International Journal of Molecular Sciences

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13 pages, 2518 KiB

Open AccessArticle

IFN-Inducible SerpinA5 Triggers Antiviral Immunity by Regulating STAT1 Phosphorylation and Nuclear Translocation

by Congcong Wang, Yajie Liu, Xinglai Liu, Jin Zhao, Bing Lang, Fan Wu, Ziyu Wen and Caijun Sun

Int. J. Mol. Sci. 2023, 24(6), 5458; https://doi.org/10.3390/ijms24065458 - 13 Mar 2023

Cited by 2 | Viewed by 2075

Abstract

Deeply understanding virus-host interactions is a prerequisite for developing effective strategies to control frequently emerging infectious diseases, which have become a serious challenge for global public health. The type I interferon (IFN)-mediated JAK/STAT pathway is well known for playing an essential role in [...] Read more.

Deeply understanding virus-host interactions is a prerequisite for developing effective strategies to control frequently emerging infectious diseases, which have become a serious challenge for global public health. The type I interferon (IFN)-mediated JAK/STAT pathway is well known for playing an essential role in host antiviral immunity, but the exact regulatory mechanisms of various IFN-stimulated genes (ISGs) are not yet fully understood. We herein reported that SerpinA5, as a novel ISG, played a previously unrecognized role in antiviral activity. Mechanistically, SerpinA5 can upregulate the phosphorylation of STAT1 and promote its nuclear translocation, thus effectively activating the transcription of IFN-related signaling pathways to impair viral infections. Our data provide insights into SerpinA5-mediated innate immune signaling during virus-host interactions. Full article

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

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16 pages, 2127 KiB

Open AccessArticle

CLEC12A Binds to Legionella pneumophila but Has No Impact on the Host’s Antibacterial Response

by Ann-Brit Klatt, Christina Diersing, Juliane Lippmann, Sabine Mayer-Lambertz, Felix Stegmann, Swantje Fischer, Sandra Caesar, Facundo Fiocca Vernengo, Katja Hönzke, Andreas C. Hocke, Jürgen Ruland, Martin Witzenrath, Bernd Lepenies and Bastian Opitz

Int. J. Mol. Sci. 2023, 24(4), 3891; https://doi.org/10.3390/ijms24043891 - 15 Feb 2023

Cited by 3 | Viewed by 2355

Abstract

Legionella pneumophila is an intracellular pathogen that can cause severe pneumonia after the inhalation of contaminated aerosols and replication in alveolar macrophages. Several pattern recognition receptors (PRRs) have been identified that contribute to the recognition of L. pneumophila by the innate immune system. [...] Read more.

Legionella pneumophila is an intracellular pathogen that can cause severe pneumonia after the inhalation of contaminated aerosols and replication in alveolar macrophages. Several pattern recognition receptors (PRRs) have been identified that contribute to the recognition of L. pneumophila by the innate immune system. However, the function of the C-type lectin receptors (CLRs), which are mainly expressed by macrophages and other myeloid cells, remains largely unexplored. Here, we used a library of CLR-Fc fusion proteins to search for CLRs that can bind the bacterium and identified the specific binding of CLEC12A to L. pneumophila. Subsequent infection experiments in human and murine macrophages, however, did not provide evidence for a substantial role of CLEC12A in controlling innate immune responses to the bacterium. Consistently, antibacterial and inflammatory responses to Legionella lung infection were not significantly influenced by CLEC12A deficiency. Collectively, CLEC12A is able to bind to L. pneumophila-derived ligands but does not appear to play a major role in the innate defense against L. pneumophila. Full article

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

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9 pages, 661 KiB

Open AccessArticle

Increased Prevalence of Unstable HLA-C Variants in HIV-1 Rapid-Progressor Patients

by Chiara Stefani, Antonella Sangalli, Elena Locatelli, Tania Federico, Giovanni Malerba, Maria Grazia Romanelli, Gustavo Adolfo Argañaraz, Bosco Christiano Maciel Da Silva, Alberto Jose Duarte Da Silva, Jorge Casseb, Enrique Roberto Argañaraz, Alessandra Ruggiero and Donato Zipeto

Int. J. Mol. Sci. 2022, 23(23), 14852; https://doi.org/10.3390/ijms232314852 - 27 Nov 2022

Cited by 2 | Viewed by 2082

Abstract

HIV-1 infection in the absence of treatment results in progression toward AIDS. Host genetic factors play a role in HIV-1 pathogenesis, but complete knowledge is not yet available. Since less-expressed HLA-C variants are associated with poor HIV-1 control and unstable HLA-C variants are [...] Read more.

HIV-1 infection in the absence of treatment results in progression toward AIDS. Host genetic factors play a role in HIV-1 pathogenesis, but complete knowledge is not yet available. Since less-expressed HLA-C variants are associated with poor HIV-1 control and unstable HLA-C variants are associated with higher HIV-1 infectivity, we investigated whether there was a correlation between the different stages of HIV-1 progression and the presence of specific HLA-C allotypes. HLA-C genotyping was performed using allele-specific PCR by analyzing a treatment-naïve cohort of 96 HIV-1-infected patients from multicentric cohorts in the USA, Canada, and Brazil. HIV-1-positive subjects were classified according to their different disease progression status as progressors (Ps, n = 48), long-term non-progressors (LTNPs, n = 37), and elite controllers (ECs, n = 11). HLA-C variants were classified as stable or unstable according to their binding stability to β2-microglobulin/peptide complex. Our results showed a significant correlation between rapid progression to AIDS and the presence of two or one unstable HLA-C variants (p-value: 0.0078, p-value: 0.0143, respectively). These findings strongly suggest a link between unstable HLA-C variants both at genotype and at allele levels and rapid progression to AIDS. This work provides further insights into the impact of host genetic factors on AIDS progression. Full article

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

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13 pages, 1856 KiB

Open AccessArticle

Nuclear Transport of Respiratory Syncytial Virus Matrix Protein Is Regulated by Dual Phosphorylation Sites

by Reena Ghildyal, Michael N. Teng, Kim C. Tran, John Mills, Marco G. Casarotto, Philip G. Bardin and David A. Jans

Int. J. Mol. Sci. 2022, 23(14), 7976; https://doi.org/10.3390/ijms23147976 - 19 Jul 2022

Cited by 1 | Viewed by 2071

Abstract

Respiratory syncytial virus (RSV) is a major cause of respiratory infections in infants and the elderly. Although the RSV matrix (M) protein has key roles in the nucleus early in infection, and in the cytoplasm later, the molecular basis of switching between the [...] Read more.

Respiratory syncytial virus (RSV) is a major cause of respiratory infections in infants and the elderly. Although the RSV matrix (M) protein has key roles in the nucleus early in infection, and in the cytoplasm later, the molecular basis of switching between the nuclear and cytoplasmic compartments is not known. Here, we show that protein kinase CK2 can regulate M nucleocytoplasmic distribution, whereby inhibition of CK2 using the specific inhibitor 4,5,6,7-tetrabromobenzo-triazole (TBB) increases M nuclear accumulation in infected cells as well as when ectopically expressed in transfected cells. We use truncation/mutagenic analysis for the first time to show that serine (S) 95 and threonine (T) 205 are key CK2 sites that regulate M nuclear localization. Dual alanine (A)-substitution to prevent phosphorylation abolished TBB- enhancement of nuclear accumulation, while aspartic acid (D) substitution to mimic phosphorylation at S95 increased nuclear accumulation. D95 also induced cytoplasmic aggregate formation, implying that a negative charge at S95 may modulate M oligomerization. A95/205 substitution in recombinant RSV resulted in reduced virus production compared with wild type, with D95/205 substitution resulting in an even greater level of attenuation. Our data support a model where unphosphorylated M is imported into the nucleus, followed by phosphorylation of T205 and S95 later in infection to facilitate nuclear export and cytoplasmic retention of M, respectively, as well as oligomerization/virus budding. In the absence of widely available, efficacious treatments to protect against RSV, the results raise the possibility of antiviral strategies targeted at CK2. Full article

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

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15 pages, 3554 KiB

Open AccessArticle

A Panel of Eight miRNAs Is Deregulated in HTLV-2 Infected PBMCs and BJABGu Cell Line

by Elisabetta Pilotti, Attilio Cannata, Giacomo Magnani, Fabio Bignami, Andrea Corsi, Maria Teresa Valenti, Mariam Shallak, Greta Forlani and Maria Grazia Romanelli

Int. J. Mol. Sci. 2022, 23(14), 7583; https://doi.org/10.3390/ijms23147583 - 8 Jul 2022

Cited by 1 | Viewed by 1889

Abstract

Despite human T-cell leukemia virus type 1 (HTLV-1) and HTLV-2 being retroviruses closely related at a genomic level, HTLV-2 differs from HTLV-1 in terms of pathogenicity in both single infection and coinfection contexts. Moreover, the HTLV-2 association with clinical outcomes is still debated [...] Read more.

Despite human T-cell leukemia virus type 1 (HTLV-1) and HTLV-2 being retroviruses closely related at a genomic level, HTLV-2 differs from HTLV-1 in terms of pathogenicity in both single infection and coinfection contexts. Moreover, the HTLV-2 association with clinical outcomes is still debated and several mechanisms underlying HTLV-2 infection remain unexplored as well. Cellular miRNAs are key factors in the post-transcriptional regulation of gene expression and they are known to be potential targets for several pathogens to control the host microenvironment and, in particular, escape immune responses. Here, we identified a HTLV-2-related signature of eight miRNAs (miR-125a-3p, miR-381-3p, miR-502-5p, miR-708-5p, miR-548d-5p, miR-548c-5p, miR-1-3p, and miR-511-5p) in both HTLV-2 infected PBMC and BJABGu cell lines. Altered miRNA expression patterns were correlated with the impairment of Th cell differentiation and signaling pathways driven by cytokines and transcriptional factors such as the Runt-related transcription factor (RUNX) family members. Specifically, we demonstrated that the RUNX2 protein was significantly more expressed in the presence of Tax-2 compared with Tax-1 in an in vitro cell model. To the best of our knowledge, these data represent the first contribution to elucidating the HTLV-2 mediated alteration of host cell miRNA profiles that may impact on HTLV-2 replication and persistent infection. Full article

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

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15 pages, 2165 KiB

Open AccessCommunication

Vector and Host C-Type Lectin Receptor (CLR)–Fc Fusion Proteins as a Cross-Species Comparative Approach to Screen for CLR–Rift Valley Fever Virus Interactions

by Kathleen Schön, Dimitri L. Lindenwald, João T. Monteiro, Julien Glanz, Klaus Jung, Stefanie C. Becker and Bernd Lepenies

Int. J. Mol. Sci. 2022, 23(6), 3243; https://doi.org/10.3390/ijms23063243 - 17 Mar 2022

Cited by 6 | Viewed by 2636

Abstract

Rift Valley fever virus (RVFV) is a mosquito-borne bunyavirus endemic to Africa and the Arabian Peninsula, which causes diseases in humans and livestock. C-type lectin receptors (CLRs) represent a superfamily of pattern recognition receptors that were reported to interact with diverse viruses and [...] Read more.

Rift Valley fever virus (RVFV) is a mosquito-borne bunyavirus endemic to Africa and the Arabian Peninsula, which causes diseases in humans and livestock. C-type lectin receptors (CLRs) represent a superfamily of pattern recognition receptors that were reported to interact with diverse viruses and contribute to antiviral immune responses but may also act as attachment factors or entry receptors in diverse species. Human DC-SIGN and L-SIGN are known to interact with RVFV and to facilitate viral host cell entry, but the roles of further host and vector CLRs are still unknown. In this study, we present a CLR–Fc fusion protein library to screen RVFV–CLR interaction in a cross-species approach and identified novel murine, ovine, and Aedes aegypti RVFV candidate receptors. Furthermore, cross-species CLR binding studies enabled observations of the differences and similarities in binding preferences of RVFV between mammalian CLR homologues, as well as more distant vector/host CLRs. Full article

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

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14 pages, 3325 KiB

Open AccessArticle

Air-Liquid-Interface Differentiated Human Nose Epithelium: A Robust Primary Tissue Culture Model of SARS-CoV-2 Infection

by Bang M. Tran, Samantha L. Grimley, Julie L. McAuley, Abderrahman Hachani, Linda Earnest, Sharon L. Wong, Leon Caly, Julian Druce, Damian F. J. Purcell, David C. Jackson, Mike Catton, Cameron J. Nowell, Laura Leonie, Georgia Deliyannis, Shafagh A. Waters, Joseph Torresi and Elizabeth Vincan

Int. J. Mol. Sci. 2022, 23(2), 835; https://doi.org/10.3390/ijms23020835 - 13 Jan 2022

Cited by 15 | Viewed by 5227

Abstract

The global urgency to uncover medical countermeasures to combat the COVID-19 pandemic caused by the severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) has revealed an unmet need for robust tissue culture models that faithfully recapitulate key features of human tissues and disease. Infection of [...] Read more.

The global urgency to uncover medical countermeasures to combat the COVID-19 pandemic caused by the severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) has revealed an unmet need for robust tissue culture models that faithfully recapitulate key features of human tissues and disease. Infection of the nose is considered the dominant initial site for SARS-CoV-2 infection and models that replicate this entry portal offer the greatest potential for examining and demonstrating the effectiveness of countermeasures designed to prevent or manage this highly communicable disease. Here, we test an air–liquid-interface (ALI) differentiated human nasal epithelium (HNE) culture system as a model of authentic SARS-CoV-2 infection. Progenitor cells (basal cells) were isolated from nasal turbinate brushings, expanded under conditionally reprogrammed cell (CRC) culture conditions and differentiated at ALI. Differentiated cells were inoculated with different SARS-CoV-2 clinical isolates. Infectious virus release into apical washes was determined by TCID₅₀, while infected cells were visualized by immunofluorescence and confocal microscopy. We demonstrate robust, reproducible SARS-CoV-2 infection of ALI-HNE established from different donors. Viral entry and release occurred from the apical surface, and infection was primarily observed in ciliated cells. In contrast to the ancestral clinical isolate, the Delta variant caused considerable cell damage. Successful establishment of ALI-HNE is donor dependent. ALI-HNE recapitulate key features of human SARS-CoV-2 infection of the nose and can serve as a pre-clinical model without the need for invasive collection of human respiratory tissue samples. Full article

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

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24 pages, 4782 KiB

Open AccessArticle

Characterizing the Interaction between the HTLV-1 Transactivator Tax-1 with Transcription Elongation Factor ELL2 and Its Impact on Viral Transactivation

by Stephan Kohrt, Sarah Strobel, Melanie C. Mann, Heinrich Sticht, Bernhard Fleckenstein and Andrea K. Thoma-Kress

Int. J. Mol. Sci. 2021, 22(24), 13597; https://doi.org/10.3390/ijms222413597 - 18 Dec 2021

Cited by 1 | Viewed by 3302

Abstract

The human T-cell leukemia virus type 1 (HTLV-1)-encoded transactivator and oncoprotein Tax-1 is essential for HTLV-1 replication. We recently found that Tax-1 interacts with transcription elongation factor for RNA polymerase II 2, ELL2, which enhances Tax-1-mediated transactivation of the HTLV-1 promotor. Here, we [...] Read more.

The human T-cell leukemia virus type 1 (HTLV-1)-encoded transactivator and oncoprotein Tax-1 is essential for HTLV-1 replication. We recently found that Tax-1 interacts with transcription elongation factor for RNA polymerase II 2, ELL2, which enhances Tax-1-mediated transactivation of the HTLV-1 promotor. Here, we characterize the Tax-1:ELL2 interaction and its impact on viral transactivation by confocal imaging, co-immunoprecipitation, and luciferase assays. We found that Tax-1 and ELL2 not only co-precipitate, but also co-localize in dot-like structures in the nucleus. Tax-1:ELL2 complex formation occurred independently of Tax-1 point mutations, which are crucial for post translational modifications (PTMs) of Tax-1, suggesting that these PTMs are irrelevant for Tax-1:ELL2 interaction. In contrast, Tax-1 deletion mutants lacking either N-terminal (aa 1–37) or C-terminal regions (aa 150–353) of Tax-1 were impaired in interacting with ELL2. Contrary to Tax-1, the related, non-oncogenic Tax-2B from HTLV-2B did not interact with ELL2. Finally, we found that ELL2-R1 (aa 1–353), which carries an RNA polymerase II binding domain, and ELL2-R3 (aa 515–640) are sufficient to interact with Tax-1; however, only ELL2-truncations expressing R1 could enhance Tax-1-mediated transactivation of the HTLV-1 promoter. Together, this study identifies domains in Tax-1 and ELL2 being required for Tax-1:ELL2 complex formation and for viral transactivation. Full article

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

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20 pages, 18951 KiB

Open AccessArticle

Mechanisms Involved in the Promoting Activity of Fibroblasts in HTLV-1-Mediated Lymphomagenesis: Insights into the Plasticity of Lymphomatous Cells

by Giulia Rigotto, Barbara Montini, Adriana Mattiolo, Nayana Lazzari, Maria Assunta Piano, Daniel Remondini, Sandra Marmiroli, Jessika Bertacchini, Luigi Chieco-Bianchi and Maria Luisa Calabrò

Int. J. Mol. Sci. 2021, 22(19), 10562; https://doi.org/10.3390/ijms221910562 - 29 Sep 2021

Viewed by 2062

Abstract

Among the mechanisms leading to progression to Adult T-cell Leukaemia/Lymphoma in Human T-cell Leukaemia Virus type 1 (HTLV-1)-infected subjects, the contribution of stromal components remains poorly understood. To dissect the role of fibroblasts in HTLV-1-mediated lymphomagenesis, transcriptome studies, cytofluorimetric and qRT-PCR analyses of [...] Read more.

Among the mechanisms leading to progression to Adult T-cell Leukaemia/Lymphoma in Human T-cell Leukaemia Virus type 1 (HTLV-1)-infected subjects, the contribution of stromal components remains poorly understood. To dissect the role of fibroblasts in HTLV-1-mediated lymphomagenesis, transcriptome studies, cytofluorimetric and qRT-PCR analyses of surface and intracellular markers linked to plasticity and stemness in coculture, and in vivo experiments were performed. A transcriptomic comparison between a more lymphomagenic (C91/III) and the parental (C91/PL) cell line evidenced hyperactivation of the PI3K/Akt pathway, confirmed by phospho-ELISA and 2-DE and WB analyses. C91/III cells also showed higher expression of mesenchymal and stemness genes. Short-term coculture with human foreskin fibroblasts (HFF) induced these features in C91/PL cells, and significantly increased not only the cancer stem cells (CSCs)-supporting CD10⁺GPR77⁺ HFF subpopulation, but also the percentage of ALDH1^bright C91/PL cells. A non-cytotoxic acetylsalicylic acid treatment decreased HFF-induced ALDH1^bright C91/PL cells, downregulated mesenchymal and stemness genes in cocultured cells, and delayed lymphoma growth in immunosuppressed mice, thus hindering the supportive activity of HFF on CSCs. These data suggest that crosstalk with HFF significantly intensifies the aggressiveness and plasticity of C91/PL cells, leading to the enrichment in lymphoma-initiating cells. Additional research is needed to better characterize these preliminary findings. Full article

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

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17 pages, 3659 KiB

Open AccessArticle

RNA Modifications in Genomic RNA of Influenza A Virus and the Relationship between RNA Modifications and Viral Infection

by Yuki Furuse

Int. J. Mol. Sci. 2021, 22(17), 9127; https://doi.org/10.3390/ijms22179127 - 24 Aug 2021

Cited by 20 | Viewed by 4742

Abstract

Recent studies about the transcriptome-wide presence of RNA modifications have revealed their importance in many cellular functions. Nevertheless, information about RNA modifications in viral RNA is scarce, especially for negative-strand RNA viruses. Here we provide a catalog of RNA modifications including m1A, ac4C, [...] Read more.

Recent studies about the transcriptome-wide presence of RNA modifications have revealed their importance in many cellular functions. Nevertheless, information about RNA modifications in viral RNA is scarce, especially for negative-strand RNA viruses. Here we provide a catalog of RNA modifications including m1A, ac4C, m7G, inosine, and pseudouridine on RNA derived from an influenza A virus infected into A549 cells, as studied by RNA immunoprecipitation followed by deep-sequencing. Possible regions with RNA modifications were found in the negative-strand segments of viral genomic RNA. In addition, our analyses of previously published data revealed that the expression levels of the host factors for RNA modifications were affected by an infection with influenza A virus, and some of the host factors likely have a proviral effect. RNA modification is a novel aspect of host–virus interactions leading to the discovery of previously unrecognized viral pathogenicity mechanisms and has the potential to aid the development of novel antivirals. Full article

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

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13 pages, 2337 KiB

Open AccessArticle

Transgenic Chicks Expressing Interferon-Inducible Transmembrane Protein 1 (IFITM1) Restrict Highly Pathogenic H5N1 Influenza Viruses

by Mohammed A. Rohaim, Mohammad Q. Al-Natour, Mohammed A. Abdelsabour, Rania F. El Naggar, Yahia M. Madbouly, Kawkab A. Ahmed and Muhammad Munir

Int. J. Mol. Sci. 2021, 22(16), 8456; https://doi.org/10.3390/ijms22168456 - 6 Aug 2021

Cited by 11 | Viewed by 3640

Abstract

Mammalian cells utilize a wide spectrum of pathways to antagonize the viral replication. These pathways are typically regulated by antiviral proteins and can be constitutively expressed but also exacerbated by interferon induction. A myriad of interferon-stimulated genes (ISGs) have been identified in mounting [...] Read more.

Mammalian cells utilize a wide spectrum of pathways to antagonize the viral replication. These pathways are typically regulated by antiviral proteins and can be constitutively expressed but also exacerbated by interferon induction. A myriad of interferon-stimulated genes (ISGs) have been identified in mounting broad-spectrum antiviral responses. Members of the interferon-induced transmembrane (IFITM) family of proteins are unique among these ISGs due to their ability to prevent virus entry through the lipid bilayer into the cell. In the current study, we generated transgenic chickens that constitutively and stably expressed chicken IFITM1 (chIFITM1) using the avian sarcoma-leukosis virus (RCAS)-based gene transfer system. The challenged transgenic chicks with clinical dose 10⁴ egg infective dose 50 (EID₅₀) of highly pathogenic avian influenza virus (HPAIV) subtype H5N1 (clade 2.2.1.2) showed 100% protection and significant infection tolerance. Although challenged transgenic chicks displayed 60% protection against challenge with the sub-lethal dose (EID₅₀ 10⁵), the transgenic chicks showed delayed clinical symptoms, reduced virus shedding, and reduced histopathologic alterations compared to non-transgenic challenged control chickens. These finding indicate that the sterile defense against H5N1 HPAIV offered by the stable expression of chIFITM1 is inadequate; however, the clinical outcome can be substantially ameliorated. In conclusion, chIFITM proteins can inhibit influenza virus replication that can infect various host species and could be a crucial barrier against zoonotic infections. Full article

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

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17 pages, 3410 KiB

Open AccessArticle

High Levels of the Cleaved Form of Galectin-9 and Osteopontin in the Plasma Are Associated with Inflammatory Markers That Reflect the Severity of COVID-19 Pneumonia

by Gaowa Bai, Daisuke Furushima, Toshiro Niki, Takashi Matsuba, Yosuke Maeda, Atsushi Takahashi, Toshio Hattori and Yugo Ashino

Int. J. Mol. Sci. 2021, 22(9), 4978; https://doi.org/10.3390/ijms22094978 - 7 May 2021

Cited by 27 | Viewed by 4233

Abstract

Numbers of patients with coronavirus disease 2019 (COVID-19) have increased rapidly worldwide. Plasma levels of full-length galectin-9 (FL-Gal9) and osteopontin (FL-OPN) as well as their truncated forms (Tr-Gal9, Ud-OPN, respectively), are representative inflammatory biomarkers. Here, we measured FL-Gal9, FL-OPN, Tr-Gal9, and Ud-OPN in [...] Read more.

Numbers of patients with coronavirus disease 2019 (COVID-19) have increased rapidly worldwide. Plasma levels of full-length galectin-9 (FL-Gal9) and osteopontin (FL-OPN) as well as their truncated forms (Tr-Gal9, Ud-OPN, respectively), are representative inflammatory biomarkers. Here, we measured FL-Gal9, FL-OPN, Tr-Gal9, and Ud-OPN in 94 plasma samples obtained from 23 COVID-19-infected patients with mild clinical symptoms (CV), 25 COVID-19 patients associated with pneumonia (CP), and 14 patients with bacterial infection (ID). The four proteins were significantly elevated in the CP group when compared with healthy individuals. ROC analysis between the CV and CP groups showed that C-reactive protein had the highest ability to differentiate, followed by Tr-Gal9 and ferritin. Spearman’s correlation analysis showed that Tr-Gal9 and Ud-OPN but not FL-Gal9 and FL-OPN, had a significant association with laboratory markers for lung function, inflammation, coagulopathy, and kidney function in CP patients. CP patients treated with tocilizumab had reduced levels of FL-Gal9, Tr-Gal9, and Ud-OPN. It was suggested that OPN is cleaved by interleukin-6-dependent proteases. These findings suggest that the cleaved forms of OPN and galectin-9 can be used to monitor the severity of pathological inflammation and the therapeutic effects of tocilizumab in CP patients. Full article

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

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15 pages, 5516 KiB

Open AccessArticle

Broadly Antiviral Activities of TAP1 through Activating the TBK1-IRF3-Mediated Type I Interferon Production

by Jin Zhao, Ruiting Li, Yanjun Li, Jiaoshan Chen, Fengling Feng and Caijun Sun

Int. J. Mol. Sci. 2021, 22(9), 4668; https://doi.org/10.3390/ijms22094668 - 28 Apr 2021

Cited by 12 | Viewed by 3225

Abstract

Deeply understanding the virus-host interaction is a prerequisite for developing effective anti-viral strategies. Traditionally, the transporter associated with antigen processing type 1 (TAP1) is critical for antigen presentation to regulate adaptive immunity. However, its role in controlling viral infections through modulating innate immune [...] Read more.

Deeply understanding the virus-host interaction is a prerequisite for developing effective anti-viral strategies. Traditionally, the transporter associated with antigen processing type 1 (TAP1) is critical for antigen presentation to regulate adaptive immunity. However, its role in controlling viral infections through modulating innate immune signaling is not yet fully understood. In the present study, we reported that TAP1, as a product of interferon-stimulated genes (ISGs), had broadly antiviral activity against various viruses such as herpes simplex virus 1 (HSV-1), adenoviruses (AdV), vesicular stomatitis virus (VSV), dengue virus (DENV), Zika virus (ZIKV), and influenza virus (PR8) etc. This antiviral activity by TAP1 was further confirmed by series of loss-of-function and gain-of-function experiments. Our further investigation revealed that TAP1 significantly promoted the interferon (IFN)-β production through activating the TANK binding kinase-1 (TBK1) and the interferon regulatory factor 3 (IRF3) signaling transduction. Our work highlighted the broadly anti-viral function of TAP1 by modulating innate immunity, which is independent of its well-known function of antigen presentation. This study will provide insights into developing novel vaccination and immunotherapy strategies against emerging infectious diseases. Full article

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

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19 pages, 2466 KiB

Open AccessArticle

Ribosome-Profiling Reveals Restricted Post Transcriptional Expression of Antiviral Cytokines and Transcription Factors during SARS-CoV-2 Infection

by Marina R. Alexander, Aaron M. Brice, Petrus Jansen van Vuren, Christina L. Rootes, Leon Tribolet, Christopher Cowled, Andrew G. D. Bean and Cameron R. Stewart

Int. J. Mol. Sci. 2021, 22(7), 3392; https://doi.org/10.3390/ijms22073392 - 25 Mar 2021

Cited by 19 | Viewed by 4896

Abstract

The global COVID-19 pandemic caused by SARS-CoV-2 has resulted in over 2.2 million deaths. Disease outcomes range from asymptomatic to severe with, so far, minimal genotypic change to the virus so understanding the host response is paramount. Transcriptomics has become incredibly important in [...] Read more.

The global COVID-19 pandemic caused by SARS-CoV-2 has resulted in over 2.2 million deaths. Disease outcomes range from asymptomatic to severe with, so far, minimal genotypic change to the virus so understanding the host response is paramount. Transcriptomics has become incredibly important in understanding host-pathogen interactions; however, post-transcriptional regulation plays an important role in infection and immunity through translation and mRNA stability, allowing tight control over potent host responses by both the host and the invading virus. Here, we apply ribosome profiling to assess post-transcriptional regulation of host genes during SARS-CoV-2 infection of a human lung epithelial cell line (Calu-3). We have identified numerous transcription factors (JUN, ZBTB20, ATF3, HIVEP2 and EGR1) as well as select antiviral cytokine genes, namely IFNB1, IFNL1,2 and 3, IL-6 and CCL5, that are restricted at the post-transcriptional level by SARS-CoV-2 infection and discuss the impact this would have on the host response to infection. This early phase restriction of antiviral transcripts in the lungs may allow high viral load and consequent immune dysregulation typically seen in SARS-CoV-2 infection. Full article

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

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Review

Jump to: Research

19 pages, 1711 KiB

Open AccessReview

Focus on Marine Animal Safety and Marine Bioresources in Response to the SARS-CoV-2 Crisis

by Yao Yang, Jiacheng Li and Fang Han

Int. J. Mol. Sci. 2022, 23(23), 15136; https://doi.org/10.3390/ijms232315136 - 1 Dec 2022

Cited by 3 | Viewed by 1912

Abstract

SARS-CoV-2 as a zoonotic virus has significantly affected daily life and social behavior since its outbreak in late 2019. The concerns over its transmission through different media directly or indirectly have evoked great attention about the survival of SARS-CoV-2 virions in the environment [...] Read more.

SARS-CoV-2 as a zoonotic virus has significantly affected daily life and social behavior since its outbreak in late 2019. The concerns over its transmission through different media directly or indirectly have evoked great attention about the survival of SARS-CoV-2 virions in the environment and its potential infection of other animals. To evaluate the risk of infection by SARS-CoV-2 and to counteract the COVID-19 disease, extensive studies have been performed to understand SARS-CoV-2 biogenesis and its pathogenesis. This review mainly focuses on the molecular architecture of SARS-CoV-2, its potential for infecting marine animals, and the prospect of drug discovery using marine natural products to combat SARS-CoV-2. The main purposes of this review are to piece together progress in SARS-CoV-2 functional genomic studies and antiviral drug development, and to raise our awareness of marine animal safety on exposure to SARS-CoV-2. Full article

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

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23 pages, 1984 KiB

Open AccessReview

ZBP1: A Powerful Innate Immune Sensor and Double-Edged Sword in Host Immunity

by Yu Hao, Bo Yang, Jinke Yang, Xijuan Shi, Xing Yang, Dajun Zhang, Dengshuai Zhao, Wenqian Yan, Lingling Chen, Haixue Zheng, Keshan Zhang and Xiangtao Liu

Int. J. Mol. Sci. 2022, 23(18), 10224; https://doi.org/10.3390/ijms231810224 - 6 Sep 2022

Cited by 29 | Viewed by 9902

Abstract

Z-conformation nucleic acid binding protein 1 (ZBP1), a powerful innate immune sensor, has been identified as the important signaling initiation factor in innate immune response and the multiple inflammatory cell death known as PANoptosis. The initiation of ZBP1 signaling requires recognition of left-handed [...] Read more.

Z-conformation nucleic acid binding protein 1 (ZBP1), a powerful innate immune sensor, has been identified as the important signaling initiation factor in innate immune response and the multiple inflammatory cell death known as PANoptosis. The initiation of ZBP1 signaling requires recognition of left-handed double-helix Z-nucleic acid (includes Z-DNA and Z-RNA) and subsequent signaling transduction depends on the interaction between ZBP1 and its adapter proteins, such as TANK-binding kinase 1 (TBK1), interferon regulatory factor 3 (IRF3), receptor-interacting serine/threonine-protein kinase 1 (RIPK1), and RIPK3. ZBP1 activated innate immunity, including type-I interferon (IFN-I) response and NF-κB signaling, constitutes an important line of defense against pathogenic infection. In addition, ZBP1-mediated PANoptosis is a double-edged sword in anti-infection, auto-inflammatory diseases, and tumor immunity. ZBP1-mediated PANoptosis is beneficial for eliminating infected cells and tumor cells, but abnormal or excessive PANoptosis can lead to a strong inflammatory response that is harmful to the host. Thus, pathogens and host have each developed multiplex tactics targeting ZBP1 signaling to maintain strong virulence or immune homeostasis. In this paper, we reviewed the mechanisms of ZBP1 signaling, the effects of ZBP1 signaling on host immunity and pathogen infection, and various antagonistic strategies of host and pathogen against ZBP1. We also discuss existent gaps regarding ZBP1 signaling and forecast potential directions for future research. Full article

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

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17 pages, 1531 KiB

Open AccessReview

Host Restriction Factors Modulating HIV Latency and Replication in Macrophages

by Isabel Pagani, Pietro Demela, Silvia Ghezzi, Elisa Vicenzi, Massimo Pizzato and Guido Poli

Int. J. Mol. Sci. 2022, 23(6), 3021; https://doi.org/10.3390/ijms23063021 - 11 Mar 2022

Cited by 12 | Viewed by 3759

Abstract

In addition to CD4⁺ T lymphocytes, myeloid cells and, particularly, differentiated macrophages are targets of human immunodeficiency virus type-1 (HIV-1) infection via the interaction of gp120Env with CD4 and CCR5 or CXCR4. Both T cells and macrophages support virus replication, although with [...] Read more.

In addition to CD4⁺ T lymphocytes, myeloid cells and, particularly, differentiated macrophages are targets of human immunodeficiency virus type-1 (HIV-1) infection via the interaction of gp120Env with CD4 and CCR5 or CXCR4. Both T cells and macrophages support virus replication, although with substantial differences. In contrast to activated CD4⁺ T lymphocytes, HIV-1 replication in macrophages occurs in nondividing cells and it is characterized by the virtual absence of cytopathicity both in vitro and in vivo. These general features should be considered in evaluating the role of cell-associated restriction factors aiming at preventing or curtailing virus replication in macrophages and T cells, particularly in the context of designing strategies to tackle the viral reservoir in infected individuals receiving combination antiretroviral therapy. In this regard, we will here also discuss a model of reversible HIV-1 latency in primary human macrophages and the role of host factors determining the restriction or reactivation of virus replication in these cells. Full article

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

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19 pages, 692 KiB

Open AccessReview

The Role of Host Glycobiology and Gut Microbiota in Rotavirus and Norovirus Infection, an Update

by Nazaret Peña-Gil, Cristina Santiso-Bellón, Roberto Gozalbo-Rovira, Javier Buesa, Vicente Monedero and Jesús Rodríguez-Díaz

Int. J. Mol. Sci. 2021, 22(24), 13473; https://doi.org/10.3390/ijms222413473 - 15 Dec 2021

Cited by 24 | Viewed by 5173

Abstract

Rotavirus (RV) and norovirus (NoV) are the leading causes of acute gastroenteritis (AGE) worldwide. Several studies have demonstrated that histo-blood group antigens (HBGAs) have a role in NoV and RV infections since their presence on the gut epithelial surfaces is essential for the [...] Read more.

Rotavirus (RV) and norovirus (NoV) are the leading causes of acute gastroenteritis (AGE) worldwide. Several studies have demonstrated that histo-blood group antigens (HBGAs) have a role in NoV and RV infections since their presence on the gut epithelial surfaces is essential for the susceptibility to many NoV and RV genotypes. Polymorphisms in genes that code for enzymes required for HBGAs synthesis lead to secretor or non-secretor and Lewis positive or Lewis negative individuals. While secretor individuals appear to be more susceptible to RV infections, regarding NoVs infections, there are too many discrepancies that prevent the ability to draw conclusions. A second factor that influences enteric viral infections is the gut microbiota of the host. In vitro and animal studies have determined that the gut microbiota limits, but in some cases enhances enteric viral infection. The ways that microbiota can enhance NoV or RV infection include virion stabilization and promotion of virus attachment to host cells, whereas experiments with microbiota-depleted and germ-free animals point to immunoregulation as the mechanism by which the microbiota restrict infection. Human trials with live, attenuated RV vaccines and analysis of the microbiota in responder and non-responder individuals also allowed the identification of bacterial taxa linked to vaccine efficacy. As more information is gained on the complex relationships that are established between the host (glycobiology and immune system), the gut microbiota and intestinal viruses, new avenues will open for the development of novel anti-NoV and anti-RV therapies. Full article

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

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19 pages, 1054 KiB

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Epigenetic Dysregulations in Merkel Cell Polyomavirus-Driven Merkel Cell Carcinoma

by John Charles Rotondo, Chiara Mazziotta, Carmen Lanzillotti, Mauro Tognon and Fernanda Martini

Int. J. Mol. Sci. 2021, 22(21), 11464; https://doi.org/10.3390/ijms222111464 - 24 Oct 2021

Cited by 40 | Viewed by 5959

Abstract

Merkel cell polyomavirus (MCPyV) is a small DNA virus with oncogenic potential. MCPyV is the causative agent of Merkel Cell Carcinoma (MCC), a rare but aggressive tumor of the skin. The role of epigenetic mechanisms, such as histone posttranslational modifications (HPTMs), DNA methylation, [...] Read more.

Merkel cell polyomavirus (MCPyV) is a small DNA virus with oncogenic potential. MCPyV is the causative agent of Merkel Cell Carcinoma (MCC), a rare but aggressive tumor of the skin. The role of epigenetic mechanisms, such as histone posttranslational modifications (HPTMs), DNA methylation, and microRNA (miRNA) regulation on MCPyV-driven MCC has recently been highlighted. In this review, we aim to describe and discuss the latest insights into HPTMs, DNA methylation, and miRNA regulation, as well as their regulative factors in the context of MCPyV-driven MCC, to provide an overview of current findings on how MCPyV is involved in the dysregulation of these epigenetic processes. The current state of the art is also described as far as potentially using epigenetic dysregulations and related factors as diagnostic and prognostic tools is concerned, in addition to targets for MCPyV-driven MCC therapy. Growing evidence suggests that the dysregulation of HPTMs, DNA methylation, and miRNA pathways plays a role in MCPyV-driven MCC etiopathogenesis, which, therefore, may potentially be clinically significant for this deadly tumor. A deeper understanding of these mechanisms and related factors may improve diagnosis, prognosis, and therapy for MCPyV-driven MCC. Full article

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

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24 pages, 1259 KiB

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HTLV-1 Infection and Pathogenesis: New Insights from Cellular and Animal Models

by Greta Forlani, Mariam Shallak, Roberto Sergio Accolla and Maria Grazia Romanelli

Int. J. Mol. Sci. 2021, 22(15), 8001; https://doi.org/10.3390/ijms22158001 - 27 Jul 2021

Cited by 24 | Viewed by 10402

Abstract

Since the discovery of the human T-cell leukemia virus-1 (HTLV-1), cellular and animal models have provided invaluable contributions in the knowledge of viral infection, transmission and progression of HTLV-associated diseases. HTLV-1 is the causative agent of the aggressive adult T-cell leukemia/lymphoma and inflammatory [...] Read more.

Since the discovery of the human T-cell leukemia virus-1 (HTLV-1), cellular and animal models have provided invaluable contributions in the knowledge of viral infection, transmission and progression of HTLV-associated diseases. HTLV-1 is the causative agent of the aggressive adult T-cell leukemia/lymphoma and inflammatory diseases such as the HTLV-1 associated myelopathy/tropical spastic paraparesis (HAM/TSP). Cell models contribute to defining the role of HTLV proteins, as well as the mechanisms of cell-to-cell transmission of the virus. Otherwise, selected and engineered animal models are currently applied to recapitulate in vivo the HTLV-1 associated pathogenesis and to verify the effectiveness of viral therapy and host immune response. Here we review the current cell models for studying virus–host interaction, cellular restriction factors and cell pathway deregulation mediated by HTLV products. We recapitulate the most effective animal models applied to investigate the pathogenesis of HTLV-1-associated diseases such as transgenic and humanized mice, rabbit and monkey models. Finally, we summarize the studies on STLV and BLV, two closely related HTLV-1 viruses in animals. The most recent anticancer and HAM/TSP therapies are also discussed in view of the most reliable experimental models that may accelerate the translation from the experimental findings to effective therapies in infected patients. Full article

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

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30 pages, 1772 KiB

Open AccessReview

Latency Reversing Agents: Kick and Kill of HTLV-1?

by Annika P. Schnell, Stephan Kohrt and Andrea K. Thoma-Kress

Int. J. Mol. Sci. 2021, 22(11), 5545; https://doi.org/10.3390/ijms22115545 - 24 May 2021

Cited by 13 | Viewed by 5817

Abstract

Human T-cell leukemia virus type 1 (HTLV-1), the cause of adult T-cell leukemia/lymphoma (ATLL), is a retrovirus, which integrates into the host genome and persistently infects CD4⁺ T-cells. Virus propagation is stimulated by (1) clonal expansion of infected cells and (2) de [...] Read more.

Human T-cell leukemia virus type 1 (HTLV-1), the cause of adult T-cell leukemia/lymphoma (ATLL), is a retrovirus, which integrates into the host genome and persistently infects CD4⁺ T-cells. Virus propagation is stimulated by (1) clonal expansion of infected cells and (2) de novo infection. Viral gene expression is induced by the transactivator protein Tax, which recruits host factors like positive transcription elongation factor b (P-TEFb) to the viral promoter. Since HTLV-1 gene expression is repressed in vivo by viral, cellular, and epigenetic mechanisms in late phases of infection, HTLV-1 avoids an efficient CD8⁺ cytotoxic T-cell (CTL) response directed against the immunodominant viral Tax antigen. Hence, therapeutic strategies using latency reversing agents (LRAs) sought to transiently activate viral gene expression and antigen presentation of Tax to enhance CTL responses towards HTLV-1, and thus, to expose the latent HTLV-1 reservoir to immune destruction. Here, we review strategies that aimed at enhancing Tax expression and Tax-specific CTL responses to interfere with HTLV-1 latency. Further, we provide an overview of LRAs including (1) histone deacetylase inhibitors (HDACi) and (2) activators of P-TEFb, that have mainly been studied in context of human immunodeficiency virus (HIV), but which may also be powerful in the context of HTLV-1. Full article

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

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22 pages, 1647 KiB

Open AccessReview

Immunopathology of Chronic Hepatitis B Infection: Role of Innate and Adaptive Immune Response in Disease Progression

by Arshi Khanam, Joel V. Chua and Shyam Kottilil

Int. J. Mol. Sci. 2021, 22(11), 5497; https://doi.org/10.3390/ijms22115497 - 23 May 2021

Cited by 70 | Viewed by 12060

Abstract

More than 250 million people are living with chronic hepatitis B despite the availability of highly effective vaccines and oral antivirals. Although innate and adaptive immune cells play crucial roles in controlling hepatitis B virus (HBV) infection, they are also accountable for inflammation [...] Read more.

More than 250 million people are living with chronic hepatitis B despite the availability of highly effective vaccines and oral antivirals. Although innate and adaptive immune cells play crucial roles in controlling hepatitis B virus (HBV) infection, they are also accountable for inflammation and subsequently cause liver pathologies. During the initial phase of HBV infection, innate immunity is triggered leading to antiviral cytokines production, followed by activation and intrahepatic recruitment of the adaptive immune system resulting in successful virus elimination. In chronic HBV infection, significant alterations in both innate and adaptive immunity including expansion of regulatory cells, overexpression of co-inhibitory receptors, presence of abundant inflammatory mediators, and modifications in immune cell derived exosome release and function occurs, which overpower antiviral response leading to persistent viral infection and subsequent immune pathologies associated with disease progression towards fibrosis, cirrhosis, and hepatocellular carcinoma. In this review, we discuss the current knowledge of innate and adaptive immune cells transformations that are associated with immunopathogenesis and disease outcome in CHB patients. Full article

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

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