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Veterinary research
May 31, 2024;55 (1): 71.

Neuropathological lesions in intravenous BCG-stimulated K18-hACE2 mice challenged with SARS-CoV-2.

Lidia S��nchez-Morales, N��stor Porras, Teresa Garc��a-Seco, Marta P��rez-Sancho, F��tima Cruz, Blanca Chinchilla, Sandra Barroso-Ar��valo, Marta Diaz-Frutos, Ar��nzazu Buend��a, Inmaculada Moreno, V��ctor Briones, Mar��a de Los ��ngeles Risalde, Jos�� de la Fuente, Ram��n Juste, Joseba Garrido, Ana Balseiro, Christian Gort��zar, Antonio Rodr��guez-Bertos, Mercedes Dom��nguez, Lucas Dom��nguez
Author Information
  1. Lidia S��nchez-Morales: VISAVET Health Surveillance Centre, Complutense University of Madrid, 28040, Madrid, Spain.
  2. N��stor Porras: VISAVET Health Surveillance Centre, Complutense University of Madrid, 28040, Madrid, Spain.
  3. Teresa Garc��a-Seco: VISAVET Health Surveillance Centre, Complutense University of Madrid, 28040, Madrid, Spain.
  4. Marta P��rez-Sancho: VISAVET Health Surveillance Centre, Complutense University of Madrid, 28040, Madrid, Spain. maperezs@ucm.es. ORCID
  5. F��tima Cruz: VISAVET Health Surveillance Centre, Complutense University of Madrid, 28040, Madrid, Spain.
  6. Blanca Chinchilla: VISAVET Health Surveillance Centre, Complutense University of Madrid, 28040, Madrid, Spain.
  7. Sandra Barroso-Ar��valo: VISAVET Health Surveillance Centre, Complutense University of Madrid, 28040, Madrid, Spain.
  8. Marta Diaz-Frutos: VISAVET Health Surveillance Centre, Complutense University of Madrid, 28040, Madrid, Spain.
  9. Ar��nzazu Buend��a: VISAVET Health Surveillance Centre, Complutense University of Madrid, 28040, Madrid, Spain.
  10. Inmaculada Moreno: Unidad de Inmunolog��a Microbiana, Centro Nacional de Microbiolog��a, Instituto de Salud Carlos III, Carretera Pozuelo-Majadahonda km 2, Majadahonda, 28220, Madrid, Spain.
  11. V��ctor Briones: VISAVET Health Surveillance Centre, Complutense University of Madrid, 28040, Madrid, Spain.
  12. Mar��a de Los ��ngeles Risalde: Departamento de Anatom��a y Anatom��a Patol��gica Comparadas y Toxicolog��a, Grupo de Investigaci��n en Sanidad Animal y Zoonosis (GISAZ), UIC Zoonosis y Enfermedades Emergentes (ENZOEM), Universidad de C��rdoba, C��rdoba, Spain.
  13. Jos�� de la Fuente: SaBio Instituto de Investigaci��n en Recursos Cineg��ticos, Ciudad Real, Spain.
  14. Ram��n Juste: Animal Health Department, NEIKER-Basque Institute for Agricultural Research and Development, Basque Research and Technology Alliance (BRTA), 48160, Derio, Bizkaia, Spain.
  15. Joseba Garrido: Animal Health Department, NEIKER-Basque Institute for Agricultural Research and Development, Basque Research and Technology Alliance (BRTA), 48160, Derio, Bizkaia, Spain.
  16. Ana Balseiro: Departamento de Sanidad Animal, Facultad de Veterinaria, Universidad de Le��n, 24071, Le��n, Spain.
  17. Christian Gort��zar: SaBio Instituto de Investigaci��n en Recursos Cineg��ticos, Ciudad Real, Spain.
  18. Antonio Rodr��guez-Bertos: VISAVET Health Surveillance Centre, Complutense University of Madrid, 28040, Madrid, Spain.
  19. Mercedes Dom��nguez: Unidad de Inmunolog��a Microbiana, Centro Nacional de Microbiolog��a, Instituto de Salud Carlos III, Carretera Pozuelo-Majadahonda km 2, Majadahonda, 28220, Madrid, Spain.
  20. Lucas Dom��nguez: VISAVET Health Surveillance Centre, Complutense University of Madrid, 28040, Madrid, Spain.
PMID: 38822398 DOI: 10.1186/s13567-024-01325-7

Abstract

In the wake of the COVID-19 pandemic caused by SARS-CoV-2, questions emerged about the potential effects of Bacillus Calmette-Gu��rin (BCG) vaccine on the immune response to SARS-CoV-2 infection, including the neurodegenerative diseases it may contribute to. To explore this, an experimental study was carried out in BCG-stimulated and non-stimulated K18-hACE2 mice challenged with SARS-CoV-2. Viral loads in tissues determined by RT-qPCR, histopathology in brain and lungs, immunohistochemical study in brain (IHC) as well as mortality rates, clinical signs and plasma inflammatory and coagulation biomarkers were assessed. Our results showed BCG-SARS-CoV-2 challenged mice presented higher viral loads in the brain and an increased frequency of neuroinvasion, with the greatest differences observed between groups at 3-4 days post-infection (dpi). Histopathological examination showed a higher severity of brain lesions in BCG-SARS-CoV-2 challenged mice, mainly consisting of neuroinflammation, increased glial cell population and neuronal degeneration, from 5 dpi onwards. This group also presented higher interstitial pneumonia and vascular thrombosis in lungs (3-4 dpi), BCG-SARS-CoV-2 mice showed higher values for TNF-�� and D-dimer values, while iNOS values were higher in SARS-CoV-2 mice at 3-4 dpi. Results presented in this study indicate that BCG stimulation could have intensified the inflammatory and neurodegenerative lesions promoting virus neuroinvasion and dissemination in this experimental model. Although K18-hACE2 mice show higher hACE2 expression and neurodissemination, this study suggests that, although the benefits of BCG on enhancing heterologous protection against pathogens and tumour cells have been broadly demonstrated, potential adverse outcomes due to the non-specific effects of BCG should be considered.

Keywords

BCG stimulation K18-hACE2 SARS-CoV-2 neuroinvasion

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Grants

  1. PR38/21/Comunidad de Madrid
  2. PID2020-112966RB-I00PID2020-112966RB-I00/Ministerio de Ciencia e Innovaci��n

MeSH Term

Animals
Mice
BCG Vaccine
COVID-19
SARS-CoV-2
Brain
Viral Load
Lung
Angiotensin-Converting Enzyme 2
Mice, Transgenic
Female

Chemicals

BCG Vaccine
Angiotensin-Converting Enzyme 2
Journal Article
Article has an altmetric score of 2

Word Cloud

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