRS1 expression in BmN cells. Additionally, the direct interaction between BmRRS1 and AcMNPV was detected by the GST pull-down assay. Finally, the homologue of BmRRS1 in Spodoptera frugiperda was found to be involved in larval resistance to AcMNPV. In a word, BmRRS1 plays a vital role in AcMNPV resistance in silkworms, and this might be related to the direct interaction with AcMNPV. The results of this study provide a potential target for protecting silkworm larvae from virus infection and controlling agricultural and forestry pests. Full article

(This article belongs to the Special Issue Virus–Host Interaction and Cell Restriction Mechanisms 2.0)

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13 pages, 2092 KiB

Open AccessArticle

A Paratope-Enhanced Method to Determine Breadth and Depth TCR Clonal Metrics of the Private Human T-Cell Vaccine Response after SARS-CoV-2 Vaccination

by Dalin Li, Ana Jimena Pavlovitch-Bedzyk, Joseph E. Ebinger, Abdul Khan, Mohamed Hamideh, Akil Merchant, Jane C. Figueiredo, Susan Cheng, Mark M. Davis, Dermot P. B. McGovern, Gil Y. Melmed, Alexander M. Xu and Jonathan Braun

Int. J. Mol. Sci. 2023, 24(18), 14223; https://doi.org/10.3390/ijms241814223 - 18 Sep 2023

Cited by 1 | Viewed by 2055

Abstract

Quantitative metrics for vaccine-induced T-cell responses are an important need for developing correlates of protection and their use in vaccine-based medical management and population health. Molecular TCR analysis is an appealing strategy but currently requires a targeted methodology involving complex integration of ex vivo data (antigen-specific functional T-cell cytokine responses and TCR molecular responses) that uncover only public antigen-specific metrics. Here, we describe an untargeted private TCR method that measures breadth and depth metrics of the T-cell response to vaccine challenge using a simple pre- and post-vaccine subject sampling, TCR immunoseq analysis, and a bioinformatic approach using self-organizing maps and GLIPH2. Among 515 subjects undergoing SARS-CoV-2 mRNA vaccination, we found that breadth and depth metrics were moderately correlated between the targeted public TCR response and untargeted private TCR response methods. The untargeted private TCR method was sufficiently sensitive to distinguish subgroups of potential clinical significance also observed using public TCR methods (the reduced T-cell vaccine response with age and the paradoxically elevated T-cell vaccine response of patients on anti-TNF immunotherapy). These observations suggest the promise of this untargeted private TCR method to produce T-cell vaccine-response metrics in an antigen-agnostic and individual-autonomous context. Full article

(This article belongs to the Special Issue Virus–Host Interaction and Cell Restriction Mechanisms 2.0)

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13 pages, 1779 KiB

Open AccessArticle

Humoral and Cellular Immune Response Elicited by the BNT162b2 COVID-19 Vaccine Booster in Elderly

by Daniela Dalla Gasperina, Giovanni Veronesi, Carlo M. Castelletti, Stefania Varchetta, Sabrina Ottolini, Dalila Mele, Giuseppe Ferrari, Amruth K. B. Shaik, Fabrizio Celesti, Francesco Dentali, Roberto S. Accolla and Greta Forlani

Int. J. Mol. Sci. 2023, 24(18), 13728; https://doi.org/10.3390/ijms241813728 - 6 Sep 2023

Cited by 4 | Viewed by 2175

Abstract

Although the safety and efficacy of COVID-19 vaccines in older people are critical to their success, little is known about their immunogenicity among elderly residents of long-term care facilities (LTCFs). A single-center prospective cohort study was conducted: a total IgG antibody titer, neutralizing antibodies against Wild-type, Delta Plus, and Omicron BA.2 variants and T cell response, were measured eight months after the second dose of BNT162b2 vaccine (T0) and at least 15 days after the booster (T1). Forty-nine LTCF residents, with a median age of 84.8 ± 10.6 years, were enrolled. Previous COVID-19 infection was documented in 42.9% of the subjects one year before T0. At T1, the IgG titers increased up to 10-fold. This ratio was lower in the subjects with previous COVID-19 infection. At T1, IgG levels were similar in both groups. The neutralizing activity against Omicron BA.2 was significantly lower (65%) than that measured against Wild-type and Delta Plus (90%). A significant increase of T cell-specific immune response was observed after the booster. Frailty, older age, sex, cognitive impairment, and comorbidities did not affect antibody titers or T cell response. In the elderly sample analyzed, the BNT162b2 mRNA COVID-19 vaccine produced immunogenicity regardless of frailty. Full article

(This article belongs to the Special Issue Virus–Host Interaction and Cell Restriction Mechanisms 2.0)

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12 pages, 1635 KiB

Open AccessArticle

Therapeutic Effect of C-Vx Substance in K18-hACE2 Transgenic Mice Infected with SARS-CoV-2

by Hivda Ulbegi Polat, Irem Abaci, Arzu Tas Ekiz, Ozge Aksoy, Fatma Betul Oktelik, Vuslat Yilmaz, Saban Tekin, Alper Okyar, Oral Oncul and Gunnur Deniz

Int. J. Mol. Sci. 2023, 24(15), 11957; https://doi.org/10.3390/ijms241511957 - 26 Jul 2023

Cited by 2 | Viewed by 1871

Abstract

C-Vx is a bioprotective product designed to boost the immune system. This study aimed to determine the antiviral activity of the C-Vx substance against SARS-CoV-2 infection. The effect of C-Vx in K18-hACE2 transgenic mice against the SARS-CoV-2 virus was investigated. For this purpose, ten mice were separated into experimental and control groups. Animals were infected with SARS-CoV-2 prior to the administration of the product to determine whether the product has a therapeutic effect similar to that demonstrated in previous human studies, at a histopathological and molecular level. C-Vx-treated mice survived the challenge, whereas the control mice became ill and/or died. The cytokine-chemokine panel with blood samples taken during the critical days of the disease revealed detailed immune responses. Our findings showed that C-Vx presented 90% protection against the SARS-CoV-2 virus-infected mice. The challenge results and cytokine responses of K18-hACE2 transgenic mice matched previous scientific studies, demonstrating the C-Vx’s antiviral efficiency. Full article

(This article belongs to the Special Issue Virus–Host Interaction and Cell Restriction Mechanisms 2.0)

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18 pages, 6130 KiB

Open AccessArticle

Role of CIV NS1 Protein in Innate Immunity and Viral Replication

by Cheng Fu, Wenhui Zhu, Nan Cao, Wenjun Liu, Zhier Lu, Ziyuan Wong, Kaiting Guan, Chunyan Hu, Baoting Han, Sen Zeng and Shuangqi Fan

Int. J. Mol. Sci. 2023, 24(12), 10056; https://doi.org/10.3390/ijms241210056 - 13 Jun 2023

Cited by 1 | Viewed by 1931

Abstract

The innate immune pathway serves as the first line of defense against viral infections and plays a crucial role in the host’s immune response in clearing viruses. Prior research has indicated that the influenza A virus has developed various strategies to avoid host immune responses. Nevertheless, the role of the NS1 protein of the canine influenza virus (CIV) in the innate immune pathway remains unclear. In this study, eukaryotic plasmids of NS1, NP, PA, PB1, and PB2 were constructed, and it was found that these proteins interact with melanoma differentiation-associated gene 5 (MDA5) and antagonize the activation of IFN-β promoters by MDA5. We selected the NS1 protein for further study and found that NS1 does not affect the interaction between the viral ribonucleoprotein (RNP) subunit and MDA5, but that it downregulates the expression of the laboratory of genetics and physiology 2 (LGP2) and retinoic acid-inducible gene-I (RIG-I) receptors in the RIG-I pathway. Additionally, NS1 was found to inhibit the expression of several antiviral proteins and cytokines, including MX dynamin like GTPase 1 (MX1), 2′-5′oligoadenylate synthetase (OAS), Signal Transducers and Activators of Transcription (STAT1), tripartite motif 25 (TRIM25), interleukin-2 (IL-2), IFN, IL-8, and IL-1β. To further investigate the role of NS1, a recombinant H3N2 virus strain (rH3N2) and an NS1-null virus (rH3N2ΔNS1) were rescued using reverse-genetic technology. The rH3N2ΔNS1 virus exhibited lower viral titers compared to rH3N2, but had a stronger activation effect on the receptors LGP2 and RIG-I. Furthermore, when compared to rH3N2, rH3N2ΔNS1 exhibited a more pronounced activation of antiviral proteins such as MX1, OAS, STAT1, and TRIM25, as well as antiviral cytokines such as IL-6, IFN-β, and IL-1β. These findings suggest a new mechanism by which NS1, a nonstructural protein of CIV, facilitates innate immune signaling and provides new avenues for the development of antiviral strategies. Full article

(This article belongs to the Special Issue Virus–Host Interaction and Cell Restriction Mechanisms 2.0)

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