Tetraspanins: Host Factors in Viral Infections

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.

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HERC5 and the ISGylation Pathway: Critical Modulators of the Antiviral Immune Response

Viruses ◽

10.3390/v13061102 ◽

2021 ◽

Vol 13 (6) ◽

pp. 1102

Author(s):

Nicholas A. Mathieu ◽

Ermela Paparisto ◽

Stephen D. Barr ◽

Donald E. Spratt

Keyword(s):

Mammalian Cells ◽

Drug Targets ◽

Influenza A ◽

Viral Infections ◽

Viral Proteins ◽

Viral Pathogens ◽

Antiviral Immune Response ◽

Immunodeficiency Virus ◽

Interferon Stimulated Gene 15

Mammalian cells have developed an elaborate network of immunoproteins that serve to identify and combat viral pathogens. Interferon-stimulated gene 15 (ISG15) is a 15.2 kDa tandem ubiquitin-like protein (UBL) that is used by specific E1–E2–E3 ubiquitin cascade enzymes to interfere with the activity of viral proteins. Recent biochemical studies have demonstrated how the E3 ligase HECT and RCC1-containing protein 5 (HERC5) regulates ISG15 signaling in response to hepatitis C (HCV), influenza-A (IAV), human immunodeficiency virus (HIV), SARS-CoV-2 and other viral infections. Taken together, the potent antiviral activity displayed by HERC5 and ISG15 make them promising drug targets for the development of novel antiviral therapeutics that can augment the host antiviral response. In this review, we examine the emerging role of ISG15 in antiviral immunity with a particular focus on how HERC5 orchestrates the specific and timely ISGylation of viral proteins in response to infection.

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PPAR Gamma and Viral Infections of the Brain

International Journal of Molecular Sciences ◽

10.3390/ijms22168876 ◽

2021 ◽

Vol 22 (16) ◽

pp. 8876

Author(s):

Pierre Layrolle ◽

Pierre Payoux ◽

Stéphane Chavanas

Keyword(s):

Viral Infections ◽

Ppar Gamma ◽

Brain Parenchyma ◽

Peroxisome Proliferator ◽

Neural Cells ◽

Peroxisome Proliferator Activated Receptor ◽

Immunodeficiency Virus ◽

Health And Disease ◽

The Brain

Peroxisome Proliferator-Activated Receptor gamma (PPARγ) is a master regulator of metabolism, adipogenesis, inflammation and cell cycle, and it has been extensively studied in the brain in relation to inflammation or neurodegeneration. Little is known however about its role in viral infections of the brain parenchyma, although they represent the most frequent cause of encephalitis and are a major threat for the developing brain. Specific to viral infections is the ability to subvert signaling pathways of the host cell to ensure virus replication and spreading, as deleterious as the consequences may be for the host. In this respect, the pleiotropic role of PPARγ makes it a critical target of infection. This review aims to provide an update on the role of PPARγ in viral infections of the brain. Recent studies have highlighted the involvement of PPARγ in brain or neural cells infected by immunodeficiency virus 1, Zika virus, or human cytomegalovirus. They have provided a better understanding on PPARγ functions in the infected brain, and revealed that it can be a double-edged sword with respect to inflammation, viral replication, or neuronogenesis. They unraveled new roles of PPARγ in health and disease and could possibly help designing new therapeutic strategies.

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Extracellular Vesicles in the Pathogenesis of Viral Infections in Humans

Viruses ◽

10.3390/v12101200 ◽

2020 ◽

Vol 12 (10) ◽

pp. 1200 ◽

Cited By ~ 1

Author(s):

Allen Caobi ◽

Madhavan Nair ◽

Andrea D. Raymond

Keyword(s):

Extracellular Vesicles ◽

Viral Infections ◽

Membrane Vesicles ◽

Response Modulation ◽

Viral Spread ◽

Neurotropic Viruses ◽

Immunodeficiency Virus ◽

Immune Response Modulation ◽

Potential Use

Most cells can release extracellular vesicles (EVs), membrane vesicles containing various proteins, nucleic acids, enzymes, and signaling molecules. The exchange of EVs between cells facilitates intercellular communication, amplification of cellular responses, immune response modulation, and perhaps alterations in viral pathogenicity. EVs serve a dual role in inhibiting or enhancing viral infection and pathogenesis. This review examines the current literature on EVs to explore the complex role of EVs in the enhancement, inhibition, and potential use as a nanotherapeutic against clinically relevant viruses, focusing on neurotropic viruses: Zika virus (ZIKV) and human immunodeficiency virus (HIV). Overall, this review’s scope will elaborate on EV-based mechanisms, which impact viral pathogenicity, facilitate viral spread, and modulate antiviral immune responses.

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BPIFB3 interacts with ARFGAP1 and TMED9 to regulate non-canonical autophagy and RNA virus infection

Journal of Cell Science ◽

10.1242/jcs.251835 ◽

2020 ◽

pp. jcs.251835

Author(s):

Azia S. Evans ◽

Nicholas J. Lennemann ◽

Carolyn B. Coyne

Keyword(s):

Mass Spectrometry ◽

Mammalian Cells ◽

Viral Infections ◽

Rna Viruses ◽

Rna Virus ◽

Negative Regulator ◽

Host Factors ◽

Important Negative Regulator ◽

Cellular Components

Autophagy is a degradative cellular pathway that targets cytoplasmic contents and organelles for turnover by the lysosome. Various autophagy pathways play key roles in the clearance of viral infections, and many families of viruses have developed unique methods for avoiding degradation. Some positive stranded RNA viruses, such as enteroviruses and flaviviruses, usurp the autophagic pathway to promote their own replication. We previously identified the endoplasmic reticulum-localized protein BPIFB3 as an important negative regulator of non-canonical autophagy that uniquely impacts the replication of enteroviruses and flaviviruses. Here, we find that many components of the canonical autophagy machinery are not required for BPIFB3 depletion induced autophagy and identify the host factors that facilitate its role in the replication of enteroviruses and flaviviruses. Using proximity-dependent biotinylation (BioID) followed by mass spectrometry, we identify ARFGAP1 and TMED9 as two cellular components that interact with BPIFB3 to regulate autophagy and viral replication. Importantly, our data demonstrate that non-canonical autophagy in mammalian cells can be controlled outside of the traditional pathway regulators and define the role of two proteins in BPIFB3 depletion mediated non-canonical autophagy.

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RNA editing enzyme adenosine deaminase is a restriction factor for controlling measles virus replication that also is required for embryogenesis

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1017241108 ◽

2010 ◽

Vol 108 (1) ◽

pp. 331-336 ◽

Cited By ~ 112

Author(s):

Simone V. Ward ◽

Cyril X. George ◽

Megan J. Welch ◽

Li-Ying Liou ◽

Bumsuk Hahm ◽

...

Keyword(s):

Adenosine Deaminase ◽

Virus Replication ◽

Measles Virus ◽

Influenza A ◽

Sendai Virus ◽

Subacute Sclerosing Panencephalitis ◽

Lymphocyte Activation ◽

Syncytium Formation ◽

Restriction Factor

Measles virus (MV), a member of the family Paramyxoviridae and an exclusively human pathogen, is among the most infectious viruses. A progressive fatal neurodegenerative complication, subacute sclerosing panencephalitis (SSPE), occurs during persistent MV infection of the CNS and is associated with biased hypermutations of the viral genome. The observed hypermutations of A-to-G are consistent with conversions catalyzed by the adenosine deaminase acting on RNA (ADAR1). To evaluate the role of ADAR1 in MV infection, we selectively disrupted expression of the IFN-inducible p150 ADAR1 isoform and found it caused embryonic lethality at embryo day (E) 11–E12. We therefore generated p150-deficient and WT mouse embryo fibroblast (MEF) cells stably expressing the MV receptor signaling lymphocyte activation molecule (SLAM or CD150). The p150−/−but not WT MEF cells displayed extensive syncytium formation and cytopathic effect (CPE) following infection with MV, consistent with an anti-MV role of the p150 isoform of ADAR1. MV titers were 3 to 4 log higher in p150−/−cells compared with WT cells at 21 h postinfection, and restoration of ADAR1 in p150−/−cells prevented MV cytopathology. In contrast to infection with MV, p150 disruption had no effect on vesicular stomatitis virus, reovirus, or lymphocytic choriomeningitis virus replication but protected against CPE resulting from infection with Newcastle disease virus, Sendai virus, canine distemper virus, and influenza A virus. Thus, ADAR1 is a restriction factor in the replication of paramyxoviruses and orthomyxoviruses.

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Activation of the aryl hydrocarbon receptor increases pulmonary neutrophilia and diminishes host resistance to influenza A virus

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00318.2004 ◽

2005 ◽

Vol 289 (1) ◽

pp. L111-L124 ◽

Cited By ~ 58

Author(s):

Sabine Teske ◽

Andrea A. Bohn ◽

Jean F. Regal ◽

Joshua J. Neumiller ◽

B. Paige Lawrence

Keyword(s):

Aryl Hydrocarbon Receptor ◽

Influenza A Virus ◽

Influenza A ◽

Viral Infections ◽

Inflammatory Responses ◽

Neutrophil Function ◽

Aryl Hydrocarbon ◽

Potent Agonist

Unlike their role in bacterial infection, less is known about the role of neutrophils during pulmonary viral infection. Exposure to pollutant 2,3,7,8-tetrachlorodibenzo- p-dioxin (TCDD, dioxin) results in excess neutrophils in the lungs of mice infected with influenza A virus. TCDD is the most potent agonist for the aryl hydrocarbon receptor (AhR), and exposure to AhR ligands has been correlated with exacerbated inflammatory lung diseases. However, knowledge of the effects of AhR agonists on neutrophils is limited. Likewise, the factors regulating neutrophil responses during respiratory viral infections are not well characterized. To address these knowledge gaps, we determined the in vivo levels of KC, MIP-1α, MIP-2, LIX, IL-6, and C5a in infected mouse lungs. Our data show that these neutrophil chemoattractants are generally produced transiently in the lung within 12–24 h of infection. We also report that expression of CD11a, CD11b, CD49d, CD31, and CD38 is increased on pulmonary neutrophils in response to influenza virus. Using AhR-deficient mice, we demonstrate that excess neutrophilia in the lung is mediated by activation of the AhR and that this enhanced neutrophilia correlates directly with decreased survival in TCDD-exposed mice. Although AhR activation results in more neutrophils in the lungs, we show that this is not mediated by deregulation in levels of common neutrophil chemoattractants, expression of adhesion molecules on pulmonary neutrophils, or delayed death of neutrophils. Likewise, exposure to TCDD did not enhance pulmonary neutrophil function. This study provides an important first step in elucidating the mechanisms by which AhR agonists exacerbate pulmonary inflammatory responses.

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Effects of APOBEC3G's Cytidine Deaminase Activity on Retroviral Evolution

Columbia Undergraduate Science Journal ◽

10.52214/cusj.v15i1.7788 ◽

2021 ◽

Vol 15 ◽

pp. 55-61

Author(s):

Mary-Benedicta Obikili

Keyword(s):

Viral Infection ◽

Mammalian Cells ◽

Viral Infections ◽

Cytidine Deaminase ◽

Viral Evolution ◽

Cytidine Deaminase Activity ◽

Immunodeficiency Virus ◽

Potential Impact ◽

Retroviral Infections

Apolipoprotein B editing complex (APOBEC3/A3) genes are found in mammalian cells. In primates, there are 7 APOBEC3 genes, namely, 3A, 3B, 3C, 3DE, 3F, 3G, and 3H. Previous research has shown that A3 proteins help to inhibit viral infection via their cytidine deaminase activity. However, it has also been found that A3 proteins could also lead to viral evolution, where viruses such as HIV (Human Immunodeficiency Virus) instead gain beneficial mutations that enable them to overcome the antiviral activity of A3 proteins, gain resistance to certain drugs used for treating viral infections and escape recognition by the immune system. This paper is a review article summarizing the role of A3G on viral infection and evolution, and the potential impact viral evolution could have in treatment of retroviral infections such as HIV.

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Successive Inoculations of Pigs with Porcine Reproductive and Respiratory Syndrome Virus 1 (PRRSV-1) and Swine H1N2 Influenza Virus Suggest a Mutual Interference between the Two Viral Infections

Viruses ◽

10.3390/v13112169 ◽

2021 ◽

Vol 13 (11) ◽

pp. 2169

Author(s):

Juliette Bougon ◽

Céline Deblanc ◽

Patricia Renson ◽

Stéphane Quéguiner ◽

Stéphane Gorin ◽

...

Keyword(s):

Influenza A ◽

Viral Infections ◽

Clinical Signs ◽

Swine Influenza ◽

Time Correlation ◽

Respiratory Syndrome Virus ◽

Cell Mediated Immune Response ◽

Specific Pathogen ◽

Porcine Respiratory

Porcine reproductive and respiratory syndrome virus (PRRSV) and swine influenza A virus (swIAV) are major pathogens of the porcine respiratory disease complex, but little is known on their interaction in super-infected pigs. In this study, we investigated clinical, virological and immunological outcomes of successive infections with PRRSV-1 and H1N2 swIAV. Twenty-four specific pathogen-free piglets were distributed into four groups and inoculated either with PRRSV at study day (SD) 0, or with swIAV at SD8, or with PRRSV and swIAV one week apart at SD0 and SD8, respectively, or mock-inoculated. In PRRSV/swIAV group, the clinical signs usually observed after swIAV infection were attenuated while higher levels of anti-swIAV antibodies were measured in lungs. Concurrently, PRRSV multiplication in lungs was significantly affected by swIAV infection, whereas the cell-mediated immune response specific to PRRSV was detected earlier in blood, as compared to PRRSV group. Moreover, levels of interferon (IFN)-α measured from SD9 in the blood of super-infected pigs were lower than those measured in the swIAV group, but higher than in the PRRSV group at the same time. Correlation analyses suggested an important role of IFN-α in the two-way interference highlighted between both viral infections.

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The Elusive Role of Placental Macrophages: The Hofbauer Cell

Journal of Innate Immunity ◽

10.1159/000497416 ◽

2019 ◽

Vol 11 (6) ◽

pp. 447-456 ◽

Cited By ~ 10

Author(s):

Michael Z. Zulu ◽

Fernando O. Martinez ◽

Siamon Gordon ◽

Clive M. Gray

Keyword(s):

Human Placenta ◽

Viral Infections ◽

Normal Pregnancy ◽

Adverse Birth Outcomes ◽

Regulatory Cells ◽

Chorionic Villi ◽

Immunodeficiency Virus ◽

Hofbauer Cells ◽

Placental Macrophages

In this review, we discuss the often overlooked tissue-resident fetal macrophages, Hofbauer cells, which are found within the chorionic villi of the human placenta. Hofbauer cells have been shown to have a phenotype associated with regulatory and anti-inflammatory functions. They are thought to play a crucial role in the regulation of pregnancy and in the maintenance of a homeostatic environment that is crucial for fetal development. Even though the numbers of these macrophages are some of the most abundant immune cells in the human placenta, which are sustained throughout pregnancy, there are very few studies that have identified their origin, their phenotype, and functions and why they are maintained throughout gestation. It is not yet understood how Hofbauer cells may change in function throughout normal pregnancy, and especially in those complicated by maternal gestational diabetes, preeclampsia, and viral infections, such as Zika, cytomegalovirus, and human immunodeficiency virus. We review what is known about the origin of these macrophages and explore how common complications of pregnancy dysregulate these cells leading to adverse birth outcomes in humans. Our synthesis sheds light on areas for human studies that can further define these innate regulatory cells.

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HIV-1 Virus Interactions With Host Proteins: Interaction of the N-terminal Domain of the HIV-1 Capsid Protein With Human Calmodulin

Natural Product Communications ◽

10.1177/1934578x19849190 ◽

2019 ◽

Vol 14 (5) ◽

pp. 1934578X1984919

Author(s):

Ywh-Min Tzou ◽

Ronald Shin ◽

N. Rama Krishna

Keyword(s):

Capsid Protein ◽

Host Factors ◽

Host Proteins ◽

Terminal Domain ◽

Immunodeficiency Virus ◽

Infected Cells ◽

Virus Interactions ◽

Precise Role ◽

Hiv 1

The human immunodeficiency virus (HIV-1 virus) exploits several host factors for assembly, infection, and replication within the infected cells. In this work, we describe the evidence for an interaction of the N-terminal domain of the HIV-1 capsid protein with human calmodulin. The precise role of this interaction within the life cycle of the HIV-1 virus is yet to be defined. Potential roles for this interaction in the viral capsid uncoating are discussed.

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