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Elimination of olfactory sensory neurons by zinc sulfate inoculation prevents SARS-CoV-2 infection of the brain in K18-hACE2 transgenic mice

Lee et al., Scientific Reports, doi:10.1038/s41598-024-78538-5
Nov 2024  
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Zinc for COVID-19
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Mouse study showing that zinc sulfate protects K18-hACE2 transgenic mice from lethal SARS-CoV-2 infection by preventing viral transmission to the brain via the olfactory nerve pathway. Authors found that mice lacking olfactory sensory neurons exhibited reduced viral transmission to the brain and significantly improved survival compared to untreated infected mice. The virus persisted longer in the olfactory epithelium of untreated mice, and this correlated with greater brain infection. The results suggest that early inhibition of the olfactory nerve pathway may effectively prevent SARS-CoV-2 neuroinvasion.
10 preclinical studies support the efficacy of zinc for COVID-19:
Lee et al., 13 Nov 2024, peer-reviewed, 16 authors. Contact: snumouse@snu.ac.kr, yangkyuc@konkuk.ac.kr.
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Elimination of olfactory sensory neurons by zinc sulfate inoculation prevents SARS-CoV-2 infection of the brain in K18-hACE2 transgenic mice
Ji-Hun Lee, Eun-Seon Yoo, Na-Won Kim, Won-Yong Shim, Han-Bi Jeong, Dong-Hyun Kim, Young-Jun Park, Sun-Min Seo, Jun-Won Yun, Jun Won Park, Kang-Seuk Choi, Ho-Young Lee, Jun-Young Seo, Ki Taek Nam, Je Kyung Seong, Yang-Kyu Choi
Scientific Reports, doi:10.1038/s41598-024-78538-5
Coronavirus disease-2019 (COVID-19), attributed to the severe acute respiratory syndrome-related coronavirus-2 (SARS-CoV-2), has posed global health challenges since it first emerged in 2019, and its impact continues to persist. The neurotropic nature of SARS-CoV-2 remains undisclosed, though researchers are proposing hypotheses on how the virus is transmitted to the central nervous system. One of the prevailing hypotheses is that SARS-CoV-2 travels through the olfactory nerve system via the olfactory epithelium (OE). Using a K18-human angiotensin converting-enzyme 2 (hACE2) transgenic mouse model with impaired olfactory sensory neurons (OSNs) induced by zinc sulfate, we examined the role of the olfactory nerve in the brain invasion by SARS-CoV-2. Mice lacking OSNs exhibited reduced levels of viral transmission to the brain, leading to significantly improved outcomes following SARS-CoV-2 infection. Moreover, a positive correlation was observed between viral persistence in the OE and brain infection. These results indicate that early inhibition of the olfactory nerve pathway effectively prevents viral invasion of the brain in K18-hACE2 mice. Our study underscores the significance of the olfactory nerve pathway in the transmission of SARS-CoV-2 to the brain.
Author contributions Declarations Competing interests The authors declare no competing interests. Additional information Supplementary Information The online version contains supplementary material available at h t t p s : / / d o i . o r g / 1 0 . 1 0 3 8 / s 4 1 5 9 8 -0 2 4 -7 8 5 3 8 -5 . Correspondence and requests for materials should be addressed to J.K.S. or Y.-K.C. Reprints and permissions information is available at www.nature.com/reprints. Publisher's note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, 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 you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. 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..
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Med.'}, { 'key': '78538_CR24', 'doi-asserted-by': 'publisher', 'first-page': '134', 'DOI': '10.1038/s41423-023-01119-5', 'volume': '21', 'author': 'SA Wellford', 'year': '2023', 'unstructured': 'Wellford, S. A. & Moseman, E. A. Olfactory immune response to ' 'SARS-CoV-2. Cell. Mol. Immunol. 21, 134–143. ' 'https://doi.org/10.1038/s41423-023-01119-5 (2023).', 'journal-title': 'Cell. Mol. Immunol.'}, { 'key': '78538_CR25', 'doi-asserted-by': 'publisher', 'first-page': '75', 'DOI': '10.1016/j.tins.2022.11.003', 'volume': '46', 'author': 'R Butowt', 'year': '2023', 'unstructured': 'Butowt, R., Bilinska, K. & von Bartheld, C. S. Olfactory dysfunction in ' 'COVID-19: new insights into the underlying mechanisms. Trends Neurosci. ' '46, 75–90. https://doi.org/10.1016/j.tins.2022.11.003 (2023).', 'journal-title': 'Trends Neurosci.'}, { 'issue': '4', 'key': '78538_CR26', 'doi-asserted-by': 'publisher', 'first-page': '392', 'DOI': '10.1038/s41592-022-01447-w', 'volume': '19', 'author': 'H Chu', 'year': '2022', 'unstructured': 'Chu, H., Chan, J. F. & Yuen, K. Y. Animal models in SARS-CoV-2 research. ' 'Nat. Methods. 19 (4), 392–394. ' 'https://doi.org/10.1038/s41592-022-01447-w (2022).', 'journal-title': 'Nat. Methods'}, { 'key': '78538_CR27', 'doi-asserted-by': 'publisher', 'first-page': 'e0272019', 'DOI': '10.1371/journal.pone.0272019', 'volume': '17', 'author': 'SM Seo', 'year': '2022', 'unstructured': 'Seo, S. M. et al. Development of transgenic models susceptible and ' 'resistant to SARS-CoV-2 infection in FVB background mice. 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' 'BMC Neurosci. 12, 86. https://doi.org/10.1186/1471-2202-12-86 (2011).', 'journal-title': 'BMC Neurosci.'}, { 'key': '78538_CR34', 'doi-asserted-by': 'publisher', 'first-page': '589', 'DOI': '10.1007/s00441-021-03467-y', 'volume': '84', 'author': 'B Bryche', 'year': '2021', 'unstructured': 'Bryche, B., Baly, C. & Meunier, N. Modulation of olfactory signal ' 'detection in the olfactory epithelium: focus on the internal and ' 'external environment, and the emerging role of the immune system. Cell. ' 'Tissue Res. 84, 589–605. https://doi.org/10.1007/s00441-021-03467-y ' '(2021).', 'journal-title': 'Cell. Tissue Res.'}, { 'key': '78538_CR35', 'doi-asserted-by': 'crossref', 'unstructured': 'Harkema, J. R. et al. Sinus, pharynx, and Larynx. in Comp. Anat. Histol. ' '71–94 (Elsevier, 2012).', 'DOI': '10.1016/B978-0-12-381361-9.00006-8'}, { 'key': '78538_CR36', 'doi-asserted-by': 'publisher', 'first-page': '18', 'DOI': '10.1186/s13064-017-0095-0', 'volume': '12', 'author': 'X Shao', 'year': '2017', 'unstructured': 'Shao, X. et al. Olfactory sensory axons target specific protoglomeruli ' 'in the olfactory bulb of zebrafish. Neural Dev. 12, 18. ' 'https://doi.org/10.1186/s13064-017-0095-0 (2017).', 'journal-title': 'Neural Dev.'}, { 'key': '78538_CR37', 'doi-asserted-by': 'publisher', 'first-page': '76', 'DOI': '10.1080/13550280290049534', 'volume': '8', 'author': 'A Matthews', 'year': '2002', 'unstructured': 'Matthews, A., Weiss, S. & Paterson, Y. Murine Hepatitis virus–a model ' 'for virus-induced CNS demyelination. J. Neurovirol. 8, 76–85. ' 'https://doi.org/10.1080/13550280290049534 (2002).', 'journal-title': 'J. Neurovirol'}, { 'key': '78538_CR38', 'doi-asserted-by': 'publisher', 'first-page': '53', 'DOI': '10.3389/fvets.2019.00053', 'volume': '6', 'author': 'JC Mora-Díaz', 'year': '2019', 'unstructured': 'Mora-Díaz, J. C., Piñeyro, P. E., Houston, E., Zimmerman, J. & ' 'Giménez-Lirola, L. G. Porcine hemagglutinating encephalomyelitis virus: ' 'a review. Front. Vet. Sci. 6, 53. ' 'https://doi.org/10.3389/fvets.2019.00053 (2019).', 'journal-title': 'Front. Vet. Sci.'}, { 'key': '78538_CR39', 'doi-asserted-by': 'publisher', 'first-page': '1051', 'DOI': '10.1007/s13760-020-01412-4', 'volume': '120', 'author': 'K Verstrepen', 'year': '2020', 'unstructured': 'Verstrepen, K., Baisier, L. & De Cauwer, H. Neurological manifestations ' 'of COVID-19, SARS and MERS. Acta Neurol. Belg. 120, 1051–1060. ' 'https://doi.org/10.1007/s13760-020-01412-4 (2020).', 'journal-title': 'Acta Neurol. 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' 'JCI Insight. 7, e160277. https://doi.org/10.1172/jci.insight.160277 ' '(2022).', 'journal-title': 'JCI Insight'}, { 'key': '78538_CR44', 'doi-asserted-by': 'publisher', 'first-page': '49', 'DOI': '10.1038/s41421-021-00290-1', 'volume': '7', 'author': 'Q Ye', 'year': '2021', 'unstructured': 'Ye, Q. et al. SARS-CoV-2 infection in the mouse olfactory system. Cell. ' 'Discov. 7, 49. https://doi.org/10.1038/s41421-021-00290-1 (2021).', 'journal-title': 'Cell. Discov'}, { 'key': '78538_CR45', 'doi-asserted-by': 'publisher', 'first-page': '101839', 'DOI': '10.1016/j.isci.2020.101839', 'volume': '23', 'author': 'L Fodoulian', 'year': '2020', 'unstructured': 'Fodoulian, L. et al. SARS-CoV-2 receptors and entry genes are expressed ' 'in the human olfactory neuroepithelium and brain. iScience. 23, 101839. 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