Protein Tyrosine Phosphatase SHP2 Suppresses Host Innate Immunity against Influenza A Virus by Regulating EGFR-Mediated Signaling
Influenza A virus (IAV) is a highly contagious pathogen, causing acute respiratory illnesses in human beings and animals and frequently giving rise to epidemic outbreaks. Evasion by IAV of host immunity facilitates viral replication and spread, which can be initiated through various mechanisms, incl...
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description | Influenza A virus (IAV) is a highly contagious pathogen, causing acute respiratory illnesses in human beings and animals and frequently giving rise to epidemic outbreaks. Evasion by IAV of host immunity facilitates viral replication and spread, which can be initiated through various mechanisms, including epidermal growth factor receptor (EGFR) activation. However, how EGFR mediates the suppression of antiviral systems remains unclear. Here, we examined host innate immune responses and their relevant signaling to EGFR upon IAV infection. IAV was found to induce the phosphorylation of EGFR and extracellular signal-regulated kinase (ERK) at an early stage of infection. Inhibition of EGFR or ERK suppressed the viral replication but increased the expression of type I and type III interferons (IFNs) and interferon-stimulated genes (ISGs), supporting the idea that IAV escapes from antiviral innate immunity by activating EGFR/ERK signaling. Meanwhile, IAV infection also induced the activation of Src homology region 2-containing protein tyrosine phosphatase 2 (SHP2). Pharmacological inhibition or small interfering RNA (siRNA)-based silencing of SHP2 enhanced the IFN-dependent antiviral activity and reduced virion production. Furthermore, knockdown of SHP2 attenuated the EGFR-mediated ERK phosphorylation triggered by viral infection or EGF stimulation. Conversely, ectopic expression of constitutively active SHP2 noticeably promoted ERK activation and viral replication, concomitant with diminished immune function. Altogether, the results indicate that SHP2 is crucial for IAV-induced activation of the EGFR/ERK pathway to suppress host antiviral responses.
Viral immune evasion is the most important strategy whereby viruses evolve for their survival. This work shows that influenza A virus (IAV) suppressed the antiviral innate immunity through downregulation of IFNs and ISGs by activating EGFR/ERK signaling. Meanwhile, IAV also induced the activation of protein tyrosine phosphatase SHP2, which was found to be responsible for modulating the EGFR-mediated ERK activity and subsequent antiviral effectiveness both
and
The results suggest that SHP2 is a key signal transducer between EGFR and ERK and plays a crucial role in suppressing host innate immunity during IAV infection. The finding enhances our understanding of influenza immune evasion and provides a new therapeutic approach to viral infection. |
doi_str_mv | 10.1128/JVI.02001-20 |
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Viral immune evasion is the most important strategy whereby viruses evolve for their survival. This work shows that influenza A virus (IAV) suppressed the antiviral innate immunity through downregulation of IFNs and ISGs by activating EGFR/ERK signaling. Meanwhile, IAV also induced the activation of protein tyrosine phosphatase SHP2, which was found to be responsible for modulating the EGFR-mediated ERK activity and subsequent antiviral effectiveness both
and
The results suggest that SHP2 is a key signal transducer between EGFR and ERK and plays a crucial role in suppressing host innate immunity during IAV infection. The finding enhances our understanding of influenza immune evasion and provides a new therapeutic approach to viral infection.</description><identifier>ISSN: 0022-538X</identifier><identifier>EISSN: 1098-5514</identifier><identifier>DOI: 10.1128/JVI.02001-20</identifier><identifier>PMID: 33361428</identifier><language>eng</language><publisher>United States: American Society for Microbiology</publisher><subject>A549 Cells ; Animals ; ErbB Receptors - antagonists & inhibitors ; ErbB Receptors - metabolism ; Extracellular Signal-Regulated MAP Kinases - antagonists & inhibitors ; Extracellular Signal-Regulated MAP Kinases - metabolism ; Humans ; Immune Evasion ; Immunity, Innate ; Influenza A virus - physiology ; Interferons - metabolism ; Mice ; Orthomyxoviridae Infections - immunology ; Orthomyxoviridae Infections - virology ; Pathogenesis and Immunity ; Phosphorylation ; Protein Tyrosine Phosphatase, Non-Receptor Type 11 - genetics ; Protein Tyrosine Phosphatase, Non-Receptor Type 11 - immunology ; Signal Transduction - immunology ; Virus Replication</subject><ispartof>Journal of virology, 2021-02, Vol.95 (6)</ispartof><rights>Copyright © 2021 American Society for Microbiology.</rights><rights>Copyright © 2021 American Society for Microbiology. 2021 American Society for Microbiology</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a461t-e384981a00ff3e1f15d598a2e672efe56cb4de841a403560d65224913b0b637e3</citedby><cites>FETCH-LOGICAL-a461t-e384981a00ff3e1f15d598a2e672efe56cb4de841a403560d65224913b0b637e3</cites><orcidid>0000-0003-4561-2476</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC8094946/pdf/$$EPDF$$P50$$Gpubmedcentral$$H</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC8094946/$$EHTML$$P50$$Gpubmedcentral$$H</linktohtml><link.rule.ids>230,314,727,780,784,885,27924,27925,53791,53793</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/33361428$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Williams, Bryan R. G</contributor><contributor>Williams, Bryan R. G.</contributor><creatorcontrib>Wang, Qingsen</creatorcontrib><creatorcontrib>Pan, Wenliang</creatorcontrib><creatorcontrib>Wang, Song</creatorcontrib><creatorcontrib>Pan, Chen</creatorcontrib><creatorcontrib>Ning, Hongya</creatorcontrib><creatorcontrib>Huang, Shile</creatorcontrib><creatorcontrib>Chiu, Shih-Hsin</creatorcontrib><creatorcontrib>Chen, Ji-Long</creatorcontrib><title>Protein Tyrosine Phosphatase SHP2 Suppresses Host Innate Immunity against Influenza A Virus by Regulating EGFR-Mediated Signaling</title><title>Journal of virology</title><addtitle>J Virol</addtitle><addtitle>J Virol</addtitle><description>Influenza A virus (IAV) is a highly contagious pathogen, causing acute respiratory illnesses in human beings and animals and frequently giving rise to epidemic outbreaks. Evasion by IAV of host immunity facilitates viral replication and spread, which can be initiated through various mechanisms, including epidermal growth factor receptor (EGFR) activation. However, how EGFR mediates the suppression of antiviral systems remains unclear. Here, we examined host innate immune responses and their relevant signaling to EGFR upon IAV infection. IAV was found to induce the phosphorylation of EGFR and extracellular signal-regulated kinase (ERK) at an early stage of infection. Inhibition of EGFR or ERK suppressed the viral replication but increased the expression of type I and type III interferons (IFNs) and interferon-stimulated genes (ISGs), supporting the idea that IAV escapes from antiviral innate immunity by activating EGFR/ERK signaling. Meanwhile, IAV infection also induced the activation of Src homology region 2-containing protein tyrosine phosphatase 2 (SHP2). Pharmacological inhibition or small interfering RNA (siRNA)-based silencing of SHP2 enhanced the IFN-dependent antiviral activity and reduced virion production. Furthermore, knockdown of SHP2 attenuated the EGFR-mediated ERK phosphorylation triggered by viral infection or EGF stimulation. Conversely, ectopic expression of constitutively active SHP2 noticeably promoted ERK activation and viral replication, concomitant with diminished immune function. Altogether, the results indicate that SHP2 is crucial for IAV-induced activation of the EGFR/ERK pathway to suppress host antiviral responses.
Viral immune evasion is the most important strategy whereby viruses evolve for their survival. This work shows that influenza A virus (IAV) suppressed the antiviral innate immunity through downregulation of IFNs and ISGs by activating EGFR/ERK signaling. Meanwhile, IAV also induced the activation of protein tyrosine phosphatase SHP2, which was found to be responsible for modulating the EGFR-mediated ERK activity and subsequent antiviral effectiveness both
and
The results suggest that SHP2 is a key signal transducer between EGFR and ERK and plays a crucial role in suppressing host innate immunity during IAV infection. The finding enhances our understanding of influenza immune evasion and provides a new therapeutic approach to viral infection.</description><subject>A549 Cells</subject><subject>Animals</subject><subject>ErbB Receptors - antagonists & inhibitors</subject><subject>ErbB Receptors - metabolism</subject><subject>Extracellular Signal-Regulated MAP Kinases - antagonists & inhibitors</subject><subject>Extracellular Signal-Regulated MAP Kinases - metabolism</subject><subject>Humans</subject><subject>Immune Evasion</subject><subject>Immunity, Innate</subject><subject>Influenza A virus - physiology</subject><subject>Interferons - metabolism</subject><subject>Mice</subject><subject>Orthomyxoviridae Infections - immunology</subject><subject>Orthomyxoviridae Infections - virology</subject><subject>Pathogenesis and Immunity</subject><subject>Phosphorylation</subject><subject>Protein Tyrosine Phosphatase, Non-Receptor Type 11 - genetics</subject><subject>Protein Tyrosine Phosphatase, Non-Receptor Type 11 - immunology</subject><subject>Signal Transduction - immunology</subject><subject>Virus Replication</subject><issn>0022-538X</issn><issn>1098-5514</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2021</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp1kc1v1DAQxS0EotvCjTPyESRS_BWvc0Gqqra7qIhVt1TcLGczybpK7OAPpO2N_5y0Wyo4cBpp5jdvNO8h9IaSY0qZ-vj5ZnlMGCG0YOQZmlFSqaIsqXiOZoQwVpRcfT9AhzHeTowQUrxEB5xzSQVTM_RrFXwC6_D1LvhoHeDV1sdxa5KJgNeLFcPrPI4BYoSIFz4mvHTOJMDLYcjOph02nbHuod_2GdydwSf4xoYccb3DV9Dl3iTrOnx2cX5VfIHGTtsNXtvOmX7qv0IvWtNHeP1Yj9C387Pr00Vx-fVieXpyWRghaSqAK1EpaghpWw60pWVTVsowkHMGLZRyU4sGlKBGEF5K0siSMVFRXpNa8jnwI_RprzvmeoBmAy4F0-sx2MGEnfbG6n8nzm51539qRSpRCTkJvHsUCP5Hhpj0YOMG-t448DlqJuZc0EpJMqEf9uhmMjUGaJ_OUKLvU9NTavohNc3u8fd73MSB6Vufw2RN_B_79u83noT_RMp_A7nGoM8</recordid><startdate>20210224</startdate><enddate>20210224</enddate><creator>Wang, Qingsen</creator><creator>Pan, Wenliang</creator><creator>Wang, Song</creator><creator>Pan, Chen</creator><creator>Ning, Hongya</creator><creator>Huang, Shile</creator><creator>Chiu, Shih-Hsin</creator><creator>Chen, Ji-Long</creator><general>American Society for Microbiology</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0003-4561-2476</orcidid></search><sort><creationdate>20210224</creationdate><title>Protein Tyrosine Phosphatase SHP2 Suppresses Host Innate Immunity against Influenza A Virus by Regulating EGFR-Mediated Signaling</title><author>Wang, Qingsen ; Pan, Wenliang ; Wang, Song ; Pan, Chen ; Ning, Hongya ; Huang, Shile ; Chiu, Shih-Hsin ; Chen, Ji-Long</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a461t-e384981a00ff3e1f15d598a2e672efe56cb4de841a403560d65224913b0b637e3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2021</creationdate><topic>A549 Cells</topic><topic>Animals</topic><topic>ErbB Receptors - antagonists & inhibitors</topic><topic>ErbB Receptors - metabolism</topic><topic>Extracellular Signal-Regulated MAP Kinases - antagonists & inhibitors</topic><topic>Extracellular Signal-Regulated MAP Kinases - metabolism</topic><topic>Humans</topic><topic>Immune Evasion</topic><topic>Immunity, Innate</topic><topic>Influenza A virus - physiology</topic><topic>Interferons - metabolism</topic><topic>Mice</topic><topic>Orthomyxoviridae Infections - immunology</topic><topic>Orthomyxoviridae Infections - virology</topic><topic>Pathogenesis and Immunity</topic><topic>Phosphorylation</topic><topic>Protein Tyrosine Phosphatase, Non-Receptor Type 11 - genetics</topic><topic>Protein Tyrosine Phosphatase, Non-Receptor Type 11 - immunology</topic><topic>Signal Transduction - immunology</topic><topic>Virus Replication</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Wang, Qingsen</creatorcontrib><creatorcontrib>Pan, Wenliang</creatorcontrib><creatorcontrib>Wang, Song</creatorcontrib><creatorcontrib>Pan, Chen</creatorcontrib><creatorcontrib>Ning, Hongya</creatorcontrib><creatorcontrib>Huang, Shile</creatorcontrib><creatorcontrib>Chiu, Shih-Hsin</creatorcontrib><creatorcontrib>Chen, Ji-Long</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Journal of virology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Wang, Qingsen</au><au>Pan, Wenliang</au><au>Wang, Song</au><au>Pan, Chen</au><au>Ning, Hongya</au><au>Huang, Shile</au><au>Chiu, Shih-Hsin</au><au>Chen, Ji-Long</au><au>Williams, Bryan R. G</au><au>Williams, Bryan R. G.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Protein Tyrosine Phosphatase SHP2 Suppresses Host Innate Immunity against Influenza A Virus by Regulating EGFR-Mediated Signaling</atitle><jtitle>Journal of virology</jtitle><stitle>J Virol</stitle><addtitle>J Virol</addtitle><date>2021-02-24</date><risdate>2021</risdate><volume>95</volume><issue>6</issue><issn>0022-538X</issn><eissn>1098-5514</eissn><abstract>Influenza A virus (IAV) is a highly contagious pathogen, causing acute respiratory illnesses in human beings and animals and frequently giving rise to epidemic outbreaks. Evasion by IAV of host immunity facilitates viral replication and spread, which can be initiated through various mechanisms, including epidermal growth factor receptor (EGFR) activation. However, how EGFR mediates the suppression of antiviral systems remains unclear. Here, we examined host innate immune responses and their relevant signaling to EGFR upon IAV infection. IAV was found to induce the phosphorylation of EGFR and extracellular signal-regulated kinase (ERK) at an early stage of infection. Inhibition of EGFR or ERK suppressed the viral replication but increased the expression of type I and type III interferons (IFNs) and interferon-stimulated genes (ISGs), supporting the idea that IAV escapes from antiviral innate immunity by activating EGFR/ERK signaling. Meanwhile, IAV infection also induced the activation of Src homology region 2-containing protein tyrosine phosphatase 2 (SHP2). Pharmacological inhibition or small interfering RNA (siRNA)-based silencing of SHP2 enhanced the IFN-dependent antiviral activity and reduced virion production. Furthermore, knockdown of SHP2 attenuated the EGFR-mediated ERK phosphorylation triggered by viral infection or EGF stimulation. Conversely, ectopic expression of constitutively active SHP2 noticeably promoted ERK activation and viral replication, concomitant with diminished immune function. Altogether, the results indicate that SHP2 is crucial for IAV-induced activation of the EGFR/ERK pathway to suppress host antiviral responses.
Viral immune evasion is the most important strategy whereby viruses evolve for their survival. This work shows that influenza A virus (IAV) suppressed the antiviral innate immunity through downregulation of IFNs and ISGs by activating EGFR/ERK signaling. Meanwhile, IAV also induced the activation of protein tyrosine phosphatase SHP2, which was found to be responsible for modulating the EGFR-mediated ERK activity and subsequent antiviral effectiveness both
and
The results suggest that SHP2 is a key signal transducer between EGFR and ERK and plays a crucial role in suppressing host innate immunity during IAV infection. The finding enhances our understanding of influenza immune evasion and provides a new therapeutic approach to viral infection.</abstract><cop>United States</cop><pub>American Society for Microbiology</pub><pmid>33361428</pmid><doi>10.1128/JVI.02001-20</doi><tpages>16</tpages><orcidid>https://orcid.org/0000-0003-4561-2476</orcidid><oa>free_for_read</oa></addata></record> |
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subjects | A549 Cells Animals ErbB Receptors - antagonists & inhibitors ErbB Receptors - metabolism Extracellular Signal-Regulated MAP Kinases - antagonists & inhibitors Extracellular Signal-Regulated MAP Kinases - metabolism Humans Immune Evasion Immunity, Innate Influenza A virus - physiology Interferons - metabolism Mice Orthomyxoviridae Infections - immunology Orthomyxoviridae Infections - virology Pathogenesis and Immunity Phosphorylation Protein Tyrosine Phosphatase, Non-Receptor Type 11 - genetics Protein Tyrosine Phosphatase, Non-Receptor Type 11 - immunology Signal Transduction - immunology Virus Replication |
title | Protein Tyrosine Phosphatase SHP2 Suppresses Host Innate Immunity against Influenza A Virus by Regulating EGFR-Mediated Signaling |
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