scholarly journals The Interferon-Inducible Proteoglycan Testican-2/SPOCK2 Functions as a Protective Barrier against Virus Infection of Lung Epithelial Cells

2019 ◽  
Vol 93 (20) ◽  
Author(s):  
Narae Ahn ◽  
Woo-Jong Kim ◽  
Nari Kim ◽  
Han Wook Park ◽  
Seung-Woo Lee ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Epithelial Cells ◽  
Virus Infection ◽  
Heparan Sulfate ◽  
Cell Attachment ◽  
Core Protein ◽  
Influenza Virus Infection ◽  
Lung Epithelial Cells ◽  
Extracellular Compartment ◽  
Lung Epithelial

ABSTRACT Proteoglycans function not only as structural components of the extracellular compartment but also as regulators of various cellular events, including cell migration, inflammation, and infection. Many microbial pathogens utilize proteoglycans to facilitate adhesion and invasion into host cells. Here we report a secreted form of a novel heparan sulfate proteoglycan that functions against virus infection. The expression of SPOCK2/testican-2 was significantly induced in virus-infected lungs or in interferon (IFN)-treated alveolar lung epithelial cells. Overexpression from a SPOCK2 expression plasmid alone or the treatment of cells with recombinant SPOCK2 protein efficiently blocked influenza virus infection at the step of viral attachment to the host cell and entry. Moreover, mice treated with purified SPOCK2 were protected against virus infection. Sialylated glycans and heparan sulfate chains covalently attached to the SPOCK2 core protein were critical for its antiviral activity. Neuraminidase (NA) of influenza virus cleaves the sialylated moiety of SPOCK2, thereby blocking its binding to the virus. Our data suggest that IFN-induced SPOCK2 functions as a decoy receptor to bind and block influenza virus infection, thereby restricting entry of the infecting virus into neighboring cells. IMPORTANCE Here we report a novel proteoglycan protein, testican-2/SPOCK2, that prevents influenza virus infection. Testican-2/SPOCK2 is a complex type of secreted proteoglycan with heparan sulfate GAG chains attached to the core protein. SPOCK2 expression is induced upon virus infection or by interferons, and the protein is secreted to an extracellular compartment, where it acts directly to block virus-cell attachment and entry. Treatment with purified testican-2/SPOCK2 protein can efficiently block influenza virus infection in vitro and in vivo. We also identified the heparan sulfate moiety as a key regulatory module for this inhibitory effect. Based on its mode of action (cell attachment/entry blocker) and site of action (extracellular compartment), we propose testican-2/SPOCK2 as a potential antiviral agent that can efficiently control influenza virus infection.

scholarly journals Hypoxia reduces cell attachment of SARS-CoV-2 spike protein by modulating the expression of ACE2 and heparan sulfate

2021 ◽  
Author(s):  
Endika Prieto-Fernández ◽  
Leire Egia-Mendikute ◽  
Laura Vila-Vecilla ◽  
So Young Lee ◽  
Alexandre Bosch ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Heparan Sulfate ◽  
Human Lung ◽  
Cell Attachment ◽  
Clinical Parameter ◽  
Lung Epithelial Cells ◽  
Spike Protein ◽  
Protein Levels ◽  
Binding Partners ◽  
Lung Epithelial

ABSTRACTA main clinical parameter of Covid-19 pathophysiology is hypoxia. Here we show that hypoxia decreases the attachment of the receptor binding domain (RBD) and the S1 subunit (S1) of the spike protein to epithelial cells. In Vero E6 cells, hypoxia reduces the protein levels of ACE2, which might in part explain the observed reduction of the infection rate. However, hypoxia also inhibits the binding of the spike to human lung epithelial cells lacking ACE2 expression, indicating that hypoxia modulates the expression of additional binding partners of SARS-CoV-2. We show that hypoxia also decreases the total cell surface levels of heparan sulfate, a known attachment receptor of SARS-CoV-2, by reducing the expression of syndecan-1 and syndecan3, the main proteoglycans containing heparan sulfate. Our study indicates that hypoxia acts to prevent SARS-CoV-2 infection, suggesting that the hypoxia signaling pathway might offer therapeutic opportunities for the treatment of Covid-19.

Cis-acting lnc-Cxcl2 restrains neutrophil-mediated lung inflammation by inhibiting epithelial cell CXCL2 expression in virus infection

2021 ◽  
Vol 118 (41) ◽  
pp. e2108276118
Author(s):  
Shuo Liu ◽  
Jiaqi Liu ◽  
Xue Yang ◽  
Minghong Jiang ◽  
Qingqing Wang ◽  
...  
Keyword(s):  
Epithelial Cell ◽  
Epithelial Cells ◽  
Virus Infection ◽  
Viral Infection ◽  
Rna Binding ◽  
Influenza Virus Infection ◽  
Lung Epithelial Cells ◽  
Mouse Lung ◽  
Chemokine Production ◽  
Lung Epithelial

Chemokine production by epithelial cells is important for neutrophil recruitment during viral infection, the appropriate regulation of which is critical for restraining inflammation and attenuating subsequent tissue damage. Epithelial cell expression of long noncoding RNAs (lncRNAs), RNA-binding proteins, and their functional interactions during viral infection and inflammation remain to be fully understood. Here, we identified an inducible lncRNA in the Cxcl2 gene locus, lnc-Cxcl2, which could selectively inhibit Cxcl2 expression in mouse lung epithelial cells but not in macrophages. lnc-Cxcl2–deficient mice exhibited increased Cxcl2 expression, enhanced neutrophils recruitment, and more severe inflammation in the lung after influenza virus infection. Mechanistically, nucleus-localized lnc-Cxcl2 bound to Cxcl2 promoter, recruited a ribonucleoprotein La, which inhibited the chromatin accessibility of chemokine promoters, and consequently inhibited Cxcl2 transcription in cis. However, unlike mouse lnc-Cxcl2, human lnc-CXCL2-4-1 inhibited multiple immune cytokine expressions including chemokines in human lung epithelial cells. Together, our results demonstrate a self-protecting mechanism within epithelial cells to restrain chemokine and neutrophil-mediated inflammation, providing clues for better understanding chemokine regulation and epithelial cell function in lung viral infection.

Influenza Virus Induced ER Stress Triggers Fas-Independent Apoptosis Of Lung Epithelial Cells

2011 ◽  
Author(s):  
Vikas Anathy ◽  
Elle C. Roberson ◽  
Jane E. Tully ◽  
Amy Guala ◽  
Karolyn Godburn ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Epithelial Cells ◽  
Er Stress ◽  
Lung Epithelial Cells ◽  
Lung Epithelial

scholarly journals Increase in CTGF mRNA expression by respiratory syncytial virus infection is abrogated by caffeine in lung epithelial cells

2018 ◽  
Vol 12 (5) ◽  
pp. 662-666
Author(s):  
Steffen Kunzmann ◽  
Christine Krempl ◽  
Silvia Seidenspinner ◽  
Kirsten Glaser ◽  
Christian P. Speer ◽  
...  
Keyword(s):  
Respiratory Syncytial Virus ◽  
Epithelial Cells ◽  
Virus Infection ◽  
Mrna Expression ◽  
Respiratory Syncytial Virus Infection ◽  
Lung Epithelial Cells ◽  
Lung Epithelial ◽  
Syncytial Virus

scholarly journals Influenza A Virus Infection Induces Apical Redistribution of Na+, K+-ATPase in Lung Epithelial Cells In Vitro and In Vivo

2019 ◽  
Vol 61 (3) ◽  
pp. 395-398
Author(s):  
Christin Peteranderl ◽  
Irina Kuznetsova ◽  
Jessica Schulze ◽  
Martin Hardt ◽  
Emilia Lecuona ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Virus Infection ◽  
Influenza A Virus ◽  
Influenza A ◽  
Lung Epithelial Cells ◽  
Lung Epithelial ◽  
Influenza A Virus Infection

scholarly journals Desialylation of airway epithelial cells during influenza virus infection enhances pneumococcal adhesion via galectin binding

2015 ◽  
Vol 65 (1) ◽  
pp. 1-16 ◽  
Author(s):  
Mihai Nita-Lazar ◽  
Aditi Banerjee ◽  
Chiguang Feng ◽  
Mohammed N. Amin ◽  
Matthew B. Frieman ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Epithelial Cells ◽  
Virus Infection ◽  
Influenza Virus Infection ◽  
Airway Epithelial Cells ◽  
Airway Epithelial

scholarly journals Critical Role of HAX-1 in Promoting Avian Influenza Virus Replication in Lung Epithelial Cells

2018 ◽  
Vol 2018 ◽  
pp. 1-12
Author(s):  
Xue Li ◽  
Bingqian Qu ◽  
Ganlin He ◽  
Carol J. Cardona ◽  
Yongchun Song ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Epithelial Cells ◽  
Avian Influenza ◽  
Avian Influenza Virus ◽  
Human Lung ◽  
Early Stage ◽  
Lung Epithelial Cells ◽  
Lung Epithelial ◽  
Induced Apoptosis ◽  
Human Lung Epithelial Cells

The PB1-F2 protein of influenza A virus has been considered a virulence factor, but its function in inducing apoptosis may be of disadvantage to viral replication. Host mechanisms to regulate PB1-F2-induced apoptosis remain unknown. We generated a PB1-F2-deficient avian influenza virus (AIV) H9N2 and found that the mutant virus replicated less efficiently in human lung epithelial cells. The PB1-F2-deficient virus produced less apoptotic cells, indicating that PB1-F2 of the H9N2 virus promotes apoptosis, occurring at the early stage of infection, in the lung epithelial cells. To understand how host cells regulate PB1-F2-induced apoptosis, we explored to identify cellular proteins interacting with PB1-F2 and found that HCLS1-associated protein X-1 (HAX-1), located mainly in the mitochondria as an apoptotic inhibitor, interacted with PB1-F2. Increased procaspase-9 activations, induced by PB1-F2, could be suppressed by HAX-1. In HAX-1 knockdown A549 cells, the replication of AIV H9N2 was suppressed in parallel to the activation of caspase-3 activation, which increased at the early stage of infection. We hypothesize that HAX-1 promotes AIV replication by interacting with PB1-F2, resulting in the suppression of apoptosis, prolonged cell survival, and enhancement of viral replication. Our data suggest that HAX-1 may be a promoting factor for AIV H9N2 replication through desensitizing PB1-F2 from its apoptotic induction in human lung epithelial cells.

Inhibitory effects of carbocisteine on type A seasonal influenza virus infection in human airway epithelial cells

2010 ◽  
Vol 299 (2) ◽  
pp. L160-L168 ◽  
Author(s):  
Mutsuo Yamaya ◽  
Hidekazu Nishimura ◽  
Kyoko Shinya ◽  
Yukimasa Hatachi ◽  
Takahiko Sasaki ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Epithelial Cells ◽  
Virus Infection ◽  
Seasonal Influenza ◽  
Influenza Virus Infection ◽  
Airway Epithelial Cells ◽  
Airway Epithelial ◽  
Human Influenza ◽  
Inhibitory Effects ◽  
Human Influenza Virus

Type A human seasonal influenza (FluA) virus infection causes exacerbations of bronchial asthma and chronic obstructive pulmonary disease (COPD). l-carbocisteine, a mucolytic agent, reduces the frequency of common colds and exacerbations in COPD. However, the inhibitory effects of l-carbocisteine on FluA virus infection are uncertain. We studied the effects of l-carbocisteine on FluA virus infection in airway epithelial cells. Human tracheal epithelial cells were pretreated with l-carbocisteine and infected with FluA virus (H3N2). Viral titers in supernatant fluids, RNA of FluA virus in the cells, and concentrations of proinflammatory cytokines in supernatant fluids, including IL-6, increased with time after infection. l-carbocisteine reduced viral titers in supernatant fluids, RNA of FluA virus in the cells, the susceptibility to FluA virus infection, and concentrations of cytokines induced by virus infection. The epithelial cells expressed sialic acid with an α2,6-linkage (SAα2,6Gal), a receptor for human influenza virus on the cells, and l-carbocisteine reduced the expression of SAα2,6Gal. l-carbocisteine reduced the number of acidic endosomes from which FluA viral RNA enters into the cytoplasm and reduced the fluorescence intensity from acidic endosomes. Furthermore, l-carbocisteine reduced NF-κB proteins including p50 and p65 in the nuclear extracts of the cells. These findings suggest that l-carbocisteine may inhibit FluA virus infection, partly through the reduced expression of the receptor for human influenza virus in the human airway epithelial cells via the inhibition of NF-κB and through increasing pH in endosomes. l-carbocisteine may reduce airway inflammation in influenza virus infection.

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