The Chemokine CCL5 Inhibits the Replication of Influenza A Virus Through SAMHD1 Modulation
Influenza A virus (IAV) is the main etiological agent of acute respiratory tract infections. During IAV infection, interferon triggers the overexpression of restriction factors (RFs), the intracellular antiviral branch of the innate immune system. Conversely, severe influenza is associated with an u...
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Frontiers Media S.A.
2021-08-01
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Online Access: | https://www.frontiersin.org/articles/10.3389/fcimb.2021.549020/full |
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DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Thauane Silva Jairo R. Temerozo Jairo R. Temerozo Gabriele do Vale André C. Ferreira André C. Ferreira André C. Ferreira André C. Ferreira Vinícius Cardoso Soares Vinícius Cardoso Soares Suelen Silva Gomes Dias Gabriela Sardella Dumith Chequer Bou-Habib Dumith Chequer Bou-Habib Marilda Siqueira Thiago Moreno L. Souza Thiago Moreno L. Souza Thiago Moreno L. Souza Milene Miranda |
spellingShingle |
Thauane Silva Jairo R. Temerozo Jairo R. Temerozo Gabriele do Vale André C. Ferreira André C. Ferreira André C. Ferreira André C. Ferreira Vinícius Cardoso Soares Vinícius Cardoso Soares Suelen Silva Gomes Dias Gabriela Sardella Dumith Chequer Bou-Habib Dumith Chequer Bou-Habib Marilda Siqueira Thiago Moreno L. Souza Thiago Moreno L. Souza Thiago Moreno L. Souza Milene Miranda The Chemokine CCL5 Inhibits the Replication of Influenza A Virus Through SAMHD1 Modulation Frontiers in Cellular and Infection Microbiology influenza restriction factors SAMHD1 CCL5/RANTES CCR5 |
author_facet |
Thauane Silva Jairo R. Temerozo Jairo R. Temerozo Gabriele do Vale André C. Ferreira André C. Ferreira André C. Ferreira André C. Ferreira Vinícius Cardoso Soares Vinícius Cardoso Soares Suelen Silva Gomes Dias Gabriela Sardella Dumith Chequer Bou-Habib Dumith Chequer Bou-Habib Marilda Siqueira Thiago Moreno L. Souza Thiago Moreno L. Souza Thiago Moreno L. Souza Milene Miranda |
author_sort |
Thauane Silva |
title |
The Chemokine CCL5 Inhibits the Replication of Influenza A Virus Through SAMHD1 Modulation |
title_short |
The Chemokine CCL5 Inhibits the Replication of Influenza A Virus Through SAMHD1 Modulation |
title_full |
The Chemokine CCL5 Inhibits the Replication of Influenza A Virus Through SAMHD1 Modulation |
title_fullStr |
The Chemokine CCL5 Inhibits the Replication of Influenza A Virus Through SAMHD1 Modulation |
title_full_unstemmed |
The Chemokine CCL5 Inhibits the Replication of Influenza A Virus Through SAMHD1 Modulation |
title_sort |
chemokine ccl5 inhibits the replication of influenza a virus through samhd1 modulation |
publisher |
Frontiers Media S.A. |
series |
Frontiers in Cellular and Infection Microbiology |
issn |
2235-2988 |
publishDate |
2021-08-01 |
description |
Influenza A virus (IAV) is the main etiological agent of acute respiratory tract infections. During IAV infection, interferon triggers the overexpression of restriction factors (RFs), the intracellular antiviral branch of the innate immune system. Conversely, severe influenza is associated with an unbalanced pro-inflammatory cytokine release. It is unclear whether other cytokines and chemokines released during IAV infection modulate RFs to control virus replication. Among the molecules enhanced in the infected respiratory tract, ligands of the CCR5 receptor play a key role, as they stimulate the migration of inflammatory cells to the alveoli. We investigated here whether ligands of the CCR5 receptor could enhance RFs to levels able to inhibit IAV replication. For this purpose, the human alveolar basal epithelial cell line (A549) was treated with endogenous (CCL3, CCL4 and CCL5) or exogenous (HIV-1 gp120) ligands prior to IAV infection. The three CC-chemokines tested reduced infectious titers between 30% to 45% upon 24 hours of infection. Eploying RT-PCR, a panel of RF mRNA levels from cells treated with CCR5 agonists was evaluated, which showed that the SAMHD1 expression was up-regulated four times over control upon exposure to CCL3, CCL4 and CCL5. We also found that IAV inhibition by CCL5 was dependent on PKC and that SAMHD1 protein levels were also increased after treatment with CCL5. In functional assays, we observed that the knockdown of SAMHD1 resulted in enhanced IAV replication in A549 cells and abolished both CCL5-mediated inhibition of IAV replication and CCL5-mediated cell death inhibition. Our data show that stimuli unrelated to interferon may trigger the upregulation of SAMHD1 and that this RF may directly interfere with IAV replication in alveolar epithelial cells. |
topic |
influenza restriction factors SAMHD1 CCL5/RANTES CCR5 |
url |
https://www.frontiersin.org/articles/10.3389/fcimb.2021.549020/full |
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doaj-8baf1f12a0ac4f528ebe70979ff753a62021-08-13T12:07:46ZengFrontiers Media S.A.Frontiers in Cellular and Infection Microbiology2235-29882021-08-011110.3389/fcimb.2021.549020549020The Chemokine CCL5 Inhibits the Replication of Influenza A Virus Through SAMHD1 ModulationThauane Silva0Jairo R. Temerozo1Jairo R. Temerozo2Gabriele do Vale3André C. Ferreira4André C. Ferreira5André C. Ferreira6André C. Ferreira7Vinícius Cardoso Soares8Vinícius Cardoso Soares9Suelen Silva Gomes Dias10Gabriela Sardella11Dumith Chequer Bou-Habib12Dumith Chequer Bou-Habib13Marilda Siqueira14Thiago Moreno L. Souza15Thiago Moreno L. Souza16Thiago Moreno L. Souza17Milene Miranda18Laboratory of Respiratory Viruses and Measles, Oswaldo Cruz Institute (IOC), Fiocruz, Rio de Janeiro, BrazilLaboratory on Thymus Research, Oswaldo Cruz Institute (IOC), Fiocruz, Rio de Janeiro, BrazilNational Institute for Science and Technology on Neuroimmunomodulation, Oswaldo Cruz Institute (IOC), Fiocruz, Rio de Janeiro, BrazilLaboratory of Respiratory Viruses and Measles, Oswaldo Cruz Institute (IOC), Fiocruz, Rio de Janeiro, BrazilIguaçu University, Nova Iguaçu, BrazilLaboratory of Immunopharmacology, Oswaldo Cruz Institute (IOC), Fiocruz, Rio de Janeiro, BrazilCenter for Technological Development in Health (CDTS), Fiocruz, Rio de Janeiro, BrazilNational Institute for Science and Technology on Innovation on Diseases of Neglected Populations (INCT/IDPN), Center for Technological Development in Health (CDTS), Fiocruz, Rio de Janeiro, BrazilLaboratory of Immunopharmacology, Oswaldo Cruz Institute (IOC), Fiocruz, Rio de Janeiro, BrazilProgram of Immunology and Inflammation, Federal University of Rio de Janeiro, UFRJ, Rio de Janeiro, BrazilLaboratory of Immunopharmacology, Oswaldo Cruz Institute (IOC), Fiocruz, Rio de Janeiro, BrazilLaboratory of Neurochemistry, Biophysics Institute, Federal University of Rio de Janeiro (UFRJ), Rio de Janeiro, BrazilLaboratory on Thymus Research, Oswaldo Cruz Institute (IOC), Fiocruz, Rio de Janeiro, BrazilNational Institute for Science and Technology on Neuroimmunomodulation, Oswaldo Cruz Institute (IOC), Fiocruz, Rio de Janeiro, BrazilLaboratory of Respiratory Viruses and Measles, Oswaldo Cruz Institute (IOC), Fiocruz, Rio de Janeiro, BrazilLaboratory of Immunopharmacology, Oswaldo Cruz Institute (IOC), Fiocruz, Rio de Janeiro, BrazilCenter for Technological Development in Health (CDTS), Fiocruz, Rio de Janeiro, BrazilNational Institute for Science and Technology on Innovation on Diseases of Neglected Populations (INCT/IDPN), Center for Technological Development in Health (CDTS), Fiocruz, Rio de Janeiro, BrazilLaboratory of Respiratory Viruses and Measles, Oswaldo Cruz Institute (IOC), Fiocruz, Rio de Janeiro, BrazilInfluenza A virus (IAV) is the main etiological agent of acute respiratory tract infections. During IAV infection, interferon triggers the overexpression of restriction factors (RFs), the intracellular antiviral branch of the innate immune system. Conversely, severe influenza is associated with an unbalanced pro-inflammatory cytokine release. It is unclear whether other cytokines and chemokines released during IAV infection modulate RFs to control virus replication. Among the molecules enhanced in the infected respiratory tract, ligands of the CCR5 receptor play a key role, as they stimulate the migration of inflammatory cells to the alveoli. We investigated here whether ligands of the CCR5 receptor could enhance RFs to levels able to inhibit IAV replication. For this purpose, the human alveolar basal epithelial cell line (A549) was treated with endogenous (CCL3, CCL4 and CCL5) or exogenous (HIV-1 gp120) ligands prior to IAV infection. The three CC-chemokines tested reduced infectious titers between 30% to 45% upon 24 hours of infection. Eploying RT-PCR, a panel of RF mRNA levels from cells treated with CCR5 agonists was evaluated, which showed that the SAMHD1 expression was up-regulated four times over control upon exposure to CCL3, CCL4 and CCL5. We also found that IAV inhibition by CCL5 was dependent on PKC and that SAMHD1 protein levels were also increased after treatment with CCL5. In functional assays, we observed that the knockdown of SAMHD1 resulted in enhanced IAV replication in A549 cells and abolished both CCL5-mediated inhibition of IAV replication and CCL5-mediated cell death inhibition. Our data show that stimuli unrelated to interferon may trigger the upregulation of SAMHD1 and that this RF may directly interfere with IAV replication in alveolar epithelial cells.https://www.frontiersin.org/articles/10.3389/fcimb.2021.549020/fullinfluenzarestriction factorsSAMHD1CCL5/RANTESCCR5 |