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2. Full protection from SARS-CoV-2 brain infection and damage in susceptible transgenic mice conferred by MVA-CoV2-S vaccine candidate

Author

Villadiego, Javier, García-Arriaza, Juan, Ramírez-Lorca, Reposo, García-Swinburn, Roberto, Cabello-Rivera, Daniel, Rosales-Nieves, Alicia E., Álvarez-Vergara, María I., Cala-Fernández, Fernando, García-Roldán, Ernesto, López-Ogáyar, Juan L., Zamora, Carmen, Astorgano, David, Albericio, Guillermo, Pérez, Patricia, Muñoz-Cabello, Ana M., Pascual, Alberto, Esteban, Mariano, López-Barneo, José, and Toledo-Aral, Juan José

Published
2023
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3. MVA-CoV2-S vaccine candidate confers full protection from SARS-CoV-2 brain infection and damage in susceptible transgenic mice

Author

Consejo Superior de Investigaciones Científicas (España), Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Instituto de Salud Carlos III, Red de Terapia Celular (España), Junta de Andalucía, Ministerio de Sanidad (España), Banco Santander, Conferencia de Rectores de las Universidades Españolas, La Caixa, Ferrovial, Fundación Mapfre, European Research Council, European Commission, Villadiego, Javier [0000-0003-2131-9013], García-Swinburn, Roberto [0000-0002-8154-0265], Rosales-Nieves, Alicia E. [0000-0001-9119-1604], Muñoz-Cabello, Ana M. [0000-0002-8047-768X], Pascual Bravo, Alberto [0000-0001-5459-6207], Villadiego, Javier, García-Arriaza, Juan, Ramírez Lorca, Reposo, Cabello-Rivera, Daniel, Álvarez-Vergara, María I., Cala-Fernández, Fernando, García-Swinburn, Roberto, García-Roldán, Ernesto, López-Ogáyar, Juan L., Zamora, Carmen, Astorgano, David, Pérez Ramírez, Patricia, Rosales-Nieves, Alicia E., Muñoz-Cabello, Ana M., Pascual Bravo, Alberto, Esteban, Mariano, López-Barneo, José, Toledo-Aral, Juan José, Consejo Superior de Investigaciones Científicas (España), Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Instituto de Salud Carlos III, Red de Terapia Celular (España), Junta de Andalucía, Ministerio de Sanidad (España), Banco Santander, Conferencia de Rectores de las Universidades Españolas, La Caixa, Ferrovial, Fundación Mapfre, European Research Council, European Commission, Villadiego, Javier [0000-0003-2131-9013], García-Swinburn, Roberto [0000-0002-8154-0265], Rosales-Nieves, Alicia E. [0000-0001-9119-1604], Muñoz-Cabello, Ana M. [0000-0002-8047-768X], Pascual Bravo, Alberto [0000-0001-5459-6207], Villadiego, Javier, García-Arriaza, Juan, Ramírez Lorca, Reposo, Cabello-Rivera, Daniel, Álvarez-Vergara, María I., Cala-Fernández, Fernando, García-Swinburn, Roberto, García-Roldán, Ernesto, López-Ogáyar, Juan L., Zamora, Carmen, Astorgano, David, Pérez Ramírez, Patricia, Rosales-Nieves, Alicia E., Muñoz-Cabello, Ana M., Pascual Bravo, Alberto, Esteban, Mariano, López-Barneo, José, and Toledo-Aral, Juan José

Abstract

The protective efficacy of vaccines against SARS-CoV-2 infection in the brain is yet unclear. Here, in the susceptible transgenic K18-hACE2 mouse model of severe COVID-19 disease, we report a detailed spatiotemporal description of the SARS-CoV-2 infection and replication in different areas of the brain. Remarkably, SARS-CoV-2 brain replication occurs primarily in neurons, producing important neuropathological alterations such as neuronal loss, incipient signs of neuroinflammation, and vascular damage in SARS-CoV-2 infected mice. Notably, one or two doses of a modified vaccinia virus Ankara (MVA) vector expressing the SARS-CoV-2 spike (S) protein (MVA-CoV2-S) conferred full protection against SARS-CoV-2 cerebral infection, preventing virus replication in all areas of the brain and its associated damage. This protection was maintained even after SARS-CoV-2 reinfection. To our knowledge, this is the first study of a COVID-19 vaccine candidate showing 100% efficacy against SARS-CoV-2 brain infection and damage, reinforcing the use of MVA-CoV2-S as a promising vaccine candidate against SARS-CoV-2/COVID-19, worth to move forward into clinical trials.

Published
2022

4. Characterization of the nigrostriatal pathway in Parkinson's Disease mice models of overexpression of human alpha-synuclein and LRRK2 mutants

Author

Toledo Aral, Juan José, Universidad de Sevilla. Departamento de Fisiología Médica y Biofísica, García Swinburn, Roberto, Toledo Aral, Juan José, Universidad de Sevilla. Departamento de Fisiología Médica y Biofísica, and García Swinburn, Roberto

Abstract

Parkinson's disease (PD) is a long-term neurodegenerative disease with a complex array of symptoms and signs, involving general symptoms such as pain and fatigue, but mostly characterised by loss of motor coordination and late-stage psychological disorders such as psychosis and dementia. Other key signs of PD are loss of dopamine and neuronal death in the nigrostriatal pathway, most notably dopaminergic neurons of the substantia nigra pars compacta, found on the ventrolateral side of the midbrain, leading to loss of dopaminergic input in the caudate and putamen of the basal ganglia (also called striatum); and the appearance of Lewy bodies and Lewy neurites, the previous being alpha-synuclein in the soma of neurons and the latter in cell processes. To date, PD is the second most prevalent neurodegenerative disease after Alzheimer’s disease. It has been reported to have a prevalence of 1-2 people out of 1000 at all times in unselected populations, affecting 1% of people over the age of 60 worldwide. This number of affected people is growing, and certain authors, experts in the topic of PD, estimate that the number of people affected by PD will exceed 12 million worldwide by 2040. Several strategies have been studied to attempt to stop the neurodegenerative process and increase the quality of life of PD patients, yet unfortunately so far no cure or therapy has been found for this disease. It is important to then continue to research PD, and this requires models to assess novel therapeutical approaches. In this thesis, we study two different mice PD models: C57BL/6J-Tg(Th-SNCA*A30P*A53T)39Eric/J and C57BL/6J-Tg(LRRK2*G2019S)2AMjff/J, and we use different strategies to improve the models for future preclinical data for therapeutic studies. We were able to find that our C57BL/6J-Tg(Th-SNCA*A30P*A53T)39Eric/J mice presented higher content in striatal dopamine, reactive microgliosis in the nigrostriatal pathway and motor dysfunctions with hypoactivity. When challenged with

Published
2023

5. Full protection from SARS-CoV-2 brain infection and damage in susceptible transgenic mice conferred by MVA-CoV2-S vaccine candidate

Author

Universidad de Sevilla. Departamento de Fisiología Médica y Biofísica, Universidad de Sevilla. CTS-516: Fisiología Celular y Biofísica, Spanish Ministry of Science and Innovation/Spanish Research Agency, Red TerCel ISCIII, Consejeria de Economia, Conocimiento, Empresas y Universidad, Junta de Andalucia, Fondo COVID-19 grant (Spanish Health Ministry, Instituto de Salud Carlos III), CSIC, La CaixaImpulse grant, European Commission-NextGenerationEU, through the CSIC's Global Health Platform (PTI Salud Global), European Research Council (ERC) Spanish Government, Spanish Government, Villadiego Luque, Francisco Javier, García-Arriaza, Juan, Ramírez Lorca, Reposo, García Swinburn, Roberto, Cabello Rivera, Daniel, Rosales Nieves, Alicia E., Muñoz Cabello, Ana María, López Barneo, José, Toledo Aral, Juan José, Universidad de Sevilla. Departamento de Fisiología Médica y Biofísica, Universidad de Sevilla. CTS-516: Fisiología Celular y Biofísica, Spanish Ministry of Science and Innovation/Spanish Research Agency, Red TerCel ISCIII, Consejeria de Economia, Conocimiento, Empresas y Universidad, Junta de Andalucia, Fondo COVID-19 grant (Spanish Health Ministry, Instituto de Salud Carlos III), CSIC, La CaixaImpulse grant, European Commission-NextGenerationEU, through the CSIC's Global Health Platform (PTI Salud Global), European Research Council (ERC) Spanish Government, Spanish Government, Villadiego Luque, Francisco Javier, García-Arriaza, Juan, Ramírez Lorca, Reposo, García Swinburn, Roberto, Cabello Rivera, Daniel, Rosales Nieves, Alicia E., Muñoz Cabello, Ana María, López Barneo, José, and Toledo Aral, Juan José

Abstract

Vaccines against SARS-CoV-2 have been shown to be safe and effective but their protective efficacy against infection in the brain is yet unclear. Here, in the susceptible transgenic K18-hACE2 mouse model of severe coronavirus disease 2019 (COVID-19), we report a spatiotemporal description of SARS-CoV-2 infection and replication through the brain. SARS-CoV-2 brain replication occurs primarily in neurons, leading to neuronal loss, signs of glial activation and vascular damage in mice infected with SARS-CoV-2. One or two doses of a modified vaccinia virus Ankara (MVA) vector expressing the SARS-CoV-2 spike (S) protein (MVA-CoV2-S) conferred full protection against SARS-CoV-2 cerebral infection, preventing virus replication in all areas of the brain and its associated damage. This protection was maintained even after SARS-CoV-2 reinfection. These findings further support the use of MVA-CoV2-S as a promising vaccine candidate against SARS-CoV-2/COVID-19.

Published
2023

6. Extracellular matrix protein anosmin-1 overexpression alters dopaminergic phenotype in the CNS and the PNS with no pathogenic consequences in a MPTP model of Parkinson’s disease

Author

Universidad de Sevilla, Conferencia de Rectores de las Universidades Españolas, Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Instituto de Salud Carlos III, Junta de Andalucía, Villadiego, Javier, García-Swinburn, Roberto, García-González, Diego, Lebrón-Galán, Rafael, Murcia-Belmonte, Verónica, García-Roldán, Ernesto, Suárez-Luna, Nela, Nombela, Cristina, Marchena, Miguel A., Castro Soubriet, Fernando de, Toledo-Aral, Juan José, Universidad de Sevilla, Conferencia de Rectores de las Universidades Españolas, Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Instituto de Salud Carlos III, Junta de Andalucía, Villadiego, Javier, García-Swinburn, Roberto, García-González, Diego, Lebrón-Galán, Rafael, Murcia-Belmonte, Verónica, García-Roldán, Ernesto, Suárez-Luna, Nela, Nombela, Cristina, Marchena, Miguel A., Castro Soubriet, Fernando de, and Toledo-Aral, Juan José

Abstract

The development and survival of dopaminergic neurons are influenced by the fibroblast growth factor (FGF) pathway. Anosmin-1 (A1) is an extracellular matrix protein that acts as a major regulator of this signaling pathway, controlling FGF diffusion, and receptor interaction and shuttling. In particular, previous work showed that A1 overexpression results in more dopaminergic neurons in the olfactory bulb. Prompted by those intriguing results, in this study, we investigated the effects of A1 overexpression on different populations of catecholaminergic neurons in the central (CNS) and the peripheral nervous systems (PNS). We found that A1 overexpression increases the number of dopaminergic substantia nigra pars compacta (SNpc) neurons and alters the striosome/matrix organization of the striatum. Interestingly, these numerical and morphological changes in the nigrostriatal pathway of A1-mice did not confer an altered susceptibility to experimental MPTP-parkinsonism with respect to wild-type controls. Moreover, the study of the effects of A1 overexpression was extended to different dopaminergic tissues associated with the PNS, detecting a significant reduction in the number of dopaminergic chemosensitive carotid body glomus cells in A1-mice. Overall, our work shows that A1 regulates the development and survival of dopaminergic neurons in different nuclei of the mammalian nervous system.

Published
2023

7. Full protection from SARS-CoV-2 brain infection and damage in susceptible transgenic mice conferred by MVA-CoV2-S vaccine candidate

Author

Consejo Superior de Investigaciones Científicas (España), Ministerio de Ciencia e Innovación (España), Agencia Estatal de Investigación (España), Instituto de Salud Carlos III, Junta de Andalucía, Ministerio de Sanidad (España), Banco Santander, Conferencia de Rectores de las Universidades Españolas, La Caixa, Ferrovial, Fundación Mapfre, European Commission, European Research Council, Villadiego, Javier, García-Arriaza, Juan, Ramírez Lorca, Reposo, García-Swinburn, Roberto, Cabello-Rivera, Daniel, Rosales-Nieves, Alicia E., Álvarez-Vergara, María I., Cala-Fernández, Fernando, García-Roldán, Ernesto, López-Ogáyar, Juan L., Zamora, Carmen, Astorgano, David, Albericio, Guillermo, Pérez Ramírez, Patricia, Muñoz-Cabello, Ana M., Pascual Bravo, Alberto, Esteban, Mariano, López-Barneo, José, Toledo-Aral, Juan José, Consejo Superior de Investigaciones Científicas (España), Ministerio de Ciencia e Innovación (España), Agencia Estatal de Investigación (España), Instituto de Salud Carlos III, Junta de Andalucía, Ministerio de Sanidad (España), Banco Santander, Conferencia de Rectores de las Universidades Españolas, La Caixa, Ferrovial, Fundación Mapfre, European Commission, European Research Council, Villadiego, Javier, García-Arriaza, Juan, Ramírez Lorca, Reposo, García-Swinburn, Roberto, Cabello-Rivera, Daniel, Rosales-Nieves, Alicia E., Álvarez-Vergara, María I., Cala-Fernández, Fernando, García-Roldán, Ernesto, López-Ogáyar, Juan L., Zamora, Carmen, Astorgano, David, Albericio, Guillermo, Pérez Ramírez, Patricia, Muñoz-Cabello, Ana M., Pascual Bravo, Alberto, Esteban, Mariano, López-Barneo, José, and Toledo-Aral, Juan José

Abstract

Vaccines against SARS-CoV-2 have been shown to be safe and effective but their protective efficacy against infection in the brain is yet unclear. Here, in the susceptible transgenic K18-hACE2 mouse model of severe coronavirus disease 2019 (COVID-19), we report a spatiotemporal description of SARS-CoV-2 infection and replication through the brain. SARS-CoV-2 brain replication occurs primarily in neurons, leading to neuronal loss, signs of glial activation and vascular damage in mice infected with SARS-CoV-2. One or two doses of a modified vaccinia virus Ankara (MVA) vector expressing the SARS-CoV-2 spike (S) protein (MVA-CoV2-S) conferred full protection against SARS-CoV-2 cerebral infection, preventing virus replication in all areas of the brain and its associated damage. This protection was maintained even after SARS-CoV-2 reinfection. These findings further support the use of MVA-CoV2-S as a promising vaccine candidate against SARS-CoV-2/COVID-19.

Published
2023

8. Extracellular matrix protein anosmin-1 overexpression regulates dopaminergic phenotype in the CNS and the PNS with no pathogenic consequences in MPTP model of Parkinson’s disease

Author

Villadiego, Javier, primary, García-Swinburn, Roberto, additional, García-González, Diego, additional, Lebrón-Galán, Rafael, additional, Murcia-Belmonte, Verónica, additional, García-Roldán, Ernesto, additional, Suárez-Luna, Nela, additional, Nombela, Cristina, additional, Marchena, Miguel, additional, de Castro, Fernando, additional, and Toledo-Aral, Juan José, additional

Published
2022
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9. MVA-CoV2-S vaccine candidate confers full protection from SARS-CoV-2 brain infection and damage in susceptible transgenic mice

Author

Villadiego, Javier, primary, García-Arriaza, Juan, additional, Ramírez-Lorca, Reposo, additional, Cabello-Rivera, Daniel, additional, Álvarez-Vergara, María I., additional, Cala-Fernández, Fernando, additional, García-Swinburn, Roberto, additional, García-Roldán, Ernesto, additional, López-Ogáyar, Juan L., additional, Zamora, Carmen, additional, Astorgano, David, additional, Pérez, Patricia, additional, Rosales-Nieves, Alicia, additional, Muñoz-Cabello, Ana M., additional, Pascual, Alberto, additional, Esteban, Mariano, additional, Lopez-Barneo, Jose, additional, and Toledo-Aral, Juan, additional

Published
2022
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10. MVA-CoV2-S vaccine candidate confers full protection from SARS-CoV-2 brain infection and damage in susceptible transgenic mice

Author

Javier Villadiego, Juan García-Arriaza, Reposo Ramírez-Lorca, Daniel Cabello-Rivera, María I. Álvarez-Vergara, Fernando Cala-Fernández, Roberto García-Swinburn, Ernesto García-Roldán, Juan L. López-Ogáyar, Carmen Zamora, David Astorgano, Patricia Pérez, Alicia Rosales-Nieves, Ana M. Muñoz-Cabello, Alberto Pascual, Mariano Esteban, Jose Lopez-Barneo, Juan Toledo-Aral, Consejo Superior de Investigaciones Científicas (España), Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Instituto de Salud Carlos III, Red de Terapia Celular (España), Junta de Andalucía, Ministerio de Sanidad (España), Banco Santander, Conferencia de Rectores de las Universidades Españolas, La Caixa, Ferrovial, Fundación Mapfre, European Research Council, European Commission, Villadiego, Javier [0000-0003-2131-9013], García-Swinburn, Roberto [0000-0002-8154-0265], Rosales-Nieves, Alicia E. [0000-0001-9119-1604], Muñoz-Cabello, Ana M. [0000-0002-8047-768X], Pascual Bravo, Alberto [0000-0001-5459-6207], Villadiego, Javier, García-Swinburn, Roberto, Rosales-Nieves, Alicia E., Muñoz-Cabello, Ana M., and Pascual Bravo, Alberto

Subjects
body regions, Transgenic K18-hACE2 mice, SARS-CoV-2, viruses, fungi, Vaccine MVA-CoV2-S ecacy, COVID-19, Brain infection, Neurodegeneration, skin and connective tissue diseases, respiratory tract diseases
Abstract

The protective efficacy of vaccines against SARS-CoV-2 infection in the brain is yet unclear. Here, in the susceptible transgenic K18-hACE2 mouse model of severe COVID-19 disease, we report a detailed spatiotemporal description of the SARS-CoV-2 infection and replication in different areas of the brain. Remarkably, SARS-CoV-2 brain replication occurs primarily in neurons, producing important neuropathological alterations such as neuronal loss, incipient signs of neuroinflammation, and vascular damage in SARS-CoV-2 infected mice. Notably, one or two doses of a modified vaccinia virus Ankara (MVA) vector expressing the SARS-CoV-2 spike (S) protein (MVA-CoV2-S) conferred full protection against SARS-CoV-2 cerebral infection, preventing virus replication in all areas of the brain and its associated damage. This protection was maintained even after SARS-CoV-2 reinfection. To our knowledge, this is the first study of a COVID-19 vaccine candidate showing 100% efficacy against SARS-CoV-2 brain infection and damage, reinforcing the use of MVA-CoV2-S as a promising vaccine candidate against SARS-CoV-2/COVID-19, worth to move forward into clinical trials., The authors thank the Centro de Investigación en Sanidad Animal (CISA)-Instituto Nacional de Investigaciones Agrarias (INIA-CSIC) (Valdeolmos, Madrid, Spain) for the BSL-3 facilities. SARS-CoV-2 MAD6 virus isolate was kindly provided by José M. Honrubia and Dr. Luis Enjuanes (CNB-CSIC, Madrid, Spain). We also thank to Dr. Konstantin L. Levitsky for excellent technical assistance with the confocal acquisition. We thank the Spanish Research Council (CSIC) and the Spanish Ministry of Science and Innovation (MICINN) for continuous support. This research was supported by MCIN/Spanish Research Agency (AEI)/ 10.13039/501100011033 grants: PID2019-105995RB-I00 (J.T.-A. and J.V.), PID2020- 114481RB-I00 (J.G.-A. and M.E.), and PID2019-106410RB-I00 (J.L.-B.). Moreover, this research work was also funded by Red TerCel ISCIII, RD16/0011/0025 (J.T.-A.); Consejería de Salud y Familias, Junta de Andalucía Grant, PECOVID-0078-2020 (R.R.-L. and J.V.); Fondo COVID-19 grant COV20/00151 [Spanish Health Ministry, Instituto de Salud Carlos III (ISCIII)], Fondo Supera COVID-19 (Crue Universidades-Banco Santander) grant and CSIC grant 202120E079 (J.G.-A.); and CSIC grant 2020E84, La CaixaImpulse grant CF01-00008, Ferrovial and MAPFRE donations (M.E.). Additionally, we have also funding from the European Commission-NextGenerationEU, through CSIC's Global Health Platform (PTI Salud Global) (J.G.-A. and M.E.) and the European Research Council (ERC Advanced Grant PRJ201502629) (J.L.-B.).

Published
2022

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