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RIG-I and MDA5 are modulated by bone morphogenetic protein (BMP6) and are essential for restricting Zika virus infection in human Sertoli cells

Sexual transmission of Zika virus (ZIKV) is associated with virus persistence in the testes and shedding in the seminal fluid for months after recovery. We previously demonstrated that ZIKV can establish long-term replication without causing cytotoxicity in human Sertoli cells (SC), responsible for...

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Autores principales: Jiyarom, Boonyanudh, Giannakopoulos, Stefanos, Strange, Daniel P., Panova, Nataliya, Gale, Michael, Verma, Saguna
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9878278/
https://www.ncbi.nlm.nih.gov/pubmed/36713156
http://dx.doi.org/10.3389/fmicb.2022.1062499
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author Jiyarom, Boonyanudh
Giannakopoulos, Stefanos
Strange, Daniel P.
Panova, Nataliya
Gale, Michael
Verma, Saguna
author_facet Jiyarom, Boonyanudh
Giannakopoulos, Stefanos
Strange, Daniel P.
Panova, Nataliya
Gale, Michael
Verma, Saguna
author_sort Jiyarom, Boonyanudh
collection PubMed
description Sexual transmission of Zika virus (ZIKV) is associated with virus persistence in the testes and shedding in the seminal fluid for months after recovery. We previously demonstrated that ZIKV can establish long-term replication without causing cytotoxicity in human Sertoli cells (SC), responsible for maintaining the immune privileged compartment of seminiferous tubules. Functional gene expression analyses also predicted activation of multiple virus sensing pathways including TLR3, RIG-I, and MDA5. Here, we elucidated which of the RNA virus sensing receptors play a decisive role in restricting ZIKV replication. We show that both poly I:C and IFN-β treatment induced a robust antiviral state and reduced ZIKV replication significantly, suggesting that virus sensing and antiviral signaling are functional in SC. Silencing of TLR3, 7, and 9 did not affect virus replication kinetics; however, both RIG-I and MDA5 played a synergistic role in inducing an anti-ZIKV response. Further, the impact of SC-specific immunosuppressive pathways that collectively regulate SC function, specifically the TGF-β superfamily members, TGF-β, Activin A, and BMP6, on ZIKV replication was investigated. While ZIKV did not modulate the expression of TGF-β and Activin A, BMP6 signaling was suppressed at later stages of infection. Notably, treatment with BMP6 increased IFN-β, p-IRF3, and p-STAT1 levels, and expression of key interferon-stimulated genes including MDA5, suggesting that BMP6 enhances antiviral response in SC. Collectively, this study further delineates the key role of the RIG-I-like receptors in sensing ZIKV in SC, and reveals a novel role of BMP6 in modulating innate immune and antiviral response in the testes.
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spelling pubmed-98782782023-01-27 RIG-I and MDA5 are modulated by bone morphogenetic protein (BMP6) and are essential for restricting Zika virus infection in human Sertoli cells Jiyarom, Boonyanudh Giannakopoulos, Stefanos Strange, Daniel P. Panova, Nataliya Gale, Michael Verma, Saguna Front Microbiol Microbiology Sexual transmission of Zika virus (ZIKV) is associated with virus persistence in the testes and shedding in the seminal fluid for months after recovery. We previously demonstrated that ZIKV can establish long-term replication without causing cytotoxicity in human Sertoli cells (SC), responsible for maintaining the immune privileged compartment of seminiferous tubules. Functional gene expression analyses also predicted activation of multiple virus sensing pathways including TLR3, RIG-I, and MDA5. Here, we elucidated which of the RNA virus sensing receptors play a decisive role in restricting ZIKV replication. We show that both poly I:C and IFN-β treatment induced a robust antiviral state and reduced ZIKV replication significantly, suggesting that virus sensing and antiviral signaling are functional in SC. Silencing of TLR3, 7, and 9 did not affect virus replication kinetics; however, both RIG-I and MDA5 played a synergistic role in inducing an anti-ZIKV response. Further, the impact of SC-specific immunosuppressive pathways that collectively regulate SC function, specifically the TGF-β superfamily members, TGF-β, Activin A, and BMP6, on ZIKV replication was investigated. While ZIKV did not modulate the expression of TGF-β and Activin A, BMP6 signaling was suppressed at later stages of infection. Notably, treatment with BMP6 increased IFN-β, p-IRF3, and p-STAT1 levels, and expression of key interferon-stimulated genes including MDA5, suggesting that BMP6 enhances antiviral response in SC. Collectively, this study further delineates the key role of the RIG-I-like receptors in sensing ZIKV in SC, and reveals a novel role of BMP6 in modulating innate immune and antiviral response in the testes. Frontiers Media S.A. 2023-01-12 /pmc/articles/PMC9878278/ /pubmed/36713156 http://dx.doi.org/10.3389/fmicb.2022.1062499 Text en Copyright © 2023 Jiyarom, Giannakopoulos, Strange, Panova, Gale and Verma. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Microbiology
Jiyarom, Boonyanudh
Giannakopoulos, Stefanos
Strange, Daniel P.
Panova, Nataliya
Gale, Michael
Verma, Saguna
RIG-I and MDA5 are modulated by bone morphogenetic protein (BMP6) and are essential for restricting Zika virus infection in human Sertoli cells
title RIG-I and MDA5 are modulated by bone morphogenetic protein (BMP6) and are essential for restricting Zika virus infection in human Sertoli cells
title_full RIG-I and MDA5 are modulated by bone morphogenetic protein (BMP6) and are essential for restricting Zika virus infection in human Sertoli cells
title_fullStr RIG-I and MDA5 are modulated by bone morphogenetic protein (BMP6) and are essential for restricting Zika virus infection in human Sertoli cells
title_full_unstemmed RIG-I and MDA5 are modulated by bone morphogenetic protein (BMP6) and are essential for restricting Zika virus infection in human Sertoli cells
title_short RIG-I and MDA5 are modulated by bone morphogenetic protein (BMP6) and are essential for restricting Zika virus infection in human Sertoli cells
title_sort rig-i and mda5 are modulated by bone morphogenetic protein (bmp6) and are essential for restricting zika virus infection in human sertoli cells
topic Microbiology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9878278/
https://www.ncbi.nlm.nih.gov/pubmed/36713156
http://dx.doi.org/10.3389/fmicb.2022.1062499
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