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Journal of General Virology header logo Journal of General Virology

Volume 105, Issue 10

BALB/c mice challenged with SARS-CoV-2 B.1.351 β variant cause pathophysiological and neurological changes within the lungs and brains Open Access

Abstract

Up to one-third of individuals suffering from acute SARS-CoV-2 infection with the onset of severe-to-mild diseases could develop several symptoms of neurological disorders, which could last long after resolving the infection, known as neuro-COVID. Effective therapeutic treatments for neuro-COVID remain unavailable, in part, due to the absence of animal models for studying its underlying mechanisms and developing medical countermeasures against it. Here, we explored the impact of SARS-CoV-2 infection on the well-being of respiratory and neurological functions of BALB/c mice by using a clinical isolate of β-variant, i.e. B.1.351. We found that this β-variant of SARS-CoV-2 primarily infected the lungs, causing tissue damage, profound inflammatory responses, altered respiratory functions and transient but significant hypoxia. Although live progeny viruses could not be isolated, viral RNAs were detected across many anatomical regions of the brains in most challenged mice and triggered activation of genes encoding for NF, , and and microglial cells. We noted that the significantly activated -encoded gene persisted at 4 weeks after infection. Together, these results suggest that this B.1.351/BALB/c model of SARS-CoV-2 infection warrants further studies to establish it as a desirable model for studies of neuropathogenesis and the development of effective therapeutics of neuro-COVID.

  • Received:
  • Accepted:
  • Published Online:
Keyword(s): B.1.351 , BALB/c , neuro-COVID , neuropathogenesis and SARS-CoV-2
Funding
This study was supported by the:
  • National Institute of Allergy and Infectious Diseases (Award HHSN272201700040I/NIAID-Task A38)
    • Principal Award Recipient: Chien-TeK. Tseng
© 2024 The Authors
  • This is an open-access article distributed under the terms of the Creative Commons Attribution License.
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2024-10-30
2025-12-14

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References

  1. Antonelli M, Pujol JC, Spector TD, Ourselin S, Steves CJ. Risk of long COVID associated with delta versus omicron variants of SARS-CoV-2. Lancet 2022; 399:2263–2264 [View Article]
     [Google Scholar]
  2. Yomogida K, Zhu S, Rubino F, Figueroa W, Balanji N et al. Post-acute sequelae of SARS-CoV-2 infection among adults aged ≥18 years - long beach, California, april 1-december 10, 2020. MMWR Morb Mortal Wkly Rep 2021; 70:1274–1277 [View Article] [PubMed]
     [Google Scholar]
  3. The Lancet Neurology Long COVID: understanding the neurological effects. Lancet Neurol 2021; 20:247 [View Article] [PubMed]
     [Google Scholar]
  4. Simonin Y. Neurobiology of long-COVID: hypotheses and unanswered questions. Anaesth Crit Care Pain Med 2023; 42:101201 [View Article] [PubMed]
     [Google Scholar]
  5. Li YC, Zhang Y, Tan BH. What can cerebrospinal fluid testing and brain autopsies tell us about viral neuroinvasion of SARS-CoV-2. J Med Virol 2021; 93:4247–4257 [View Article] [PubMed]
     [Google Scholar]
  6. Bauer L, Laksono BM, de Vrij FMS, Kushner SA, Harschnitz O et al. The neuroinvasiveness, neurotropism, and neurovirulence of SARS-CoV-2. Trends Neurosci 2022; 45:358–368 [View Article] [PubMed]
     [Google Scholar]
  7. Ludlow M, Kortekaas J, Herden C, Hoffmann B, Tappe D et al. Neurotropic virus infections as the cause of immediate and delayed neuropathology. Acta Neuropathol 2016; 131:159–184 [View Article] [PubMed]
     [Google Scholar]
  8. Meinhardt J, Radke J, Dittmayer C, Franz J, Thomas C et al. Olfactory transmucosal SARS-CoV-2 invasion as a port of central nervous system entry in individuals with COVID-19. Nat Neurosci 2021; 24:168–175 [View Article] [PubMed]
     [Google Scholar]
  9. Leng A, Shah M, Ahmad SA, Premraj L, Wildi K et al. Pathogenesis underlying neurological manifestations of long COVID syndrome and potential therapeutics. Cells 2023; 12:816 [View Article] [PubMed]
     [Google Scholar]
  10. Sun J, Zhuang Z, Zheng J, Li K, Wong RL-Y et al. Generation of a broadly useful model for COVID-19 pathogenesis, vaccination, and treatment. Cell 2020; 182:734–743 [View Article] [PubMed]
     [Google Scholar]
  11. Tseng C-TK, Huang C, Newman P, Wang N, Narayanan K et al. Severe acute respiratory syndrome coronavirus infection of mice transgenic for the human Angiotensin-converting enzyme 2 virus receptor. J Virol 2007; 81:1162–1173 [View Article] [PubMed]
     [Google Scholar]
  12. Yinda CK, Port JR, Bushmaker T, Offei Owusu I, Purushotham JN et al. K18-hACE2 mice develop respiratory disease resembling severe COVID-19. PLoS Pathog 2021; 17:e1009195 [View Article]
     [Google Scholar]
  13. Drelich AK, Rayavara K, Hsu J, Saenkham-Huntsinger P, Judy BM et al. Characterization of unique pathological features of COVID-associated coagulopathy: studies with AC70 hACE2 transgenic mice highly permissive to SARS-CoV-2 infection. PLoS Pathog 2024; 20:e1011777 [View Article] [PubMed]
     [Google Scholar]
  14. Snouwaert JN, Jania LA, Nguyen T, Martinez DR, Schäfer A et al. Human ACE2 expression, a major tropism determinant for SARS-CoV-2, is regulated by upstream and intragenic elements. PLoS Pathog 2023; 19:e1011168 [View Article] [PubMed]
     [Google Scholar]
  15. Dinnon KH III, Leist SR, Schäfer A, Edwards CE, Martinez DR et al. A mouse-adapted model of SARS-CoV-2 to test COVID-19 countermeasures. Nature 2020; 586:560–566 [View Article]
     [Google Scholar]
  16. Gholami M, Safari S, Ulloa L, Motaghinejad M. Neuropathies and neurological dysfunction induced by coronaviruses. J Neurovirol 2021; 27:380–396 [View Article] [PubMed]
     [Google Scholar]
  17. Arabi YM, Harthi A, Hussein J, Bouchama A, Johani S et al. Severe neurologic syndrome associated with Middle East respiratory syndrome corona virus (MERS-CoV). Infection 2015; 43:495–501 [View Article] [PubMed]
     [Google Scholar]
  18. Li Y, Li H, Fan R, Wen B, Zhang J et al. Coronavirus infections in the central nervous system and respiratory tract show distinct features in hospitalized children. Intervirology 2016; 59:163–169 [View Article] [PubMed]
     [Google Scholar]
  19. Varatharaj A, Thomas N, Ellul MA, Davies NWS, Pollak TA et al. Neurological and neuropsychiatric complications of COVID-19 in 153 patients: a UK-wide surveillance study. Lancet Psychiatry 2020; 7:875–882 [View Article]
     [Google Scholar]
  20. Leist SR, Dinnon KH 3rd, Schäfer A, Tse LV, Okuda K et al. A mouse-adapted SARS-CoV-2 induces acute lung injury and mortality in standard laboratory mice. Cell 2020; 183:1070–1085 [View Article] [PubMed]
     [Google Scholar]
  21. Gu H, Chen Q, Yang G, He L, Fan H et al. Adaptation of SARS-CoV-2 in BALB/c mice for testing vaccine efficacy. Science 2020; 369:1603–1607 [View Article] [PubMed]
     [Google Scholar]
  22. Yasui F, Matsumoto Y, Yamamoto N, Sanada T, Honda T et al. Infection with the SARS-CoV-2 B.1.351 variant is lethal in aged BALB/c mice. Sci Rep 2022; 12:4150 [View Article] [PubMed]
     [Google Scholar]
  23. Theofilis P, Sagris M, Antonopoulos AS, Oikonomou E, Tsioufis C et al. Inflammatory mediators of platelet activation: focus on atherosclerosis and COVID-19. Int J Mol Sci 2021; 22:11170 [View Article] [PubMed]
     [Google Scholar]
  24. McFadyen JD, Stevens H, Peter K. The emerging threat of (Micro)thrombosis in COVID-19 and its therapeutic implications. Circ Res 2020; 127:571–587 [View Article] [PubMed]
     [Google Scholar]
  25. Pignatelli A, Belluzzi O. Dopaminergic neurones in the main olfactory bulb: an overview from an electrophysiological perspective. Front Neuroanat 2017; 11:7 [View Article] [PubMed]
     [Google Scholar]
  26. Baltanas F, Weruaga E, Airado C, Valero J, José RA et al. Chemical heterogeneity of the periglomerular neurons in the olfactory bulb. A review. Eur J Anat 2015; 11:
     [Google Scholar]
  27. Mazzoni A, Salvati L, Maggi L, Annunziato F, Cosmi L. Hallmarks of immune response in COVID-19: exploring dysregulation and exhaustion. Semin Immunol 2021; 55:101508 [View Article] [PubMed]
     [Google Scholar]
  28. Dinnon KH III, Leist SR, Okuda K, Dang H, Fritch EJ et al. A model of persistent post SARS-CoV-2 induced lung disease for target identification and testing of therapeutic strategies. bioRxiv 2022 [View Article]
     [Google Scholar]
  29. Antonioli L, Fornai M, Pellegrini C, Masi S, Puxeddu I et al. Ectopic lymphoid organs and immune-mediated diseases: molecular basis for pharmacological approaches. Trends Mol Med 2020; 26:1021–1033 [View Article] [PubMed]
     [Google Scholar]
  30. Sato Y, Yanagita M. Immunology of the ageing kidney. Nat Rev Nephrol 2019; 15:625–640 [View Article]
     [Google Scholar]
  31. Gago da Graça C, van Baarsen LGM, Mebius RE. Tertiary lymphoid structures: diversity in their development, composition, and role. J Immunol 2021; 206:273–281 [View Article] [PubMed]
     [Google Scholar]
  32. Hottz ED, Azevedo-Quintanilha IG, Palhinha L, Teixeira L, Barreto EA et al. Platelet activation and platelet-monocyte aggregate formation trigger tissue factor expression in patients with severe COVID-19. Blood 2020; 136:1330–1341
     [Google Scholar]
  33. Manne BK, Denorme F, Middleton EA, Portier I, Rowley JW et al. Platelet gene expression and function in patients with COVID-19. Blood 2020; 136:1317–1329 [View Article] [PubMed]
     [Google Scholar]
  34. Martins-Gonçalves R, Campos MM, Palhinha L, Azevedo-Quintanilha IG, Abud Mendes M et al. Persisting platelet activation and hyperactivity in COVID-19 survivors. Circ Res 2022; 131:944–947 [View Article] [PubMed]
     [Google Scholar]
  35. Amruta N, Ismael S, Leist SR, Gressett TE, Srivastava A et al. Mouse adapted SARS-CoV-2 (MA10) viral infection induces neuroinflammation in standard laboratory mice. Viruses 2022; 15:114 [View Article]
     [Google Scholar]
  36. Pan T, Chen R, He X, Yuan Y, Deng X et al. Infection of wild-type mice by SARS-CoV-2 B.1.351 variant indicates a possible novel cross-species transmission route. Signal Transduct Target Ther 2021; 6:420 [View Article] [PubMed]
     [Google Scholar]
  37. Montalvan V, Lee J, Bueso T, De Toledo J, Rivas K. Neurological manifestations of COVID-19 and other coronavirus infections: a systematic review. Clin Neurol Neurosurg 2020; 194:105921 [View Article] [PubMed]
     [Google Scholar]
  38. Li YC, Bai WZ, Hashikawa T. The neuroinvasive potential of SARS-CoV2 may play a role in the respiratory failure of COVID-19 patients. J Med Virol 2020; 92:552–555 [View Article] [PubMed]
     [Google Scholar]
  39. Peng H, Xie P, Liu L, Kuang X, Wang Y et al. Morphological diversity of single neurons in molecularly defined cell types. Nature 2021; 598:174–181 [View Article]
     [Google Scholar]
  40. Sudarov A, Zhang X-J, Braunstein L, LoCastro E, Singh S et al. Mature hippocampal neurons require LIS1 for synaptic integrity: implications for cognition. Biol Psychiatry 2018; 83:518–529 [View Article] [PubMed]
     [Google Scholar]
  41. Barth AL, Ray A. Progressive circuit changes during learning and disease. Neuron 2019; 104:37–46 [View Article] [PubMed]
     [Google Scholar]
  42. Halász N, Johansson O, Hökfelt T, Ljungdahl A, Goldstein M. Immunohistochemical identification of two types of dopamine neuron in the rat olfactory bulb as seen by serial sectioning. J Neurocytol 1981; 10:251–259 [View Article] [PubMed]
     [Google Scholar]
  43. McLean JH, Shipley MT. Postmitotic, postmigrational expression of tyrosine hydroxylase in olfactory bulb dopaminergic neurons. J Neurosci 1988; 8:3658–3669 [View Article] [PubMed]
     [Google Scholar]
  44. Panzanelli P, Fritschy JM, Yanagawa Y, Obata K, Sassoè-Pognetto M. GABAergic phenotype of periglomerular cells in the rodent olfactory bulb. J Comp Neurol 2007; 502:990–1002 [View Article] [PubMed]
     [Google Scholar]
  45. Verma AK, Zheng J, Meyerholz DK, Perlman S. SARS-CoV-2 infection of sustentacular cells disrupts olfactory signaling pathways. JCI Insight 2022; 7:e160277 [View Article] [PubMed]
     [Google Scholar]
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BALB/c mice challenged with SARS-CoV-2 B.1.351 β variant cause pathophysiological and neurological changes within the lungs and brains
J. Gen. Virol. 105, 002039 (2024); https://doi.org/10.1099/jgv.0.002039
/content/journal/jgv/10.1099/jgv.0.002039
/content/journal/jgv/10.1099/jgv.0.002039
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