International Journal of Molecular Sciences

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5 pages, 447 KiB

Open AccessEditorial

Role of Signaling Pathways in the Viral Life Cycle 2.0

by Ugo Moens

Int. J. Mol. Sci. 2022, 23(14), 7857; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23147857 - 16 Jul 2022

Cited by 1 | Viewed by 1251

Abstract

Viral infections can lead to the generation of new virus particles, whereas other viruses behave as chameleons by camouflaging themselves to evade or mislead the immune system of the host, thereby establishing a latent infection [...] Full article

(This article belongs to the Special Issue Role of Signaling Pathways in the Viral Life Cycle 2.0)

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Research

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23 pages, 4792 KiB

Open AccessArticle

The Merkel Cell Polyomavirus T-Antigens and IL-33/ST2-IL1RAcP Axis: Possible Role in Merkel Cell Carcinoma

by Kashif Rasheed, Ugo Moens, Benedetta Policastro, John Inge Johnsen, Virve Koljonen, Harri Sihto, Weng-Onn Lui and Baldur Sveinbjørnsson

Int. J. Mol. Sci. 2022, 23(7), 3702; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23073702 - 28 Mar 2022

Cited by 5 | Viewed by 2562

Abstract

Merkel cell polyomavirus (MCPyV) is a causal factor in Merkel cell carcinoma (MCC). The oncogenic potential is mediated through its viral oncoproteins large T-antigen (LT) and small T-antigen (sT). Cytokines produced by tumor cells play an important role in cancer pathogenesis, and viruses [...] Read more.

Merkel cell polyomavirus (MCPyV) is a causal factor in Merkel cell carcinoma (MCC). The oncogenic potential is mediated through its viral oncoproteins large T-antigen (LT) and small T-antigen (sT). Cytokines produced by tumor cells play an important role in cancer pathogenesis, and viruses affect their expression. Therefore, we compared human cytokine and receptor transcript levels in virus positive (V+) and virus negative (V−) MCC cell lines. Increased expression of IL-33, a potent modulator of tumor microenvironment, was observed in V+ MCC cell lines when compared to V− MCC-13 cells. Transient transfection studies with luciferase reporter plasmids demonstrated that LT and sT stimulated IL-33, ST2/IL1RL1 and IL1RAcP promoter activity. The induction of IL-33 expression was confirmed by transfecting MCC-13 cells with MCPyV LT. Furthermore, recombinant human cytokine domain IL-33 induced activation of MAP kinase and NF-κB pathways, which could be blocked by a ST2 receptor antibody. Immunohistochemical analysis demonstrated a significantly stronger IL-33, ST2, and IL1RAcP expression in MCC tissues compared to normal skin. Of interest, significantly higher IL-33 and IL1RAcP protein levels were observed in MCC patient plasma compared to plasma from healthy controls. Previous studies have demonstrated the implication of the IL-33/STL2 pathway in cancer. Because our results revealed a T-antigens-dependent induction of the IL-33/ST2 axis, IL-33/ST2 may play a role in the tumorigenesis of MCPyV-positive MCC. Therefore, neutralizing the IL-33/ST2 axis may present a novel therapeutic approach for MCC patients. Full article

(This article belongs to the Special Issue Role of Signaling Pathways in the Viral Life Cycle 2.0)

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15 pages, 1792 KiB

Open AccessArticle

Antiviral Gene Expression in Young and Aged Murine Lung during H1N1 and H3N2

by Rebecca Harris, Jianjun Yang, Kassandra Pagan, Soo Jung Cho and Heather Stout-Delgado

Int. J. Mol. Sci. 2021, 22(22), 12097; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222212097 - 09 Nov 2021

Cited by 3 | Viewed by 1734

Abstract

Influenza is a respiratory virus that alone or in combination with secondary bacterial pathogens can contribute to the development of acute pneumonia in persons >65 years of age. Host innate immune antiviral signaling early in response to influenza is essential to inhibit early [...] Read more.

Influenza is a respiratory virus that alone or in combination with secondary bacterial pathogens can contribute to the development of acute pneumonia in persons >65 years of age. Host innate immune antiviral signaling early in response to influenza is essential to inhibit early viral replication and guide the initiation of adaptive immune responses. Using young adult (3 months) and aged adult mice infected with mouse adapted H1N1 or H3N2, the results of our study illustrate dysregulated and/or diminished activation of key signaling pathways in aged lung contribute to increased lung inflammation and morbidity. Specifically, within the first seven days of infection, there were significant changes in genes associated with TLR and RIG-I signaling detected in aged murine lung in response to H1N1 or H3N2. Taken together, the results of our study expand our current understanding of age-associated changes in antiviral signaling in the lung. Full article

(This article belongs to the Special Issue Role of Signaling Pathways in the Viral Life Cycle 2.0)

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18 pages, 3072 KiB

Open AccessArticle

Cellular Protein Phosphatase 2A Regulates Cell Survival Mechanisms in Influenza A Virus Infection

by Vanessa Gerlt, Juliane Mayr, Juliana Del Sarto, Stephan Ludwig and Yvonne Boergeling

Int. J. Mol. Sci. 2021, 22(20), 11164; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222011164 - 16 Oct 2021

Cited by 1 | Viewed by 2287

Abstract

Influenza A viruses (IAVs) are respiratory pathogens that are able to hijack multiple cellular mechanisms to drive their replication. Consequently, several viral and cellular proteins undergo posttranslational modifications such as dynamic phosphorylation/dephosphorylation. In eukaryotic cells, dephosphorylation is mainly catalyzed by protein phosphatase 2A [...] Read more.

Influenza A viruses (IAVs) are respiratory pathogens that are able to hijack multiple cellular mechanisms to drive their replication. Consequently, several viral and cellular proteins undergo posttranslational modifications such as dynamic phosphorylation/dephosphorylation. In eukaryotic cells, dephosphorylation is mainly catalyzed by protein phosphatase 2A (PP2A). While the function of kinases in IAV infection is quite well studied, only little is known about the role of PP2A in IAV replication. Here, we show, by using knockdown and inhibition approaches of the catalytic subunit PP2Ac, that this phosphatase is important for efficient replication of several IAV subtypes. This could neither be attributed to alterations in the antiviral immune response nor to changes in transcription or translation of viral genes. Interestingly, decreased PP2Ac levels resulted in a significantly reduced cell viability after IAV infection. Comprehensive kinase activity profiling identified an enrichment of process networks related to apoptosis and indicated a synergistic action of hyper-activated PI3K/Akt, MAPK/JAK-STAT and NF-kB signaling pathways, collectively resulting in increased cell death. Taken together, while IAV seems to effectively tap leftover PP2A activity to ensure efficient viral replication, reduced PP2Ac levels fail to orchestrate cell survival mechanisms to protect infected cells from early cell death. Full article

(This article belongs to the Special Issue Role of Signaling Pathways in the Viral Life Cycle 2.0)

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Review

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14 pages, 1083 KiB

Open AccessReview

Neurotropic RNA Virus Modulation of Immune Responses within the Central Nervous System

by Christine Vazquez and Kellie A. Jurado

Int. J. Mol. Sci. 2022, 23(7), 4018; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23074018 - 05 Apr 2022

Cited by 5 | Viewed by 2909

Abstract

The central nervous system (CNS) necessitates intricately coordinated immune responses to prevent neurological disease. However, the emergence of viruses capable of entering the CNS and infecting neurons threatens this delicate balance. Our CNS is protected from foreign invaders and excess solutes by a [...] Read more.

The central nervous system (CNS) necessitates intricately coordinated immune responses to prevent neurological disease. However, the emergence of viruses capable of entering the CNS and infecting neurons threatens this delicate balance. Our CNS is protected from foreign invaders and excess solutes by a semipermeable barrier of endothelial cells called the blood–brain barrier. Thereby, viruses have implemented several strategies to bypass this protective layer and modulate immune responses within the CNS. In this review, we outline these immune regulatory mechanisms and provide perspectives on future questions in this rapidly expanding field. Full article

(This article belongs to the Special Issue Role of Signaling Pathways in the Viral Life Cycle 2.0)

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17 pages, 832 KiB

Open AccessReview

Roles of Nucleoporin RanBP2/Nup358 in Acute Necrotizing Encephalopathy Type 1 (ANE1) and Viral Infection

by Jing Jiang, Yifan E. Wang, Alexander F. Palazzo and Qingtang Shen

Int. J. Mol. Sci. 2022, 23(7), 3548; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23073548 - 24 Mar 2022

Cited by 16 | Viewed by 4029

Abstract

Ran Binding Protein 2 (RanBP2 or Nucleoporin358) is one of the main components of the cytoplasmic filaments of the nuclear pore complex. Mutations in the RANBP2 gene are associated with acute necrotizing encephalopathy type 1 (ANE1), a rare condition where patients experience a [...] Read more.

Ran Binding Protein 2 (RanBP2 or Nucleoporin358) is one of the main components of the cytoplasmic filaments of the nuclear pore complex. Mutations in the RANBP2 gene are associated with acute necrotizing encephalopathy type 1 (ANE1), a rare condition where patients experience a sharp rise in cytokine production in response to viral infection and undergo hyperinflammation, seizures, coma, and a high rate of mortality. Despite this, it remains unclear howRanBP2 and its ANE1-associated mutations contribute to pathology. Mounting evidence has shown that RanBP2 interacts with distinct viruses to regulate viral infection. In addition, RanBP2 may regulate innate immune response pathways. This review summarizes recent advances in our understanding of how mutations in RANBP2 contribute to ANE1 and discusses how RanBP2 interacts with distinct viruses and affects viral infection. Recent findings indicate that RanBP2 might be an important therapeutic target, not only in the suppression of ANE1-driven cytokine storms, but also to combat hyperinflammation in response to viral infections. Full article

(This article belongs to the Special Issue Role of Signaling Pathways in the Viral Life Cycle 2.0)

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19 pages, 1316 KiB

Open AccessReview

Dual Role of YY1 in HPV Life Cycle and Cervical Cancer Development

by Alicja Warowicka, Justyna Broniarczyk, Martyna Węglewska, Wojciech Kwaśniewski and Anna Goździcka-Józefiak

Int. J. Mol. Sci. 2022, 23(7), 3453; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23073453 - 22 Mar 2022

Cited by 10 | Viewed by 2906

Abstract

Human papillomaviruses (HPVs) are considered to be key etiological agents responsible for the induction and development of cervical cancer. However, it has been suggested that HPV infection alone may not be sufficient to promote cervical carcinogenesis, and other unknown factors might be required [...] Read more.

Human papillomaviruses (HPVs) are considered to be key etiological agents responsible for the induction and development of cervical cancer. However, it has been suggested that HPV infection alone may not be sufficient to promote cervical carcinogenesis, and other unknown factors might be required to establish the disease. One of the suggested proteins whose deregulation has been linked with oncogenesis is transcription factor Yin Yang 1 (YY1). YY1 is a multifunctional protein that is involved not only in the regulation of gene transcription and protein modification, but can also control important cell signaling pathways, such as cell growth, development, differentiation, and apoptosis. Vital functions of YY1 also indicate that the protein could be involved in tumorigenesis. The overexpression of this protein has been observed in different tumors, and its level has been correlated with poor prognoses of many types of cancers. YY1 can also regulate the transcription of viral genes. It has been documented that YY1 can bind to the HPV long control region and regulate the expression of viral oncogenes E6 and E7; however, its role in the HPV life cycle and cervical cancer development is different. In this review, we explore the role of YY1 in regulating the expression of cellular and viral genes and subsequently investigate how these changes inadvertently contribute toward the development of cervical malignancy. Full article

(This article belongs to the Special Issue Role of Signaling Pathways in the Viral Life Cycle 2.0)

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21 pages, 3202 KiB

Open AccessReview

Tetraspanins: Host Factors in Viral Infections

by ChihSheng New, Zhao-Yong Lee, Kai Sen Tan, Amanda Huee-Ping Wong, De Yun Wang and Thai Tran

Int. J. Mol. Sci. 2021, 22(21), 11609; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222111609 - 27 Oct 2021

Cited by 23 | Viewed by 4752

Abstract

Tetraspanins are transmembrane glycoproteins that have been shown increasing interest as host factors in infectious diseases. In particular, they were implicated in the pathogenesis of both non-enveloped (human papillomavirus (HPV)) and enveloped (human immunodeficiency virus (HIV), Zika, influenza A virus, (IAV), and coronavirus) [...] Read more.

Tetraspanins are transmembrane glycoproteins that have been shown increasing interest as host factors in infectious diseases. In particular, they were implicated in the pathogenesis of both non-enveloped (human papillomavirus (HPV)) and enveloped (human immunodeficiency virus (HIV), Zika, influenza A virus, (IAV), and coronavirus) viruses through multiple stages of infection, from the initial cell membrane attachment to the syncytium formation and viral particle release. However, the mechanisms by which different tetraspanins mediate their effects vary. This review aimed to compare and contrast the role of tetraspanins in the life cycles of HPV, HIV, Zika, IAV, and coronavirus viruses, which cause the most significant health and economic burdens to society. In doing so, a better understanding of the relative contribution of tetraspanins in virus infection will allow for a more targeted approach in the treatment of these diseases. Full article

(This article belongs to the Special Issue Role of Signaling Pathways in the Viral Life Cycle 2.0)

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10 pages, 982 KiB

Open AccessReview

Receptor-Loaded Virion Endangers GPCR Signaling: Mechanistic Exploration of SARS-CoV-2 Infections and Pharmacological Implications

by Qiangmin Zhang and Peter A. Friedman

Int. J. Mol. Sci. 2021, 22(20), 10963; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222010963 - 11 Oct 2021

Cited by 5 | Viewed by 3054

Abstract

SARS-CoV-2 exploits the respiratory tract epithelium including lungs as the primary entry point and reaches other organs through hematogenous expansion, consequently causing multiorgan injury. Viral E protein interacts with cell junction-associated proteins PALS1 or ZO-1 to gain massive penetration by disrupting the inter-epithelial [...] Read more.

SARS-CoV-2 exploits the respiratory tract epithelium including lungs as the primary entry point and reaches other organs through hematogenous expansion, consequently causing multiorgan injury. Viral E protein interacts with cell junction-associated proteins PALS1 or ZO-1 to gain massive penetration by disrupting the inter-epithelial barrier. Conversely, receptor-mediated viral invasion ensures limited but targeted infections in multiple organs. The ACE2 receptor represents the major virion loading site by virtue of its wide tissue distribution as demonstrated in highly susceptible lung, intestine, and kidney. In brain, NRP1 mediates viral endocytosis in a similar manner to ACE2. Prominently, PDZ interaction involves the entire viral loading process either outside or inside the host cells, whereas E, ACE2, and NRP1 provide the PDZ binding motif required for interacting with PDZ domain-containing proteins PALS1, ZO-1, and NHERF1, respectively. Hijacking NHERF1 and β-arrestin by virion loading may impair specific sensory GPCR signalosome assembling and cause disordered cellular responses such as loss of smell and taste. PDZ interaction enhances SARS-CoV-2 invasion by supporting viral receptor membrane residence, implying that the disruption of these interactions could diminish SARS-CoV-2 infections and be another therapeutic strategy against COVID-19 along with antibody therapy. GPCR-targeted drugs are likely to alleviate pathogenic symptoms-associated with SARS-CoV-2 infection. Full article

(This article belongs to the Special Issue Role of Signaling Pathways in the Viral Life Cycle 2.0)

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13 pages, 710 KiB

Open AccessReview

Mechanisms of DNA Methylation in Virus-Host Interaction in Hepatitis B Infection: Pathogenesis and Oncogenetic Properties

by Dake Zhang, Shicheng Guo and Steven J. Schrodi

Int. J. Mol. Sci. 2021, 22(18), 9858; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22189858 - 12 Sep 2021

Cited by 17 | Viewed by 3981

Abstract

Hepatitis B virus (HBV), the well-studied oncovirus that contributes to the majority of hepatocellular carcinomas (HCC) worldwide, can cause a severe inflammatory microenvironment leading to genetic and epigenetic changes in hepatocyte clones. HBV replication contributes to the regulation of DNA methyltransferase gene expression, [...] Read more.

Hepatitis B virus (HBV), the well-studied oncovirus that contributes to the majority of hepatocellular carcinomas (HCC) worldwide, can cause a severe inflammatory microenvironment leading to genetic and epigenetic changes in hepatocyte clones. HBV replication contributes to the regulation of DNA methyltransferase gene expression, particularly by X protein (HBx), and subsequent methylation changes may lead to abnormal transcription activation of adjacent genes and genomic instability. Undoubtedly, the altered expression of these genes has been known to cause diverse aspects of infected hepatocytes, including apoptosis, proliferation, reactive oxygen species (ROS) accumulation, and immune responses. Additionally, pollutant-induced DNA methylation changes and aberrant methylation of imprinted genes in hepatocytes also complicate the process of tumorigenesis. Meanwhile, hepatocytes also contribute to epigenetic modification of the viral genome to affect HBV replication or viral protein production. Meanwhile, methylation levels of HBV integrants and surrounding host regions also play crucial roles in their ability to produce viral proteins in affected hepatocytes. Both host and viral changes can provide novel insights into tumorigenesis, individualized responses to therapeutic intervention, disease progress, and early diagnosis. As such, DNA methylation-mediated epigenetic silencing of cancer-related genes and viral replication is a compelling therapeutic goal to reduce morbidity and mortality from liver cancer caused by chronic HBV infection. In this review, we summarize the most recent research on aberrant DNA methylation associated with HBV infection, which is involved in HCC development, and provide an outlook on the future direction of the research. Full article

(This article belongs to the Special Issue Role of Signaling Pathways in the Viral Life Cycle 2.0)

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