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SARS-CoV-2 N Protein Induces Acute Lung Injury in Mice via NF-ĸB Activation
BACKGROUND: Infection of SARS-CoV-2 may cause acute respiratory syndrome. It has been reported that SARS-CoV-2 nucleocapsid protein (N-protein) presents early in body fluids during infection. The direct involvement of N-protein in lung injury is poorly understood. METHODS: Recombinant N-protein was...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8688532/ https://www.ncbi.nlm.nih.gov/pubmed/34950152 http://dx.doi.org/10.3389/fimmu.2021.791753 |
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author | Xia, Jie Tang, Wenqi Wang, Jiangmei Lai, Dengming Xu, Qi Huang, Ruoqiong Hu, Yaoqin Gong, Xiaojue Fan, Jiajie Shu, Qiang Xu, Jianguo |
author_facet | Xia, Jie Tang, Wenqi Wang, Jiangmei Lai, Dengming Xu, Qi Huang, Ruoqiong Hu, Yaoqin Gong, Xiaojue Fan, Jiajie Shu, Qiang Xu, Jianguo |
author_sort | Xia, Jie |
collection | PubMed |
description | BACKGROUND: Infection of SARS-CoV-2 may cause acute respiratory syndrome. It has been reported that SARS-CoV-2 nucleocapsid protein (N-protein) presents early in body fluids during infection. The direct involvement of N-protein in lung injury is poorly understood. METHODS: Recombinant N-protein was pretreated with polymyxin B, a lipopolysaccharide (LPS)-neutralizing agent. C57BL/6, C3H/HeJ (resistant to LPS), and C3H/HeN (control for C3H/HeJ) mice were exposed to N-protein via intratracheal administration to examine acute lung injury. In vitro, bone marrow–derived macrophages (BMDMs) were cultured with N-protein to study phosphorylation of nuclear factor kappa B (NF-ĸB) p65, macrophage polarization, and expression of proinflammatory cytokines. RESULTS: N-protein produced acute lung injury in C57BL/6 mice, with elevated protein permeability, total cell count, neutrophil infiltration, and proinflammatory cytokines in the bronchioalveolar lavage. N-protein also induced lung injury in both C3H/HeJ and C3H/HeN mice, indicating that the effect could not be attributed to the LPS contamination. N-protein triggered phosphorylation of NF-ĸB p65 in vitro, which was abolished by both N-protein denaturation and treatment with an antibody for N-protein, demonstrating that the effect is N-protein specific. In addition, N-protein promoted M1 macrophage polarization and the expression of proinflammatory cytokines, which was also blocked by N-protein denaturation and antibody for N-protein. Furthermore, N-protein induced NF-ĸB p65 phosphorylation in the lung, while pyrrolidine dithiocarbamate, an NF-ĸB inhibitor, alleviated the effect of N-protein on acute lung injury. CONCLUSIONS: SARS-CoV-2 N-protein itself is toxic and induces acute lung injury in mice. Both N-protein and NF-ĸB pathway may be therapeutic targets for treating multi-organ injuries in Coronavirus disease 2019 (COVID-19). |
format | Online Article Text |
id | pubmed-8688532 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-86885322021-12-22 SARS-CoV-2 N Protein Induces Acute Lung Injury in Mice via NF-ĸB Activation Xia, Jie Tang, Wenqi Wang, Jiangmei Lai, Dengming Xu, Qi Huang, Ruoqiong Hu, Yaoqin Gong, Xiaojue Fan, Jiajie Shu, Qiang Xu, Jianguo Front Immunol Immunology BACKGROUND: Infection of SARS-CoV-2 may cause acute respiratory syndrome. It has been reported that SARS-CoV-2 nucleocapsid protein (N-protein) presents early in body fluids during infection. The direct involvement of N-protein in lung injury is poorly understood. METHODS: Recombinant N-protein was pretreated with polymyxin B, a lipopolysaccharide (LPS)-neutralizing agent. C57BL/6, C3H/HeJ (resistant to LPS), and C3H/HeN (control for C3H/HeJ) mice were exposed to N-protein via intratracheal administration to examine acute lung injury. In vitro, bone marrow–derived macrophages (BMDMs) were cultured with N-protein to study phosphorylation of nuclear factor kappa B (NF-ĸB) p65, macrophage polarization, and expression of proinflammatory cytokines. RESULTS: N-protein produced acute lung injury in C57BL/6 mice, with elevated protein permeability, total cell count, neutrophil infiltration, and proinflammatory cytokines in the bronchioalveolar lavage. N-protein also induced lung injury in both C3H/HeJ and C3H/HeN mice, indicating that the effect could not be attributed to the LPS contamination. N-protein triggered phosphorylation of NF-ĸB p65 in vitro, which was abolished by both N-protein denaturation and treatment with an antibody for N-protein, demonstrating that the effect is N-protein specific. In addition, N-protein promoted M1 macrophage polarization and the expression of proinflammatory cytokines, which was also blocked by N-protein denaturation and antibody for N-protein. Furthermore, N-protein induced NF-ĸB p65 phosphorylation in the lung, while pyrrolidine dithiocarbamate, an NF-ĸB inhibitor, alleviated the effect of N-protein on acute lung injury. CONCLUSIONS: SARS-CoV-2 N-protein itself is toxic and induces acute lung injury in mice. Both N-protein and NF-ĸB pathway may be therapeutic targets for treating multi-organ injuries in Coronavirus disease 2019 (COVID-19). Frontiers Media S.A. 2021-12-07 /pmc/articles/PMC8688532/ /pubmed/34950152 http://dx.doi.org/10.3389/fimmu.2021.791753 Text en Copyright © 2021 Xia, Tang, Wang, Lai, Xu, Huang, Hu, Gong, Fan, Shu and Xu 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 | Immunology Xia, Jie Tang, Wenqi Wang, Jiangmei Lai, Dengming Xu, Qi Huang, Ruoqiong Hu, Yaoqin Gong, Xiaojue Fan, Jiajie Shu, Qiang Xu, Jianguo SARS-CoV-2 N Protein Induces Acute Lung Injury in Mice via NF-ĸB Activation |
title | SARS-CoV-2 N Protein Induces Acute Lung Injury in Mice via NF-ĸB Activation |
title_full | SARS-CoV-2 N Protein Induces Acute Lung Injury in Mice via NF-ĸB Activation |
title_fullStr | SARS-CoV-2 N Protein Induces Acute Lung Injury in Mice via NF-ĸB Activation |
title_full_unstemmed | SARS-CoV-2 N Protein Induces Acute Lung Injury in Mice via NF-ĸB Activation |
title_short | SARS-CoV-2 N Protein Induces Acute Lung Injury in Mice via NF-ĸB Activation |
title_sort | sars-cov-2 n protein induces acute lung injury in mice via nf-ĸb activation |
topic | Immunology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8688532/ https://www.ncbi.nlm.nih.gov/pubmed/34950152 http://dx.doi.org/10.3389/fimmu.2021.791753 |
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