Changes in desoxyribonucleic-acid and in glycoprotein content of mouse-lung epithelial cells during influenza virus infection

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.

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

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.2108276118 ◽

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.

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Diversity of locally produced IFN-α subtypes in human nasopharyngeal epithelial cells and mouse lung tissues during influenza virus infection

Applied Microbiology and Biotechnology ◽

10.1007/s00253-020-10676-y ◽

2020 ◽

Vol 104 (14) ◽

pp. 6351-6361

Author(s):

Lei Yang ◽

Shengnan Wang ◽

Ying Wang ◽

Peiyan Zhao ◽

Cuiyun Cui ◽

...

Keyword(s):

Influenza Virus ◽

Epithelial Cells ◽

Virus Infection ◽

Influenza Virus Infection ◽

Mouse Lung ◽

Nasopharyngeal Epithelial

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Effect of Slit/Robo signaling on regeneration in lung emphysema

Experimental & Molecular Medicine ◽

10.1038/s12276-021-00633-8 ◽

2021 ◽

Author(s):

Jin-Soo Park ◽

RyeonJin Cho ◽

Eun-Young Kang ◽

Yeon-Mok Oh

Keyword(s):

Epithelial Cells ◽

Mouse Model ◽

Lung Epithelial Cells ◽

Mouse Lung ◽

Chronic Obstructive ◽

Irreversible Damage ◽

Lung Epithelial ◽

And Migration ◽

Proliferation And Migration

AbstractEmphysema, a pathological component of chronic obstructive pulmonary disease, causes irreversible damage to the lung. Previous studies have shown that Slit plays essential roles in cell proliferation, angiogenesis, and organ development. In this study, we evaluated the effect of Slit2 on the proliferation and migration of mouse lung epithelial cells and its role in regeneration in an emphysema lung mouse model. Here, we have shown that Slit2/Robo signaling contributes to the regeneration of lungs damaged by emphysema. Mouse epithelial lung cells treated with Slit2 exhibited increased proliferation and migration in vitro. Our results also showed that Slit2 administration improved alveolar regeneration in the emphysema mouse model in vivo. Furthermore, Slit2/Robo signaling increased the phosphorylation of ERK and Akt, which was mediated by Ras activity. These Slit2-mediated cellular signaling processes may be involved in the proliferation and migration of mouse lung epithelial cells and are also associated with the potential mechanism of lung regeneration. Our findings suggest that Slit2 administration may be beneficial for alveolar regeneration in lungs damaged by emphysema.

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