scholarly journals Equine Arteritis Virus Uses Equine CXCL16 as an Entry Receptor

2016 ◽  
Vol 90 (7) ◽  
pp. 3366-3384 ◽  
Author(s):  
Sanjay Sarkar ◽  
Lakshman Chelvarajan ◽  
Yun Young Go ◽  
Frank Cook ◽  
Sergey Artiushin ◽  
...  
Keyword(s):  
Transmembrane Protein ◽  
Critical Role ◽  
Equine Arteritis Virus ◽  
Cell Entry ◽  
Significant Advance ◽  
Type I ◽  
Small Interfering Rnas ◽  
Chromosome 11 ◽  
Trade Restrictions ◽  
Entry Receptor

ABSTRACTPrevious studies in our laboratory have identified equine CXCL16 (EqCXCL16) to be a candidate molecule and possible cell entry receptor for equine arteritis virus (EAV). In horses, the CXCL16 gene is located on equine chromosome 11 (ECA11) and encodes a glycosylated, type I transmembrane protein with 247 amino acids. Stable transfection of HEK-293T cells with plasmid DNA carrying EqCXCL16 (HEK-EqCXCL16 cells) increased the proportion of the cell population permissive to EAV infection from <3% to almost 100%. The increase in permissiveness was blocked either by transfection of HEK-EqCXCL16 cells with small interfering RNAs (siRNAs) directed against EqCXCL16 or by pretreatment with guinea pig polyclonal antibody against EqCXCL16 protein (Gp anti-EqCXCL16 pAb). Furthermore, using a virus overlay protein-binding assay (VOPBA) in combination with far-Western blotting, gradient-purified EAV particles were shown to bind directly to the EqCXCL16 proteinin vitro. The binding of biotinylated virulent EAV strain Bucyrus at 4°C was significantly higher in HEK-EqCXCL16 cells than nontransfected HEK-293T cells. Finally, the results demonstrated that EAV preferentially infects subpopulations of horse CD14+monocytes expressing EqCXCL16 and that infection of these cells is significantly reduced by pretreatment with Gp anti-EqCXCL16 pAb. The collective data from this study provide confirmatory evidence that the transmembrane form of EqCXCL16 likely plays a major role in EAV host cell entry processes, possibly acting as a primary receptor molecule for this virus.IMPORTANCEOutbreaks of EVA can be a source of significant economic loss for the equine industry from high rates of abortion in pregnant mares, death in young foals, establishment of the carrier state in stallions, and trade restrictions imposed by various countries. Similar to other arteriviruses, EAV primarily targets cells of the monocyte/macrophage lineage, which, when infected, are believed to play a critical role in EVA pathogenesis. To this point, however, the host-specified molecules involved in EAV binding and entry into monocytes/macrophages have not been identified. Identification of the cellular receptors for EAV may provide insights to design antivirals and better prophylactic reagents. In this study, we have demonstrated that EqCXCL16 acts as an EAV entry receptor in EAV-susceptible cells, equine monocytes. These findings represent a significant advance in our understanding of the fundamental mechanisms associated with the entry of EAV into susceptible cells.

scholarly journals Equine Arteritis Virus Does Not Induce Interferon Production in Equine Endothelial Cells: Identification of Nonstructural Protein 1 as a Main Interferon Antagonist

2014 ◽  
Vol 2014 ◽  
pp. 1-13 ◽  
Author(s):  
Yun Young Go ◽  
Yanhua Li ◽  
Zhenhai Chen ◽  
Mingyuan Han ◽  
Dongwan Yoo ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Nonstructural Protein ◽  
Critical Role ◽  
Equine Arteritis Virus ◽  
Luciferase Reporter ◽  
Type I ◽  
Mrna Levels ◽  
Type I Ifn ◽  
Rt Pcr ◽  
Nonstructural Protein 1

The objective of this study was to investigate the effect of equine arteritis virus (EAV) on type I interferon (IFN) production. Equine endothelial cells (EECs) were infected with the virulent Bucyrus strain (VBS) of EAV and expression of IFN-βwas measured at mRNA and protein levels by quantitative real-time RT-PCR and IFN bioassay using vesicular stomatitis virus expressing the green fluorescence protein (VSV-GFP), respectively. Quantitative RT-PCR results showed that IFN-βmRNA levels in EECs infected with EAV VBS were not increased compared to those in mock-infected cells. Consistent with quantitative RT-PCR, Sendai virus- (SeV-) induced type I IFN production was inhibited by EAV infection. Using an IFN-βpromoter-luciferase reporter assay, we subsequently demonstrated that EAV nsps 1, 2, and 11 had the capability to inhibit type I IFN activation. Of these three nsps, nsp1 exhibited the strongest inhibitory effect. Taken together, these data demonstrate that EAV has the ability to suppress the type I IFN production in EECs and nsp1 may play a critical role to subvert the equine innate immune response.

scholarly journals Murine Coronavirus Induces Type I Interferon in Oligodendrocytes through Recognition by RIG-I and MDA5

2010 ◽  
Vol 84 (13) ◽  
pp. 6472-6482 ◽  
Author(s):  
Jianfeng Li ◽  
Yin Liu ◽  
Xuming Zhang
Keyword(s):  
Nuclear Translocation ◽  
Type I Interferon ◽  
Hepatitis Virus ◽  
Uv Light ◽  
Critical Role ◽  
Nuclear Factor Κb ◽  
Binding Activity ◽  
Type I ◽  
Small Interfering Rnas ◽  
Murine Coronavirus

ABSTRACT The murine coronavirus mouse hepatitis virus (MHV) induced the expression of type I interferon (alpha/beta interferon [IFN-α/β]) in mouse oligodendrocytic N20.1 cells. This induction is completely dependent on virus replication, since infection with UV light-inactivated virus could no longer induce IFN-α/β. We show that MHV infection activated both transcription factors, the IFN regulatory factor 3 (IRF-3) and nuclear factor κB (NF-κB), as evidenced by phosphorylation and nuclear translocation of IRF-3 and an increased promoter binding activity for IRF-3 and NF-κB. Furthermore, the cytoplasmic pattern recognition receptor retinoic acid-inducible gene I (RIG-I) was induced by MHV infection. Knockdown of RIG-I by small interfering RNAs blocked the activation of IRF-3 and subsequent IFN-α/β production induced by MHV infection. Knockdown of another cytoplasmic receptor, the melanoma-differentiation-associated gene 5 (MDA5), by small interfering RNAs also blocked IFN-β induction. These results demonstrate that MHV is recognized by both RIG-I and MDA5 and induces IFN-α/β through the activation of the IRF-3 signaling pathway. However, knockdown of RIG-I only partially blocked NF-κB activity induced by MHV infection and inhibition of NF-κB activity by a decoy peptide inhibitor had little effect on IFN-α/β production. These data suggest that activation of the NF-κB pathway might not play a critical role in IFN-α/β induction by MHV infection in oligodendrocytes.

Search for mutations of the interferon-induced transmembrane protein 5 (IFITM5) gene in patients with osteogenesis imperfecta

2019 ◽  
pp. 21-29
Author(s):  
А.Р. Зарипова ◽  
Л.Р. Нургалиева ◽  
А.В. Тюрин ◽  
И.Р. Минниахметов ◽  
Р.И. Хусаинова
Keyword(s):  
Osteogenesis Imperfecta ◽  
De Novo ◽  
Transmembrane Protein ◽  
Clinical Signs ◽  
Clinical Manifestations ◽  
Heterozygous Mutation ◽  
Type I ◽  
New Genes ◽  
Wide Range ◽  
Type V

Проведено исследование гена интерферон индуцированного трансмембранного белка 5 (IFITM5) у 99 пациентов с несовершенным остеогенезом (НО) из 86 неродственных семей. НО - клинически и генетически гетерогенное наследственное заболевание соединительной ткани, основное клиническое проявление которого - множественные переломы, начиная с неонатального периода жизни, зачастую приводящие к инвалидизации с детского возраста. К основным клиническим признакам НО относятся голубые склеры, потеря слуха, аномалия дентина, повышенная ломкость костей, нарушения роста и осанки с развитием характерных инвалидизирующих деформаций костей и сопутствующих проблем, включающих дыхательные, неврологические, сердечные, почечные нарушения. НО встречается как у мужчин, так и у женщин. До сих пор не определена степень генетической гетерогенности заболевания. На сегодняшний день известно 20 генов, вовлеченных в патогенез НО, и исследователи разных стран продолжают искать новые гены. В последнее десятилетие стало известно, что аутосомно-рецессивные, аутосомно-доминантные и Х-сцепленные мутации в широком спектре генов, кодирующих белки, которые участвуют в синтезе коллагена I типа, его процессинге, секреции и посттрансляционной модификации, а также в белках, которые регулируют дифференцировку и активность костеобразующих клеток, вызывают НО. Мутации в гене IFITM5, также называемом BRIL (bone-restricted IFITM-like protein), участвующем в формировании остеобластов, приводят к развитию НО типа V. До 5% пациентов имеют НО типа V, который характеризуется образованием гиперпластического каллуса после переломов, кальцификацией межкостной мембраны предплечья и сетчатым рисунком ламелирования, наблюдаемого при гистологическом исследовании кости. В 2012 г. гетерозиготная мутация (c.-14C> T) в 5’-нетранслируемой области (UTR) гена IFITM5 была идентифицирована как основная причина НО V типа. В представленной работе проведен анализ гена IFITM5 и идентифицирована мутация c.-14C>T, возникшая de novo, у одного пациента с НО, которому впоследствии был установлен V тип заболевания. Также выявлены три известных полиморфных варианта: rs57285449; c.80G>C (p.Gly27Ala) и rs2293745; c.187-45C>T и rs755971385 c.279G>A (p.Thr93=) и один ранее не описанный вариант: c.128G>A (p.Ser43Asn) AGC>AAC (S/D), которые не являются патогенными. В статье уделяется внимание особенностям клинических проявлений НО V типа и рекомендуется определение мутации c.-14C>T в гене IFITM5 при подозрении на данную форму заболевания. A study was made of interferon-induced transmembrane protein 5 gene (IFITM5) in 99 patients with osteogenesis imperfecta (OI) from 86 unrelated families and a search for pathogenic gene variants involved in the formation of the disease phenotype. OI is a clinically and genetically heterogeneous hereditary disease of the connective tissue, the main clinical manifestation of which is multiple fractures, starting from the natal period of life, often leading to disability from childhood. The main clinical signs of OI include blue sclera, hearing loss, anomaly of dentin, increased fragility of bones, impaired growth and posture, with the development of characteristic disabling bone deformities and associated problems, including respiratory, neurological, cardiac, and renal disorders. OI occurs in both men and women. The degree of genetic heterogeneity of the disease has not yet been determined. To date, 20 genes are known to be involved in the pathogenesis of OI, and researchers from different countries continue to search for new genes. In the last decade, it has become known that autosomal recessive, autosomal dominant and X-linked mutations in a wide range of genes encoding proteins that are involved in the synthesis of type I collagen, its processing, secretion and post-translational modification, as well as in proteins that regulate the differentiation and activity of bone-forming cells cause OI. Mutations in the IFITM5 gene, also called BRIL (bone-restricted IFITM-like protein), involved in the formation of osteoblasts, lead to the development of OI type V. Up to 5% of patients have OI type V, which is characterized by the formation of a hyperplastic callus after fractures, calcification of the interosseous membrane of the forearm, and a mesh lamellar pattern observed during histological examination of the bone. In 2012, a heterozygous mutation (c.-14C> T) in the 5’-untranslated region (UTR) of the IFITM5 gene was identified as the main cause of OI type V. In the present work, the IFITM5 gene was analyzed and the de novo c.-14C> T mutation was identified in one patient with OI who was subsequently diagnosed with type V of the disease. Three known polymorphic variants were also identified: rs57285449; c.80G> C (p.Gly27Ala) and rs2293745; c.187-45C> T and rs755971385 c.279G> A (p.Thr93 =) and one previously undescribed variant: c.128G> A (p.Ser43Asn) AGC> AAC (S / D), which were not pathogenic. The article focuses on the features of the clinical manifestations of OI type V, and it is recommended to determine the c.-14C> T mutation in the IFITM5 gene if this form of the disease is suspected.

Recent Advances on Epidermal Growth Factor Receptor as a Molecular Target for Breast Cancer Therapeutics

2020 ◽  
Vol 21 ◽  
Author(s):  
Swathi R. Shetty ◽  
Ragini Yeeravalli ◽  
Tanya Bera ◽  
Amitava Das
Keyword(s):  
Breast Cancer ◽  
Epidermal Growth Factor Receptor ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Tyrosine Kinase ◽  
Critical Role ◽  
Growth Factor Receptor ◽  
Type I ◽  
Egfr Inhibition ◽  
Epidermal Growth

: Epidermal growth factor receptor (EGFR), a type-I transmembrane protein with intrinsic tyrosine kinase activity is activated by peptide growth factors such as EGF, epigen, amphiregulin, etc. EGFR plays a vital role in regulating cell growth, migration, and differentiation in various tissue-specific cancers. It has been reported to be overexpressed in lung, head, and neck, colon, brain, pancreatic, and breast cancer that trigger tumor progression and drug resistance. EGFR overexpression alters the signaling pathway and induces cell division, invasion, and cell survival. Our prior studies demonstrated that EGFR inhibition modulates chemosensitivity in breast cancer stem cells thereby serving as a potential drug target for breast cancer mitigation. Tyrosine kinase inhibitors (Lapatinib, Neratinib) and monoclonal antibodies (Trastuzumab) targeting EGFR have been developed and approved by the US FDA for clinical use against breast cancer. This review highlights the critical role of EGFR in breast cancer progression and enumerates the various approaches being undertaken to inhibit aggressive breast cancers by suppressing the downstream pathways. Further, the mechanisms of action of potential molecules at various stages of drug development as well as clinically approved drugs for breast cancer treatment are illustrated.

scholarly journals ACE2, TMPRSS2 and L-SIGN expression in placentae from HIV-positive pregnancies exposed to antiretroviral therapy–implications for SARS-CoV-2 placental infection

2021 ◽  
Author(s):  
Smriti Kala ◽  
Ksenia Meteleva ◽  
Lena Serghides
Keyword(s):  
Antiretroviral Therapy ◽  
Pregnant Women ◽  
Viral Entry ◽  
Cell Entry ◽  
Hiv Positive ◽  
Mrna Levels ◽  
Black Race ◽  
Entry Receptor ◽  
Lower Expression ◽  
Human Placentae

Abstract Background SARS-CoV-2 binding receptor ACE2 and the spike protein priming protease TMPRSS2 are co-expressed in human placentae. It is unknown whether their expression is altered in the context of HIV infection and antiretroviral therapy (ART). Methods We compared mRNA levels of SARS-CoV-2 cell-entry mediators ACE2, TMPRSS2 and L-SIGN (an alternative entry receptor) by qPCR in 105 placentae: 45 from pregnant women with HIV (WHIV) exposed to protease inhibitor (PI)-based ART, 17 from WHIV on non-PI-based ART, and 43 from HIV-uninfected women. Results ACE2 levels were lower, while L-SIGN levels were higher in placentae from WHIV on PI-based ART as compared to those on non-PI-based ART and to HIV-uninfected women. TMPRSS2 levels were similar between groups. Black race was significantly associated with lower expression of ACE2 and higher expression of L-SIGN. ACE2 levels were significantly higher in placentae of female fetuses. Discussion We have identified pregnant women of Black race and WHIV who are on PI-based ART to have relatively lower expression of placental ACE2 than those of White race and HIV-uninfected women. This effect may potentially contribute to altered susceptibility to COVID-19 in these women, either favorably; by reduced viral entry, or detrimentally; by loss of ACE2 protection against hyperinflammation.

scholarly journals Collagen molecular phenotypic switch between non-neoplastic and neoplastic canine mammary tissues

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Masahiko Terajima ◽  
Yuki Taga ◽  
Becky K. Brisson ◽  
Amy C. Durham ◽  
Kotaro Sato ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Mammary Gland ◽  
Mammary Carcinoma ◽  
Cancer Biology ◽  
Type I Collagen ◽  
Critical Role ◽  
Premature Death ◽  
Mammary Tissue ◽  
Type I ◽  
Cross Links

AbstractIn spite of major advances over the past several decades in diagnosis and treatment, breast cancer remains a global cause of morbidity and premature death for both human and veterinary patients. Due to multiple shared clinicopathological features, dogs provide an excellent model of human breast cancer, thus, a comparative oncology approach may advance our understanding of breast cancer biology and improve patient outcomes. Despite an increasing awareness of the critical role of fibrillar collagens in breast cancer biology, tumor-permissive collagen features are still ill-defined. Here, we characterize the molecular and morphological phenotypes of type I collagen in canine mammary gland tumors. Canine mammary carcinoma samples contained longer collagen fibers as well as a greater population of wider fibers compared to non-neoplastic and adenoma samples. Furthermore, the total number of collagen cross-links enriched in the stable hydroxylysine-aldehyde derived cross-links was significantly increased in neoplastic mammary gland samples compared to non-neoplastic mammary gland tissue. The mass spectrometric analyses of type I collagen revealed that in malignant mammary tumor samples, lysine residues, in particular those in the telopeptides, were markedly over-hydroxylated in comparison to non-neoplastic mammary tissue. The extent of glycosylation of hydroxylysine residues was comparable among the groups. Consistent with these data, expression levels of genes encoding lysyl hydroxylase 2 (LH2) and its molecular chaperone FK506-binding protein 65 were both significantly increased in neoplastic samples. These alterations likely lead to an increase in the LH2-mediated stable collagen cross-links in mammary carcinoma that may promote tumor cell metastasis in these patients.

scholarly journals Listeria exploits IFITM3 to suppress antibacterial activity in phagocytes

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Joel M. J. Tan ◽  
Monica E. Garner ◽  
James M. Regeimbal ◽  
Catherine J. Greene ◽  
Jorge D. Rojas Márquez ◽  
...  
Keyword(s):  
Antibacterial Activity ◽  
Molecular Mechanisms ◽  
Immune Cell ◽  
Transmembrane Protein ◽  
Foodborne Pathogen ◽  
Systemic Infection ◽  
Cytokine Signaling ◽  
Type I ◽  
Type I Ifn ◽  
Antiviral Protein

AbstractThe type I interferon (IFN) signaling pathway has important functions in resistance to viral infection, with the downstream induction of interferon stimulated genes (ISG) protecting the host from virus entry, replication and spread. Listeria monocytogenes (Lm), a facultative intracellular foodborne pathogen, can exploit the type I IFN response as part of their pathogenic strategy, but the molecular mechanisms involved remain unclear. Here we show that type I IFN suppresses the antibacterial activity of phagocytes to promote systemic Lm infection. Mechanistically, type I IFN suppresses phagosome maturation and proteolysis of Lm virulence factors ActA and LLO, thereby promoting phagosome escape and cell-to-cell spread; the antiviral protein, IFN-induced transmembrane protein 3 (IFITM3), is required for this type I IFN-mediated alteration. Ifitm3−/− mice are resistant to systemic infection by Lm, displaying decreased bacterial spread in tissues, and increased immune cell recruitment and pro-inflammatory cytokine signaling. Together, our findings show how an antiviral mechanism in phagocytes can be exploited by bacterial pathogens, and implicate IFITM3 as a potential antimicrobial therapeutic target.

scholarly journals Essential role of IPS-1 in innate immune responses against RNA viruses

2006 ◽  
Vol 203 (7) ◽  
pp. 1795-1803 ◽  
Author(s):  
Himanshu Kumar ◽  
Taro Kawai ◽  
Hiroki Kato ◽  
Shintaro Sato ◽  
Ken Takahashi ◽  
...  
Keyword(s):  
Rna Viruses ◽  
Rna Virus ◽  
Critical Role ◽  
Nuclear Factor Κb ◽  
Type I ◽  
Innate Immune Responses ◽  
Antiviral Responses ◽  
Deficient Mice

IFN-β promoter stimulator (IPS)-1 was recently identified as an adapter for retinoic acid–inducible gene I (RIG-I) and melanoma differentiation-associated gene 5 (Mda5), which recognize distinct RNA viruses. Here we show the critical role of IPS-1 in antiviral responses in vivo. IPS-1–deficient mice showed severe defects in both RIG-I– and Mda5-mediated induction of type I interferon and inflammatory cytokines and were susceptible to RNA virus infection. RNA virus–induced interferon regulatory factor-3 and nuclear factor κB activation was also impaired in IPS-1–deficient cells. IPS-1, however, was not essential for the responses to either DNA virus or double-stranded B-DNA. Thus, IPS-1 is the sole adapter in both RIG-I and Mda5 signaling that mediates effective responses against a variety of RNA viruses.

scholarly journals Control of Herpes Simplex Virus Replication Is Mediated through an Interferon Regulatory Factor 3-Dependent Pathway

2009 ◽  
Vol 83 (23) ◽  
pp. 12399-12406 ◽  
Author(s):  
Vineet D. Menachery ◽  
David A. Leib
Keyword(s):  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Virus Replication ◽  
Early Recognition ◽  
Critical Role ◽  
Type I ◽  
Type I Ifn ◽  
Regulatory Factor ◽  
Simplex Virus ◽  
Hsv 1

ABSTRACT The type I interferon (IFN) cascade is critical in controlling viral replication and pathogenesis. Recognition pathways triggered by viral infection rapidly induce the type I IFN cascade, often in an IFN regulatory factor 3 (IRF-3)-dependent fashion. This dependence predicts that loss of IRF-3 would render early recognition pathways inoperative and thereby impact virus replication, but this has not been observed previously with herpes simplex virus type 1 (HSV-1) in vitro. In this study, HSV-1-infected IRF-3−/− bone marrow-derived dendritic cells (BMDCs) and macrophages supported increased HSV replication compared to control cells. In addition, IRF-3-deficient BMDCs exhibited delayed type I IFN synthesis compared to control cells. However, while IFN pretreatment of IRF-3−/− BMDCs resulted in reduced virus titers, a far greater reduction was seen after IFN treatment of wild-type cells. This suggests that even in the presence of exogenously supplied IFN, IRF-3−/− BMDCs are inherently defective in the control of HSV-1 replication. Together, these results demonstrate a critical role for IRF-3-mediated pathways in controlling HSV-1 replication in cells of the murine immune system.

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