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Lung Inflammation Induced by Inactivated SARS-CoV-2 in C57BL/6 Female Mice Is Controlled by Intranasal Instillation of Vitamin D

Fernandes de Souza et al., Cells, doi:10.3390/cells12071092
Apr 2023  
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Vitamin D for COVID-19
8th treatment shown to reduce risk in October 2020
 
*, now with p < 0.00000000001 from 122 studies, recognized in 9 countries.
No treatment is 100% effective. Protocols combine treatments. * >10% efficacy, ≥3 studies.
4,400+ studies for 81 treatments. c19early.org
C57BL/6 mouse study showing intranasal administration of vitamin D decreased inflammation following intranasal inactivated SARS-CoV-2. Authors suggest a promising potential of intranasal vitamin D to control pulmonary inflammation associated with SARS-CoV-2.
21 preclinical studies support the efficacy of vitamin D for COVID-19:
Vitamin D has been identified by the European Food Safety Authority (EFSA) as having sufficient evidence for a causal relationship between intake and optimal immune system function20-23. Vitamin D inhibits SARS-CoV-2 replication in vitro10,17, mitigates lung inflammation, damage, and lethality in mice with an MHV-3 model for β-CoV respiratory infections10,17, reduces SARS-CoV-2 replication in nasal epithelial cells via increased type I interferon expression13, downregulates proinflammatory cytokines IL-1β and TNF-α in SARS-CoV-2 spike protein-stimulated cells9, attenuates nucleocapsid protein-induced hyperinflammation by inactivating the NLRP3 inflammasome through the VDR-BRCC3 signaling pathway14, may be neuroprotective by protecting the blood-brain barrier, reducing neuroinflammation, and via immunomodulatory effects24, minimizes platelet aggregation mediated by SARS-CoV-2 spike protein via inhibiting integrin αIIbβ3 outside-in signaling8, and improves regulatory immune cell levels and control of proinflammatory cytokines in severe COVID-1925. Symptomatic COVID-19 is associated with a lower frequency of natural killer (NK) cells and vitamin D has been shown to improve NK cell activity26,27.
Fernandes de Souza et al., 6 Apr 2023, USA, peer-reviewed, 13 authors. Contact: wdansouza@hotmail.com (corresponding author), denisefonseca@usp.br.
This PaperVitamin DAll
Lung Inflammation Induced by Inactivated SARS-CoV-2 in C57BL/6 Female Mice Is Controlled by Intranasal Instillation of Vitamin D
William Danilo Fernandes De Souza, Sofia Fernanda Gonçalves Zorzella-Pezavento, Marina Caçador Ayupe, Caio Loureiro Salgado, Bernardo De Castro Oliveira, Francielly Moreira, Guilherme William Da Silva, Stefanie Primon Muraro, Gabriela Fabiano De Souza, José Luiz Proença-Módena, Joao Pessoa Araujo Junior, Denise Morais Da Fonseca, Alexandrina Sartori
Cells, doi:10.3390/cells12071092
The COVID-19 pandemic was triggered by the coronavirus SARS-CoV-2, whose peak occurred in the years 2020 and 2021. The main target of this virus is the lung, and the infection is associated with an accentuated inflammatory process involving mainly the innate arm of the immune system. Here, we described the induction of a pulmonary inflammatory process triggered by the intranasal (IN) instillation of UV-inactivated SARS-CoV-2 in C57BL/6 female mice, and then the evaluation of the ability of vitamin D (VitD) to control this process. The assays used to estimate the severity of lung involvement included the total and differential number of cells in the bronchoalveolar lavage fluid (BALF), histopathological analysis, quantification of T cell subsets, and inflammatory mediators by RT-PCR, cytokine quantification in lung homogenates, and flow cytometric analysis of cells recovered from lung parenchyma. The IN instillation of inactivated SARS-CoV-2 triggered a pulmonary inflammatory process, consisting of various cell types and mediators, resembling the typical inflammation found in transgenic mice infected with SARS-CoV-2. This inflammatory process was significantly decreased by the IN delivery of VitD, but not by its IP administration, suggesting that this hormone could have a therapeutic potential in COVID-19 if locally applied. To our knowledge, the local delivery of VitD to downmodulate lung inflammation in COVID-19 is an original proposition.
Supplementary Materials: The following supporting information can be downloaded at: https:// www.mdpi.com/article/10.3390/cells12071092/s1. Conflicts of Interest: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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The main target of this virus is the lung, and the ' 'infection is associated with an accentuated inflammatory process involving mainly the innate ' 'arm of the immune system. Here, we described the induction of a pulmonary inflammatory ' 'process triggered by the intranasal (IN) instillation of UV-inactivated SARS-CoV-2 in C57BL/6 ' 'female mice, and then the evaluation of the ability of vitamin D (VitD) to control this ' 'process. The assays used to estimate the severity of lung involvement included the total and ' 'differential number of cells in the bronchoalveolar lavage fluid (BALF), histopathological ' 'analysis, quantification of T cell subsets, and inflammatory mediators by RT-PCR, cytokine ' 'quantification in lung homogenates, and flow cytometric analysis of cells recovered from lung ' 'parenchyma. The IN instillation of inactivated SARS-CoV-2 triggered a pulmonary inflammatory ' 'process, consisting of various cell types and mediators, resembling the typical inflammation ' 'found in transgenic mice infected with SARS-CoV-2. This inflammatory process was ' 'significantly decreased by the IN delivery of VitD, but not by its IP administration, ' 'suggesting that this hormone could have a therapeutic potential in COVID-19 if locally ' 'applied. To our knowledge, the local delivery of VitD to downmodulate lung inflammation in ' 'COVID-19 is an original proposition.</jats:p>', 'DOI': '10.3390/cells12071092', 'type': 'journal-article', 'created': {'date-parts': [[2023, 4, 6]], 'date-time': '2023-04-06T07:59:55Z', 'timestamp': 1680767995000}, 'page': '1092', 'source': 'Crossref', 'is-referenced-by-count': 0, 'title': 'Lung Inflammation Induced by Inactivated SARS-CoV-2 in C57BL/6 Female Mice Is Controlled by ' 'Intranasal Instillation of Vitamin D', 'prefix': '10.3390', 'volume': '12', 'author': [ { 'ORCID': 'http://orcid.org/0000-0001-9610-694X', 'authenticated-orcid': False, 'given': 'William Danilo', 'family': 'Fernandes de Souza', 'sequence': 'first', 'affiliation': [ { 'name': 'Department of Chemical and Biological Sciences, Institute of ' 'Biosciences, São Paulo State University (UNESP), Botucatu ' '18618-689, SP, Brazil'}]}, { 'given': 'Sofia Fernanda Gonçalves', 'family': 'Zorzella-Pezavento', 'sequence': 'additional', 'affiliation': [ { 'name': 'Department of Chemical and Biological Sciences, Institute of ' 'Biosciences, São Paulo State University (UNESP), Botucatu ' '18618-689, SP, Brazil'}]}, { 'given': 'Marina Caçador', 'family': 'Ayupe', 'sequence': 'additional', 'affiliation': [ { 'name': 'Laboratory of Mucosal Immunology, Department of Immunology, ' 'Institute of Biomedical Sciences, University of São Paulo (USP), ' 'São Paulo 05508-000, SP, Brazil'}]}, { 'given': 'Caio Loureiro', 'family': 'Salgado', 'sequence': 'additional', 'affiliation': [ { 'name': 'Laboratory of Mucosal Immunology, Department of Immunology, ' 'Institute of Biomedical Sciences, University of São Paulo (USP), ' 'São Paulo 05508-000, SP, Brazil'}]}, { 'given': 'Bernardo de Castro', 'family': 'Oliveira', 'sequence': 'additional', 'affiliation': [ { 'name': 'Laboratory of Mucosal Immunology, Department of Immunology, ' 'Institute of Biomedical Sciences, University of São Paulo (USP), ' 'São Paulo 05508-000, SP, Brazil'}]}, { 'given': 'Francielly', 'family': 'Moreira', 'sequence': 'additional', 'affiliation': [ { 'name': 'Laboratory of Mucosal Immunology, Department of Immunology, ' 'Institute of Biomedical Sciences, University of São Paulo (USP), ' 'São Paulo 05508-000, SP, Brazil'}]}, { 'ORCID': 'http://orcid.org/0000-0002-3398-6035', 'authenticated-orcid': False, 'given': 'Guilherme William', 'family': 'da Silva', 'sequence': 'additional', 'affiliation': [ { 'name': 'Laboratory of Mucosal Immunology, Department of Immunology, ' 'Institute of Biomedical Sciences, University of São Paulo (USP), ' 'São Paulo 05508-000, SP, Brazil'}]}, { 'ORCID': 'http://orcid.org/0000-0002-5105-6659', 'authenticated-orcid': False, 'given': 'Stefanie Primon', 'family': 'Muraro', 'sequence': 'additional', 'affiliation': [ { 'name': 'Laboratory of Emerging Viruses, Department of Genetics, ' 'Evolution, Microbiology and Immunology, Institute of Biology, ' 'University of Campinas (UNICAMP), Campinas 13083-862, SP, ' 'Brazil'}]}, { 'given': 'Gabriela Fabiano', 'family': 'de Souza', 'sequence': 'additional', 'affiliation': [ { 'name': 'Laboratory of Emerging Viruses, Department of Genetics, ' 'Evolution, Microbiology and Immunology, Institute of Biology, ' 'University of Campinas (UNICAMP), Campinas 13083-862, SP, ' 'Brazil'}]}, { 'ORCID': 'http://orcid.org/0000-0002-4996-3153', 'authenticated-orcid': False, 'given': 'José Luiz', 'family': 'Proença-Módena', 'sequence': 'additional', 'affiliation': [ { 'name': 'Laboratory of Emerging Viruses, Department of Genetics, ' 'Evolution, Microbiology and Immunology, Institute of Biology, ' 'University of Campinas (UNICAMP), Campinas 13083-862, SP, ' 'Brazil'}]}, { 'ORCID': 'http://orcid.org/0000-0002-9153-1485', 'authenticated-orcid': False, 'given': 'Joao Pessoa', 'family': 'Araujo Junior', 'sequence': 'additional', 'affiliation': [ { 'name': 'Department of Chemical and Biological Sciences, Institute of ' 'Biosciences, São Paulo State University (UNESP), Botucatu ' '18618-689, SP, Brazil'}]}, { 'given': 'Denise Morais da', 'family': 'Fonseca', 'sequence': 'additional', 'affiliation': [ { 'name': 'Laboratory of Mucosal Immunology, Department of Immunology, ' 'Institute of Biomedical Sciences, University of São Paulo (USP), ' 'São Paulo 05508-000, SP, Brazil'}]}, { 'given': 'Alexandrina', 'family': 'Sartori', 'sequence': 'additional', 'affiliation': [ { 'name': 'Department of Chemical and Biological Sciences, Institute of ' 'Biosciences, São Paulo State University (UNESP), Botucatu ' '18618-689, SP, Brazil'}]}], 'member': '1968', 'published-online': {'date-parts': [[2023, 4, 6]]}, 'reference': [ { 'key': 'ref_1', 'doi-asserted-by': 'crossref', 'first-page': '106356', 'DOI': '10.1016/j.rmed.2021.106356', 'article-title': 'COVID-19: Why Does Disease Severity Vary among Individuals?', 'volume': '180', 'author': 'Samadizadeh', 'year': '2021', 'journal-title': 'Respir. 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