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Genetic alteration of heparan sulfate in CD11c + immune cells inhibits inflammation and facilitates pathogen clearance during influenza A virus infection

Survival from influenza A virus (IAV) infection largely depends on an intricate balance between pathogen clearance and immunomodulation in the lung. We demonstrate that genetic alteration of the glycan heparan sulfate (HS) in CD11c + cells via Ndst1f/f CD11cCre + mutation, which inhibits HS sulfatio...

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Autores principales: Kim, So Young, Gupta, Purva, Johns, Scott C., Zuniga, Elina I., Teijaro, John R., Fuster, Mark M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8968721/
https://www.ncbi.nlm.nih.gov/pubmed/35354833
http://dx.doi.org/10.1038/s41598-022-09197-7
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author Kim, So Young
Gupta, Purva
Johns, Scott C.
Zuniga, Elina I.
Teijaro, John R.
Fuster, Mark M.
author_facet Kim, So Young
Gupta, Purva
Johns, Scott C.
Zuniga, Elina I.
Teijaro, John R.
Fuster, Mark M.
author_sort Kim, So Young
collection PubMed
description Survival from influenza A virus (IAV) infection largely depends on an intricate balance between pathogen clearance and immunomodulation in the lung. We demonstrate that genetic alteration of the glycan heparan sulfate (HS) in CD11c + cells via Ndst1f/f CD11cCre + mutation, which inhibits HS sulfation in a major antigen presenting cell population, reduces lung inflammation by A/Puerto Rico/8/1934(H1N1) influenza in mice. Mutation was also characterized by a reduction in lung infiltration by CD4(+) regulatory T (T(reg)) cells in the late infection/effector phase, 9 days post inoculation (p.i.), without significant differences in lung CD8 + T cells, or T(reg) cells at an earlier point (day 5) following infection. Induction of under-sulfated HS via Ndst1 silencing in a model dendritic cell line (DC2.4) resulted in up-regulated basal expression of the antiviral cytokine interferon β (IFN-β) relative to control. Stimulating cells with the TLR9 ligand CpG resulted in greater nuclear factor-κB (NFκB) phosphorylation in Ndst1 silenced DC2.4 cells. While stimulating cells with CpG also modestly increased IFN-β expression, this did not lead to significant increases in IFN-β protein production. In further IFN-β protein response studies using primary bone marrow DCs from Ndst1f/f CD11cCre + mutant and Cre− control mice, while trace IFN-β protein was detected in response to CpG, stimulation with the TLR7 ligand R848 resulted in robust IFN-β production, with significantly higher levels associated with DC Ndst1 mutation. In vivo, improved pathogen clearance in Ndst1f/f CD11cCre + mutant mice was suggested by reduced IAV AA5H nucleoprotein in lung examined in the late/effector phase. Earlier in the course of infection (day 5 p.i.), mean viral load, as measured by viral RNA, was not significantly different among genotypes. These findings point to novel regulatory roles for DC HS in innate and adaptive immunity during viral infection. This may have therapeutic potential and guide DC targeted HS engineering platforms in the setting of IAV or other respiratory viruses.
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spelling pubmed-89687212022-04-01 Genetic alteration of heparan sulfate in CD11c + immune cells inhibits inflammation and facilitates pathogen clearance during influenza A virus infection Kim, So Young Gupta, Purva Johns, Scott C. Zuniga, Elina I. Teijaro, John R. Fuster, Mark M. Sci Rep Article Survival from influenza A virus (IAV) infection largely depends on an intricate balance between pathogen clearance and immunomodulation in the lung. We demonstrate that genetic alteration of the glycan heparan sulfate (HS) in CD11c + cells via Ndst1f/f CD11cCre + mutation, which inhibits HS sulfation in a major antigen presenting cell population, reduces lung inflammation by A/Puerto Rico/8/1934(H1N1) influenza in mice. Mutation was also characterized by a reduction in lung infiltration by CD4(+) regulatory T (T(reg)) cells in the late infection/effector phase, 9 days post inoculation (p.i.), without significant differences in lung CD8 + T cells, or T(reg) cells at an earlier point (day 5) following infection. Induction of under-sulfated HS via Ndst1 silencing in a model dendritic cell line (DC2.4) resulted in up-regulated basal expression of the antiviral cytokine interferon β (IFN-β) relative to control. Stimulating cells with the TLR9 ligand CpG resulted in greater nuclear factor-κB (NFκB) phosphorylation in Ndst1 silenced DC2.4 cells. While stimulating cells with CpG also modestly increased IFN-β expression, this did not lead to significant increases in IFN-β protein production. In further IFN-β protein response studies using primary bone marrow DCs from Ndst1f/f CD11cCre + mutant and Cre− control mice, while trace IFN-β protein was detected in response to CpG, stimulation with the TLR7 ligand R848 resulted in robust IFN-β production, with significantly higher levels associated with DC Ndst1 mutation. In vivo, improved pathogen clearance in Ndst1f/f CD11cCre + mutant mice was suggested by reduced IAV AA5H nucleoprotein in lung examined in the late/effector phase. Earlier in the course of infection (day 5 p.i.), mean viral load, as measured by viral RNA, was not significantly different among genotypes. These findings point to novel regulatory roles for DC HS in innate and adaptive immunity during viral infection. This may have therapeutic potential and guide DC targeted HS engineering platforms in the setting of IAV or other respiratory viruses. Nature Publishing Group UK 2022-03-30 /pmc/articles/PMC8968721/ /pubmed/35354833 http://dx.doi.org/10.1038/s41598-022-09197-7 Text en © This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply 2022 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Kim, So Young
Gupta, Purva
Johns, Scott C.
Zuniga, Elina I.
Teijaro, John R.
Fuster, Mark M.
Genetic alteration of heparan sulfate in CD11c + immune cells inhibits inflammation and facilitates pathogen clearance during influenza A virus infection
title Genetic alteration of heparan sulfate in CD11c + immune cells inhibits inflammation and facilitates pathogen clearance during influenza A virus infection
title_full Genetic alteration of heparan sulfate in CD11c + immune cells inhibits inflammation and facilitates pathogen clearance during influenza A virus infection
title_fullStr Genetic alteration of heparan sulfate in CD11c + immune cells inhibits inflammation and facilitates pathogen clearance during influenza A virus infection
title_full_unstemmed Genetic alteration of heparan sulfate in CD11c + immune cells inhibits inflammation and facilitates pathogen clearance during influenza A virus infection
title_short Genetic alteration of heparan sulfate in CD11c + immune cells inhibits inflammation and facilitates pathogen clearance during influenza A virus infection
title_sort genetic alteration of heparan sulfate in cd11c + immune cells inhibits inflammation and facilitates pathogen clearance during influenza a virus infection
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8968721/
https://www.ncbi.nlm.nih.gov/pubmed/35354833
http://dx.doi.org/10.1038/s41598-022-09197-7
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