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1. Immune response in SARS-CoV-2 infection

Author

Morte Romea, Elena [0000-0001-9262-2461], Uranga Murillo, Iratxe [0000-0001-8411-984X], Hidalgo, Sandra [0000-0003-1629-9978], Ramírez-Labrada, Ariel [0000-0002-3888-7036], Miguel, Diego de [0000-0002-8486-8514], Gálvez Buerba, Eva Mª [0000-0001-6928-5516], Martínez Lostao, Luis [0000-0003-3043-147X], Pellejero, Galadriel [0000-0002-2728-5435], Pardo, Julián [0000-0003-0154-0730], Paño, José Ramón [0000-0002-9600-8116], Morte Romea, Elena, Uranga Murillo, Iratxe, Hidalgo, Sandra, Ramírez-Labrada, Ariel, Miguel, Diego de, Gálvez Buerba, Eva Mª, Martínez Lostao, Luis, Pellejero, Galadriel, Letona Jiménez, Santiago, Pardo, Julián, Paño, José Ramón, Morte Romea, Elena [0000-0001-9262-2461], Uranga Murillo, Iratxe [0000-0001-8411-984X], Hidalgo, Sandra [0000-0003-1629-9978], Ramírez-Labrada, Ariel [0000-0002-3888-7036], Miguel, Diego de [0000-0002-8486-8514], Gálvez Buerba, Eva Mª [0000-0001-6928-5516], Martínez Lostao, Luis [0000-0003-3043-147X], Pellejero, Galadriel [0000-0002-2728-5435], Pardo, Julián [0000-0003-0154-0730], Paño, José Ramón [0000-0002-9600-8116], Morte Romea, Elena, Uranga Murillo, Iratxe, Hidalgo, Sandra, Ramírez-Labrada, Ariel, Miguel, Diego de, Gálvez Buerba, Eva Mª, Martínez Lostao, Luis, Pellejero, Galadriel, Letona Jiménez, Santiago, Pardo, Julián, and Paño, José Ramón

Abstract

We analyzed several parameters of the immune response of COVID-19 patients who required hospital admission, com paring them to healthy donors (HDs) and other patients admitted for respiratory infections not caused by SARS-CoV-2 (non-COV-RTI). We focused on the main cells involved in innate immunity and soluble inflammatory factors that regulate their activity.

Published
2024

2. Identification of FasL as a crucial host factor driving COVID-19 pathology and lethality

Author

Albert, Marie Christine, Uranga-Murillo, Iratxe, Arias, Maykel, De Miguel, Diego, Peña, Natacha, Montinaro, Antonella, Varanda, Ana Beatriz, Theobald, Sebastian J., Areso, Itziar, Saggau, Julia, Koch, Manuel, Liccardi, Gianmaria, Peltzer, Nieves, Rybniker, Jan, Hurtado-Guerrero, Ramón, Merino, Pedro, Monzón, Marta, Badiola, Juan J., Reindl-Schwaighofer, Roman, Sanz-Pamplona, Rebeca, Cebollada-Solanas, Alberto, Megyesfalvi, Zsolt, Dome, Balazs, Secrier, Maria, Hartmann, Boris, Bergmann, Michael, Pardo, Julián, Walczak, Henning, Albert, Marie Christine, Uranga-Murillo, Iratxe, Arias, Maykel, De Miguel, Diego, Peña, Natacha, Montinaro, Antonella, Varanda, Ana Beatriz, Theobald, Sebastian J., Areso, Itziar, Saggau, Julia, Koch, Manuel, Liccardi, Gianmaria, Peltzer, Nieves, Rybniker, Jan, Hurtado-Guerrero, Ramón, Merino, Pedro, Monzón, Marta, Badiola, Juan J., Reindl-Schwaighofer, Roman, Sanz-Pamplona, Rebeca, Cebollada-Solanas, Alberto, Megyesfalvi, Zsolt, Dome, Balazs, Secrier, Maria, Hartmann, Boris, Bergmann, Michael, Pardo, Julián, and Walczak, Henning

Abstract

The dysregulated immune response and inflammation resulting in severe COVID-19 are still incompletely understood. Having recently determined that aberrant death-ligand-induced cell death can cause lethal inflammation, we hypothesized that this process might also cause or contribute to inflammatory disease and lung failure following SARS-CoV-2 infection. To test this hypothesis, we developed a novel mouse-adapted SARS-CoV-2 model (MA20) that recapitulates key pathological features of COVID-19. Concomitantly with occurrence of cell death and inflammation, FasL expression was significantly increased on inflammatory monocytic macrophages and NK cells in the lungs of MA20-infected mice. Importantly, therapeutic FasL inhibition markedly increased survival of both, young and old MA20-infected mice coincident with substantially reduced cell death and inflammation in their lungs. Intriguingly, FasL was also increased in the bronchoalveolar lavage fluid of critically-ill COVID-19 patients. Together, these results identify FasL as a crucial host factor driving the immuno-pathology that underlies COVID-19 severity and lethality, and imply that patients with severe COVID-19 may significantly benefit from therapeutic inhibition of FasL., The dysregulated immune response and inflammation resulting in severe COVID-19 are still incompletely understood. Having recently determined that aberrant death-ligand-induced cell death can cause lethal inflammation, we hypothesized that this process might also cause or contribute to inflammatory disease and lung failure following SARS-CoV-2 infection. To test this hypothesis, we developed a novel mouse-adapted SARS-CoV-2 model (MA20) that recapitulates key pathological features of COVID-19. Concomitantly with occurrence of cell death and inflammation, FasL expression was significantly increased on inflammatory monocytic macrophages and NK cells in the lungs of MA20-infected mice. Importantly, therapeutic FasL inhibition markedly increased survival of both, young and old MA20-infected mice coincident with substantially reduced cell death and inflammation in their lungs. Intriguingly, FasL was also increased in the bronchoalveolar lavage fluid of critically-ill COVID-19 patients. Together, these results identify FasL as a crucial host factor driving the immuno-pathology that underlies COVID-19 severity and lethality, and imply that patients with severe COVID-19 may significantly benefit from therapeutic inhibition of FasL.

Published
2024

3. Identification of FasL as a crucial host factor driving COVID-19 pathology and lethality

Author

Albert, Marie Christine, Uranga-Murillo, Iratxe, Arias, Maykel, De Miguel, Diego, Peña, Natacha, Montinaro, Antonella, Varanda, Ana Beatriz, Theobald, Sebastian J., Areso, Itziar, Saggau, Julia, Koch, Manuel, Liccardi, Gianmaria, Peltzer, Nieves, Rybniker, Jan, Hurtado-Guerrero, Ramón, Merino, Pedro, Monzón, Marta, Badiola, Juan J., Reindl-Schwaighofer, Roman, Sanz-Pamplona, Rebeca, Cebollada-Solanas, Alberto, Megyesfalvi, Zsolt, Dome, Balazs, Secrier, Maria, Hartmann, Boris, Bergmann, Michael, Pardo, Julián, Walczak, Henning, Albert, Marie Christine, Uranga-Murillo, Iratxe, Arias, Maykel, De Miguel, Diego, Peña, Natacha, Montinaro, Antonella, Varanda, Ana Beatriz, Theobald, Sebastian J., Areso, Itziar, Saggau, Julia, Koch, Manuel, Liccardi, Gianmaria, Peltzer, Nieves, Rybniker, Jan, Hurtado-Guerrero, Ramón, Merino, Pedro, Monzón, Marta, Badiola, Juan J., Reindl-Schwaighofer, Roman, Sanz-Pamplona, Rebeca, Cebollada-Solanas, Alberto, Megyesfalvi, Zsolt, Dome, Balazs, Secrier, Maria, Hartmann, Boris, Bergmann, Michael, Pardo, Julián, and Walczak, Henning

Abstract

The dysregulated immune response and inflammation resulting in severe COVID-19 are still incompletely understood. Having recently determined that aberrant death-ligand-induced cell death can cause lethal inflammation, we hypothesized that this process might also cause or contribute to inflammatory disease and lung failure following SARS-CoV-2 infection. To test this hypothesis, we developed a novel mouse-adapted SARS-CoV-2 model (MA20) that recapitulates key pathological features of COVID-19. Concomitantly with occurrence of cell death and inflammation, FasL expression was significantly increased on inflammatory monocytic macrophages and NK cells in the lungs of MA20-infected mice. Importantly, therapeutic FasL inhibition markedly increased survival of both, young and old MA20-infected mice coincident with substantially reduced cell death and inflammation in their lungs. Intriguingly, FasL was also increased in the bronchoalveolar lavage fluid of critically-ill COVID-19 patients. Together, these results identify FasL as a crucial host factor driving the immuno-pathology that underlies COVID-19 severity and lethality, and imply that patients with severe COVID-19 may significantly benefit from therapeutic inhibition of FasL., The dysregulated immune response and inflammation resulting in severe COVID-19 are still incompletely understood. Having recently determined that aberrant death-ligand-induced cell death can cause lethal inflammation, we hypothesized that this process might also cause or contribute to inflammatory disease and lung failure following SARS-CoV-2 infection. To test this hypothesis, we developed a novel mouse-adapted SARS-CoV-2 model (MA20) that recapitulates key pathological features of COVID-19. Concomitantly with occurrence of cell death and inflammation, FasL expression was significantly increased on inflammatory monocytic macrophages and NK cells in the lungs of MA20-infected mice. Importantly, therapeutic FasL inhibition markedly increased survival of both, young and old MA20-infected mice coincident with substantially reduced cell death and inflammation in their lungs. Intriguingly, FasL was also increased in the bronchoalveolar lavage fluid of critically-ill COVID-19 patients. Together, these results identify FasL as a crucial host factor driving the immuno-pathology that underlies COVID-19 severity and lethality, and imply that patients with severe COVID-19 may significantly benefit from therapeutic inhibition of FasL.

Published
2024

4. Supplementary material for Integrated analysis of circulating immune cellular and soluble mediators reveals specific COVID19 signatures at hospital admission with utility for prediction of clinical outcomes [Dataset]

Author

European Commission, Gobierno de Aragón, Instituto de Salud Carlos III, Fundación Banco Santander, Universidad de Zaragoza, Agencia Estatal de Investigación (España), Fundación Inocente Inocente, Aspanoa, Asociación Carrera de la Mujer Ciudad de Monzón, Asociación Española Contra el Cáncer, Ministerio de Ciencia, Innovación y Universidades (España), ARAID Foundation, Uranga Murillo, Iratxe [0000-0001-8411-984X], Morte Romea, Elena [0000-0001-9262-2461], Hidalgo, Sandra [0000-0003-1629-9978], Pesini, Cecilia [0000-0002-8707-2722], García-Mulero, Sandra [0000-0003-4931-1267], Sierra Monzón, José L. [0000-0002-8796-2717], Santiago, Llipsy [0000-0002-1861-5981], Arias, Maykel [0000-0002-9730-2210], Miguel, Diego de [0000-0002-8486-8514], Encabo-Berzosa, M. Mar [0000-0001-5533-804X], Gracia Tello, Borja [0000-0003-3248-2908], Sanz-Pamplona, Rebeca [0000-0002-2187-3527], Martínez Lostao, Luis [0000-0003-3043-147X], Gálvez Buerba, Eva Mª [0000-0001-6928-5516], Paño, José Ramón [0000-0002-9600-8116], Ramírez-Labrada, Ariel [0000-0002-3888-7036], Pardo, Julián [0000-0003-0154-0730], Paño, José Ramón; Ramírez-Labrada, Ariel; Pardo, Julián, Uranga Murillo, Iratxe, Morte Romea, Elena, Hidalgo, Sandra, Pesini, Cecilia, García-Mulero, Sandra, Sierra Monzón, José L., Santiago, Llipsy, Arias, Maykel, Miguel, Diego de, Encabo-Berzosa, M. Mar, Gracia Tello, Borja, Sanz-Pamplona, Rebeca, Martínez-Lostao, Luis, Gálvez Buerba, Eva Mª, Paño, José Ramón, Ramírez-Labrada, Ariel, Pardo, Julián, European Commission, Gobierno de Aragón, Instituto de Salud Carlos III, Fundación Banco Santander, Universidad de Zaragoza, Agencia Estatal de Investigación (España), Fundación Inocente Inocente, Aspanoa, Asociación Carrera de la Mujer Ciudad de Monzón, Asociación Española Contra el Cáncer, Ministerio de Ciencia, Innovación y Universidades (España), ARAID Foundation, Uranga Murillo, Iratxe [0000-0001-8411-984X], Morte Romea, Elena [0000-0001-9262-2461], Hidalgo, Sandra [0000-0003-1629-9978], Pesini, Cecilia [0000-0002-8707-2722], García-Mulero, Sandra [0000-0003-4931-1267], Sierra Monzón, José L. [0000-0002-8796-2717], Santiago, Llipsy [0000-0002-1861-5981], Arias, Maykel [0000-0002-9730-2210], Miguel, Diego de [0000-0002-8486-8514], Encabo-Berzosa, M. Mar [0000-0001-5533-804X], Gracia Tello, Borja [0000-0003-3248-2908], Sanz-Pamplona, Rebeca [0000-0002-2187-3527], Martínez Lostao, Luis [0000-0003-3043-147X], Gálvez Buerba, Eva Mª [0000-0001-6928-5516], Paño, José Ramón [0000-0002-9600-8116], Ramírez-Labrada, Ariel [0000-0002-3888-7036], Pardo, Julián [0000-0003-0154-0730], Paño, José Ramón; Ramírez-Labrada, Ariel; Pardo, Julián, Uranga Murillo, Iratxe, Morte Romea, Elena, Hidalgo, Sandra, Pesini, Cecilia, García-Mulero, Sandra, Sierra Monzón, José L., Santiago, Llipsy, Arias, Maykel, Miguel, Diego de, Encabo-Berzosa, M. Mar, Gracia Tello, Borja, Sanz-Pamplona, Rebeca, Martínez-Lostao, Luis, Gálvez Buerba, Eva Mª, Paño, José Ramón, Ramírez-Labrada, Ariel, and Pardo, Julián

Abstract

Supplementary materials and methods: sample processing, flow cytometry, high dimensional flow cytometry data analysis, multiplex plasma protein analyses, granzyme activity assay in serum, statistics. Supplementary figure legends (1-5). Supplementary table legends (1-7).

Published
2022

5. All about (NK cell-mediated) death in two acts and an unexpected encore: initiation, execution and activation of adaptive immunity

Author

Instituto de Salud Carlos III, Ministerio de Ciencia e Innovación (España), European Commission, Gobierno de Aragón, Agencia Estatal de Investigación (España), Aspanoa, Asociación Carrera de la Mujer Ciudad de Monzón, ARAID Foundation, Asociación Española Contra el Cáncer, Ministerio de Ciencia, Innovación y Universidades (España), Ramírez-Labrada, Ariel [0000-0002-3888-7036], Pesini, Cecilia [0000-0002-8707-2722], Santiago, Llipsy [0000-0002-1861-5981], Hidalgo, Sandra [0000-0003-1629-9978], Uranga Murillo, Iratxe [0000-0001-8411-984X], Arias, Maykel [0000-0002-9730-2210], Gálvez Buerba, Eva Mª [0000-0001-6928-5516], Pardo, Julián [0000-0003-0154-0730], Ramírez-Labrada, Ariel, Pesini, Cecilia, Santiago, Llipsy, Hidalgo, Sandra, Calvo Pérez, Adanys, Oñate, Carmen, Andrés Tovar, Alejandro, Garzón Tituaña, Marcela, Uranga Murillo, Iratxe, Arias, Maykel, Gálvez Buerba, Eva Mª, Pardo, Julián, Instituto de Salud Carlos III, Ministerio de Ciencia e Innovación (España), European Commission, Gobierno de Aragón, Agencia Estatal de Investigación (España), Aspanoa, Asociación Carrera de la Mujer Ciudad de Monzón, ARAID Foundation, Asociación Española Contra el Cáncer, Ministerio de Ciencia, Innovación y Universidades (España), Ramírez-Labrada, Ariel [0000-0002-3888-7036], Pesini, Cecilia [0000-0002-8707-2722], Santiago, Llipsy [0000-0002-1861-5981], Hidalgo, Sandra [0000-0003-1629-9978], Uranga Murillo, Iratxe [0000-0001-8411-984X], Arias, Maykel [0000-0002-9730-2210], Gálvez Buerba, Eva Mª [0000-0001-6928-5516], Pardo, Julián [0000-0003-0154-0730], Ramírez-Labrada, Ariel, Pesini, Cecilia, Santiago, Llipsy, Hidalgo, Sandra, Calvo Pérez, Adanys, Oñate, Carmen, Andrés Tovar, Alejandro, Garzón Tituaña, Marcela, Uranga Murillo, Iratxe, Arias, Maykel, Gálvez Buerba, Eva Mª, and Pardo, Julián

Abstract

NK cells are key mediators of immune cell-mediated cytotoxicity toward infected and transformed cells, being one of the main executors of cell death in the immune system. NK cells recognize target cells through an array of inhibitory and activating receptors for endogenous or exogenous pathogen-derived ligands, which together with adhesion molecules form a structure known as immunological synapse that regulates NK cell effector functions. The main and best characterized mechanisms involved in NK cell-mediated cytotoxicity are the granule exocytosis pathway (perforin/granzymes) and the expression of death ligands. These pathways are recognized as activators of different cell death programmes on the target cells leading to their destruction. However, most studies analyzing these pathways have used pure recombinant or native proteins instead of intact NK cells and, thus, extrapolation of the results to NK cell-mediated cell death might be difficult. Specially, since the activation of granule exocytosis and/or death ligands during NK cell-mediated elimination of target cells might be influenced by the stimulus received from target cells and other microenvironment components, which might affect the cell death pathways activated on target cells. Here we will review and discuss the available experimental evidence on how NK cells kill target cells, with a special focus on the different cell death modalities that have been found to be activated during NK cell-mediated cytotoxicity; including apoptosis and more inflammatory pathways like necroptosis and pyroptosis. In light of this new evidence, we will develop the new concept of cell death induced by NK cells as a new regulatory mechanism linking innate immune response with the activation of tumour adaptive T cell responses, which might be the initiating stimulus that trigger the cancer-immunity cycle. The use of the different cell death pathways and the modulation of the tumour cell molecular machinery regulating them might

Published
2022

6. Adoptive NK cell transfer as a treatment in colorectal cancer patients: analyses of tumour cell determinants correlating with efficacy in vitro and in vivo

Author

Aspanoa, Instituto de Salud Carlos III, Ministerio de Ciencia e Innovación (España), European Commission, Fundación Inocente Inocente, Asociación Carrera de la Mujer Ciudad de Monzón, Gobierno de Aragón, Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), ARAID Foundation, Institut Català d'Oncologia, Ministerio de Economía, Industria y Competitividad (España), Centro de Investigación Biomédica en Red Epidemiología y Salud Pública (España), Agència de Gestió d'Ajuts Universitaris i de Recerca, European Cooperation in Science and Technology, Lanuza, Pilar M. [0000-0001-7328-2094], Alonso, M. Henar [0000-0003-0285-5451], Hidalgo, Sandra [0000-0003-1629-9978], Uranga Murillo, Iratxe [0000-0001-8411-984X], García-Mulero, Sandra [0000-0003-4931-1267], Sanjuan, Xavier [0000-0002-5253-822X], Santiago, Llipsy [0000-0002-1861-5981], Comas, Laura [0000-0002-3843-1231], Redrado, Sergio [0000-0002-8404-0012], Pazo-Cid, Roberto [0000-0002-8026-7391], Jaime Sánchez, Paula [0000-0002-8731-4269], Pesini, Cecilia [0000-0002-8707-2722], Gálvez Buerba, Eva Mª [0000-0001-6928-5516], Ramírez-Labrada, Ariel [0000-0002-3888-7036], Arias, Maykel [0000-0002-9730-2210], Sanz-Pamplona, Rebeca [0000-0002-2187-3527], Pardo, Julián [0000-0003-0154-0730], Lanuza, Pilar M., Alonso, M. Henar, Hidalgo, Sandra, Uranga Murillo, Iratxe, García-Mulero, Sandra, Arnau, Raquel, Santos Vivas, Cristina, Sanjuan, Xavier, Santiago, Llipsy, Comas, Laura, Redrado, Sergio, Pazo-Cid, Roberto, Agustín Ferrández, M. J., Jaime Sánchez, Paula, Pesini, Cecilia, Gálvez Buerba, Eva Mª, Ramírez-Labrada, Ariel, Arias, Maykel, Sanz-Pamplona, Rebeca, Pardo, Julián, Aspanoa, Instituto de Salud Carlos III, Ministerio de Ciencia e Innovación (España), European Commission, Fundación Inocente Inocente, Asociación Carrera de la Mujer Ciudad de Monzón, Gobierno de Aragón, Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), ARAID Foundation, Institut Català d'Oncologia, Ministerio de Economía, Industria y Competitividad (España), Centro de Investigación Biomédica en Red Epidemiología y Salud Pública (España), Agència de Gestió d'Ajuts Universitaris i de Recerca, European Cooperation in Science and Technology, Lanuza, Pilar M. [0000-0001-7328-2094], Alonso, M. Henar [0000-0003-0285-5451], Hidalgo, Sandra [0000-0003-1629-9978], Uranga Murillo, Iratxe [0000-0001-8411-984X], García-Mulero, Sandra [0000-0003-4931-1267], Sanjuan, Xavier [0000-0002-5253-822X], Santiago, Llipsy [0000-0002-1861-5981], Comas, Laura [0000-0002-3843-1231], Redrado, Sergio [0000-0002-8404-0012], Pazo-Cid, Roberto [0000-0002-8026-7391], Jaime Sánchez, Paula [0000-0002-8731-4269], Pesini, Cecilia [0000-0002-8707-2722], Gálvez Buerba, Eva Mª [0000-0001-6928-5516], Ramírez-Labrada, Ariel [0000-0002-3888-7036], Arias, Maykel [0000-0002-9730-2210], Sanz-Pamplona, Rebeca [0000-0002-2187-3527], Pardo, Julián [0000-0003-0154-0730], Lanuza, Pilar M., Alonso, M. Henar, Hidalgo, Sandra, Uranga Murillo, Iratxe, García-Mulero, Sandra, Arnau, Raquel, Santos Vivas, Cristina, Sanjuan, Xavier, Santiago, Llipsy, Comas, Laura, Redrado, Sergio, Pazo-Cid, Roberto, Agustín Ferrández, M. J., Jaime Sánchez, Paula, Pesini, Cecilia, Gálvez Buerba, Eva Mª, Ramírez-Labrada, Ariel, Arias, Maykel, Sanz-Pamplona, Rebeca, and Pardo, Julián

Abstract

[Background]: Colorectal cancer (CRC) is a heterogeneous disease with variable mutational profile and tumour microenvironment composition that influence tumour progression and response to treatment. While chemoresistant and poorly immunogenic CRC remains a challenge, the development of new strategies guided by biomarkers could help stratify and treat patients. Allogeneic NK cell transfer emerges as an alternative against chemoresistant and poorly immunogenic CRC., [Methods]: NK cell-related immunological markers were analysed by transcriptomics and immunohistochemistry in human CRC samples and correlated with tumour progression and overall survival. The anti-tumour ability of expanded allogeneic NK cells using a protocol combining cytokines and feeder cells was analysed in vitro and in vivo and correlated with CRC mutational status and the expression of ligands for immune checkpoint (IC) receptors regulating NK cell activity., [Results]: HLA-I downmodulation and NK cell infiltration correlated with better overall survival in patients with a low-stage (II) microsatellite instability-high (MSI-H) CRC, suggesting a role of HLA-I as a prognosis biomarker and a potential benefit of NK cell immunotherapy. Activated allogeneic NK cells were able to eliminate CRC cultures without PD-1 and TIM-3 restriction but were affected by HLA-I expression. In vivo experiments confirmed the efficacy of the therapy against both HLA+ and HLA− CRC cell lines. Concomitant administration of pembrolizumab failed to improve tumour control., [Conclusions]: Our results reveal an immunological profile of CRC tumours in which immunogenicity (MSI-H) and immune evasion mechanisms (HLA downmodulation) favour NK cell immunosurveillance at early disease stages. Accordingly, we have shown that allogeneic NK cell therapy can target tumours expressing mutations conferring poor prognosis regardless of the expression of T cell-related inhibitory IC ligands. Overall, this study provides a rationale for a new potential basis for CRC stratification and NK cell-based therapy.

Published
2022

7. Granzyme A inhibition reduces inflammation and increases survival during abdominal sepsis

Author

Garzón, Marcela [0000-0001-6778-0636], Comas, Laura [0000-0002-3843-1231], Santiago, Llipsy [0000-0002-1861-5981], Uranga Murillo, Iratxe [0000-0001-8411-984X], Ramírez-Labrada, Ariel [0000-0002-3888-7036], Gálvez Buerba, Eva Mª [0000-0001-6928-5516], Pardo, Julián [0000-0003-0154-0730], Arias, Maykel [0000-0002-9730-2210], Garzón, Marcela, Comas, Laura, Santiago, Llipsy, Uranga Murillo, Iratxe, Ramírez-Labrada, Ariel, Gálvez Buerba, Eva Mª, Pardo, Julián, Arias, Maykel, Garzón, Marcela [0000-0001-6778-0636], Comas, Laura [0000-0002-3843-1231], Santiago, Llipsy [0000-0002-1861-5981], Uranga Murillo, Iratxe [0000-0001-8411-984X], Ramírez-Labrada, Ariel [0000-0002-3888-7036], Gálvez Buerba, Eva Mª [0000-0001-6928-5516], Pardo, Julián [0000-0003-0154-0730], Arias, Maykel [0000-0002-9730-2210], Garzón, Marcela, Comas, Laura, Santiago, Llipsy, Uranga Murillo, Iratxe, Ramírez-Labrada, Ariel, Gálvez Buerba, Eva Mª, Pardo, Julián, and Arias, Maykel

Abstract

Peritonitis is one of the most common causes of sepsis. Evidence suggests that Granzyme A (GzmA), a serine protease mainly expressed by NK and T cells, could act as proinflammatory mediator and could play an important role in the pathogenesis of sepsis. Here, we aim to analyze the role and therapeutic potential of GzmA in the pathogenesis of peritoneal sepsis.

Published
2021

8. Determination of the concentration of IgG against the spike receptor-binding domain that predicts the viral neutralizing activity of convalescent plasma and serum against SARS-CoV-2

Author

Gobierno de Aragón, Fundación Banco Santander, Universidad de Zaragoza, Instituto de Salud Carlos III, European Commission, Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Fundación Inocente Inocente, Aspanoa, Asociación Carrera de la Mujer Ciudad de Monzón, ARAID Foundation, Santiago, Llipsy [0000-0002-1861-5981], Uranga Murillo, Iratxe [0000-0001-8411-984X], Arias, Maykel [0000-0002-9730-2210], González Ramírez, Andrés Manuel [0000-0002-5838-0857], Macías León, Javier [0000-0001-6815-6720], Moreo, Eduardo [0000-0002-0182-201X], Redrado, Sergio [0000-0002-8404-0012], Taleb, V. [0000-0001-9224-5854], Lira-Navarrete, Erandi [0000-0003-2462-7580], Hurtado-Guerrero, R. [0000-0002-3122-9401], Encabo-Berzosa, M. Mar [0000-0001-5533-804X], Hidalgo, Sandra [0000-0003-1629-9978], Gálvez Buerba, Eva Mª [0000-0001-6928-5516], Ramírez-Labrada, Ariel [0000-0002-3888-7036], Miguel, Diego de [0000-0002-8486-8514], Benito, Rafael [0000-0001-5134-1006], Fernández Casanovas, Antonio [0000-0002-2557-4890], Serrano Barcos, Laura [0000-0002-9291-9801], Yuste, Cristina [0000-0003-3667-523X], Villanueva-Saz, Sergio [0000-0001-6209-4282], Paño, José Ramón [0000-0002-9600-8116], Pardo, Julián [0000-0003-0154-0730], Santiago, Llipsy, Uranga Murillo, Iratxe, Arias, Maykel, González Ramírez, Andrés Manuel, Macías-León, Javier, Moreo, Eduardo, Redrado, Sergio, García García, Ana, Taleb, V., Lira-Navarrete, Erandi, Hurtado-Guerrero, R., Aguiló, Nacho, Encabo-Berzosa, M. Mar, Hidalgo, Sandra, Gálvez Buerba, Eva Mª, Ramírez-Labrada, Ariel, Miguel, Diego de, Benito, Rafael, Miranda, Patricia, Fernández Casanovas, Antonio, Domingo, José María, Serrano Barcos, Laura, Yuste, Cristina, Villanueva-Saz, Sergio, Paño, José Ramón, Pardo, Julián, Gobierno de Aragón, Fundación Banco Santander, Universidad de Zaragoza, Instituto de Salud Carlos III, European Commission, Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Fundación Inocente Inocente, Aspanoa, Asociación Carrera de la Mujer Ciudad de Monzón, ARAID Foundation, Santiago, Llipsy [0000-0002-1861-5981], Uranga Murillo, Iratxe [0000-0001-8411-984X], Arias, Maykel [0000-0002-9730-2210], González Ramírez, Andrés Manuel [0000-0002-5838-0857], Macías León, Javier [0000-0001-6815-6720], Moreo, Eduardo [0000-0002-0182-201X], Redrado, Sergio [0000-0002-8404-0012], Taleb, V. [0000-0001-9224-5854], Lira-Navarrete, Erandi [0000-0003-2462-7580], Hurtado-Guerrero, R. [0000-0002-3122-9401], Encabo-Berzosa, M. Mar [0000-0001-5533-804X], Hidalgo, Sandra [0000-0003-1629-9978], Gálvez Buerba, Eva Mª [0000-0001-6928-5516], Ramírez-Labrada, Ariel [0000-0002-3888-7036], Miguel, Diego de [0000-0002-8486-8514], Benito, Rafael [0000-0001-5134-1006], Fernández Casanovas, Antonio [0000-0002-2557-4890], Serrano Barcos, Laura [0000-0002-9291-9801], Yuste, Cristina [0000-0003-3667-523X], Villanueva-Saz, Sergio [0000-0001-6209-4282], Paño, José Ramón [0000-0002-9600-8116], Pardo, Julián [0000-0003-0154-0730], Santiago, Llipsy, Uranga Murillo, Iratxe, Arias, Maykel, González Ramírez, Andrés Manuel, Macías-León, Javier, Moreo, Eduardo, Redrado, Sergio, García García, Ana, Taleb, V., Lira-Navarrete, Erandi, Hurtado-Guerrero, R., Aguiló, Nacho, Encabo-Berzosa, M. Mar, Hidalgo, Sandra, Gálvez Buerba, Eva Mª, Ramírez-Labrada, Ariel, Miguel, Diego de, Benito, Rafael, Miranda, Patricia, Fernández Casanovas, Antonio, Domingo, José María, Serrano Barcos, Laura, Yuste, Cristina, Villanueva-Saz, Sergio, Paño, José Ramón, and Pardo, Julián

Abstract

Passive immunization with hyperimmune plasma from convalescent patients has been proposed as a potentially useful treatment for COVID-19. Nevertheless, its efficacy in patients with COVID-19 remains uncertain. Thus, the establishment and validation of standardized methods that predict the viral neutralizing (VN) activity of plasma against SARS-CoV-2 is of utmost importance to appraise its therapeutic value. Using an in-house quantitative ELISA test and two independent cohorts with a total of 345 donors, we found that plasma and serum from most convalescent donors contained IgG antibodies specific to the spike receptor-binding domain (RBD) of SARS-CoV-2, with varying concentrations which correlate with previous disease severity and gender. Anti-RBD IgG plasma concentration significantly correlated with the plasma/serum VN activity against SARS-CoV-2 in vitro., Several hundred millions of people have been diagnosed of coronavirus disease 2019 (COVID-19), causing millions of deaths and a high socioeconomic burden. SARS-CoV-2, the causative agent of COVID-19, induces both specific T- and B-cell responses, being antibodies against the virus detected a few days after infection. Passive immunization with hyperimmune plasma from convalescent patients has been proposed as a potentially useful treatment for COVID-19. Using an in-house quantitative ELISA test, we found that plasma from 177 convalescent donors contained IgG antibodies specific to the spike receptor-binding domain (RBD) of SARS-CoV-2, although at very different concentrations which correlated with previous disease severity and gender. Anti-RBD IgG plasma concentrations significantly correlated with the plasma viral neutralizing activity (VN) against SARS-CoV-2 in vitro. Similar results were found using an independent cohort of serum from 168 convalescent health workers. These results validate an in-house RBD IgG ELISA test in a large cohort of COVID-19 convalescent patients and indicate that plasma from all convalescent donors does not contain a high enough amount of anti-SARS-CoV-2-RBD neutralizing IgG to prevent SARS-CoV-2 infection in vitro. The use of quantitative anti-RBD IgG detection systems might help to predict the efficacy of the passive immunization using plasma from patients recovered from SARS-CoV-2.

Published
2021

9. Inflammatory cell death induced by cytotoxic lymphocytes: a dangerous but necessary liaison

Author

European Commission, Gobierno de Aragón, Ministerio de Ciencia, Innovación y Universidades (España), Instituto de Salud Carlos III, Agencia Estatal de Investigación (España), Fundación Inocente Inocente, Aspanoa, Asociación Carrera de la Mujer Ciudad de Monzón, ARAID Foundation, de Miguel, Diego [0000-0002-8486-8514], Ramírez-Labrada, Ariel [0000-0002-3888-7036], Uranga Murillo, Iratxe [0000-0001-8411-984X], Hidalgo, Sandra [0000-0003-1629-9978], Santiago, Llipsy [0000-0002-1861-5981], Gálvez Buerba, Eva Mª [0000-0001-6928-5516], Arias, Maykel [0000-0002-9730-2210], Pardo, Julián [0000-0003-0154-0730], Miguel, Diego de, Ramírez-Labrada, Ariel, Uranga Murillo, Iratxe, Hidalgo, Sandra, Santiago, Llipsy, Gálvez Buerba, Eva Mª, Arias, Maykel, Pardo, Julián, European Commission, Gobierno de Aragón, Ministerio de Ciencia, Innovación y Universidades (España), Instituto de Salud Carlos III, Agencia Estatal de Investigación (España), Fundación Inocente Inocente, Aspanoa, Asociación Carrera de la Mujer Ciudad de Monzón, ARAID Foundation, de Miguel, Diego [0000-0002-8486-8514], Ramírez-Labrada, Ariel [0000-0002-3888-7036], Uranga Murillo, Iratxe [0000-0001-8411-984X], Hidalgo, Sandra [0000-0003-1629-9978], Santiago, Llipsy [0000-0002-1861-5981], Gálvez Buerba, Eva Mª [0000-0001-6928-5516], Arias, Maykel [0000-0002-9730-2210], Pardo, Julián [0000-0003-0154-0730], Miguel, Diego de, Ramírez-Labrada, Ariel, Uranga Murillo, Iratxe, Hidalgo, Sandra, Santiago, Llipsy, Gálvez Buerba, Eva Mª, Arias, Maykel, and Pardo, Julián

Abstract

Cytotoxic lymphocytes (CLs), and more specifically Tc and NK cells, are the main executors of cell death in the immune system, playing a key role during both immunosurveillance and immunotherapy. These cells induce regulated cell death (RCD) by different mechanisms, being granular exocytosis and expression of death ligands the most prominent and best characterized ones. Apoptosis, a traditionally considered low-inflammatory type of cell death, has been accepted for years as the paradigm of RCD induced by CLs. However, several recent studies have demonstrated that NK cells and Tc cells can also induce more inflammatory forms of cell death, namely, necroptosis, pyroptosis, and ferroptosis. Activation of these highly inflammatory types of cell death appears to critically contribute to the activation of a successful antitumour immune response. Additionally, the role of specific cell death pathways in immunogenic cell death is still under intense debate, especially considering the interconnections with other inflammatory forms of cell death. These evidences, together with the advent of new cancer immunotherapies, highlight the necessity to deepen our understanding of the link between the cell death triggered by CLs and inflammation. This knowledge will be instrumental to maximize the antitumour potential of immunotherapies, minimizing deleterious effects associated with these treatments. In this review, we will briefly summarize the main features of apoptosis, necroptosis, pyroptosis and ferroptosis, to subsequently discuss the most recent evidences about the role of these RCD pathways during the elimination of cancer cells mediated by CLs and its modulation to increase the efficacy of cancer immunotherapy.

Published
2021

10. Serum active Granzyme A: a new biomarker that contributes to the pathogenesis of peritoneal sepsis

Author

Garzón, Marcela [0000-0001-6778-0636], Sierra Monzón, José L. [0000-0002-8796-2717], Comas, Laura [0000-0002-3843-1231], Uranga Murillo, Iratxe [0000-0001-8411-984X], Morte Romea, Elena [0000-0001-9262-2461], Algarate, Sonia [0000-0002-0036-6630], Ushakova, Tatiana Khaliulina [0000-0002-7930-2129], Luque Gómez, Pilar [0000-0001-7790-409X], Paño, José Ramón [0000-0002-9600-8116], Gálvez Buerba, Eva Mª [0000-0001-6928-5516], Arias, Maykel [0000-0002-9730-2210], Pardo, Julián [0000-0003-0154-0730], Garzón, Marcela, Sierra Monzón, José L., Comas, Laura, Uranga Murillo, Iratxe, Morte Romea, Elena, Algarate, Sonia, Ushakova, Tatiana Khaliulina, Seral, Cristina, Luque Gómez, Pilar, Paño, José Ramón, Gálvez Buerba, Eva Mª, Arias, Maykel, Pardo, Julián, Garzón, Marcela [0000-0001-6778-0636], Sierra Monzón, José L. [0000-0002-8796-2717], Comas, Laura [0000-0002-3843-1231], Uranga Murillo, Iratxe [0000-0001-8411-984X], Morte Romea, Elena [0000-0001-9262-2461], Algarate, Sonia [0000-0002-0036-6630], Ushakova, Tatiana Khaliulina [0000-0002-7930-2129], Luque Gómez, Pilar [0000-0001-7790-409X], Paño, José Ramón [0000-0002-9600-8116], Gálvez Buerba, Eva Mª [0000-0001-6928-5516], Arias, Maykel [0000-0002-9730-2210], Pardo, Julián [0000-0003-0154-0730], Garzón, Marcela, Sierra Monzón, José L., Comas, Laura, Uranga Murillo, Iratxe, Morte Romea, Elena, Algarate, Sonia, Ushakova, Tatiana Khaliulina, Seral, Cristina, Luque Gómez, Pilar, Paño, José Ramón, Gálvez Buerba, Eva Mª, Arias, Maykel, and Pardo, Julián

Abstract

[Background] Peritonitis is one of the most common leading cause of sepsis. Recent evidence suggests that Granzyme A (GzmA), a serine protease mainly expressed in NK cells and T cells, could act as a proinflammatory mediator and could play an important role in the pathogenesis of sepsis. This work aims to analyze the role of serum GzmA as a biomarker and therapeutic target in peritoneal sepsis., [Materials/methods] Concentration and enzyme activity of soluble GzmA were sequentially analyzed in serum from healthy donors and patients with peritonitis and were correlated with the Sequential Organ Failure Assessment (SOFA) score. Peritonitis was induced in C57Bl/6 (Wt) and GzmA-KO mice by cecal ligation and puncture (CLP). Mice were treated intraperitoneally with antibiotics and with serpinb6b, a specific GzmA inhibitor, for 5 days. Mouse survival was monitored during 14 days and the levels of serum proinflammatory cytokines and bacterial load in blood and spleen were analyzed at 6 and 24h from CLP., [Results] We have found high levels of GzmA in serum of patient with peritonitis. Most importantly, we observed that GzmA activity in serum correlates with SOFA score, suggesting that active GzmA could play an important role in sepsis development in peritonitis patients and could be a new biomarker of sepsis severity. In order to analyze the therapeutical potential of soluble GzmA in peritoneal sepsis, we used the CLP mouse model. After peritonitis induction, GzmA-KO mice exhibit increased survival compared with Wt mice, which correlated with reduced levels of proinflammatory cytokines in serum. The analysis of bacterial load in blood and spleen showed no differences between Wt and GzmA-KO mice suggesting that GzmA does not play an important role in bacterial control. Treatment with serpinb6b reduced mortality, which correlated with reduced cytokine serum levels in serum, confirming the therapeutical potential of gzmA to treat peritoneal sepsis., [Conclusions] Our findings confirm that soluble GzmA plays an important role in the pathogenesis of sepsis and could be a new therapeutic target and a biomarker for the treatment of peritoneal sepsis.

Published
2020

11. Silver nanoparticles–polyethyleneimine-based coatings with antiviral activity against SARS-CoV-2: A new method to functionalize filtration media

Author

Instituto de Salud Carlos III, European Commission, Gobierno de Aragón, Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Fundación Inocente Inocente, Miguel, Diego de [0000-0002-8486-8514], Sebastián, Víctor [0000-0002-6873-5244], Arruebo, Manuel [0000-0003-3165-0156], Baselga, Marta, Uranga Murillo, Iratxe, Miguel, Diego de, Arias, Maykel, Sebastián, Víctor, Pardo, Julián, Arruebo, Manuel, Instituto de Salud Carlos III, European Commission, Gobierno de Aragón, Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Fundación Inocente Inocente, Miguel, Diego de [0000-0002-8486-8514], Sebastián, Víctor [0000-0002-6873-5244], Arruebo, Manuel [0000-0003-3165-0156], Baselga, Marta, Uranga Murillo, Iratxe, Miguel, Diego de, Arias, Maykel, Sebastián, Víctor, Pardo, Julián, and Arruebo, Manuel

Abstract

The use of face masks and air purification systems has been key to curbing the transmission of SARS-CoV-2 aerosols in the context of the current COVID-19 pandemic. However, some masks or air conditioning filtration systems are designed to remove large airborne particles or bacteria from the air, being limited their effectiveness against SARS-CoV-2. Continuous research has been aimed at improving the performance of filter materials through nanotechnology. This article presents a new low-cost method based on electrostatic forces and coordination complex formation to generate antiviral coatings on filter materials using silver nanoparticles and polyethyleneimine. Initially, the AgNPs synthesis procedure was optimized until reaching a particle size of 6.2 ± 2.6 nm, promoting a fast ionic silver release due to its reduced size, obtaining a stable colloid over time and having reduced size polydispersity. The stability of the binding of the AgNPs to the fibers was corroborated using polypropylene, polyester-viscose, and polypropylene-glass spunbond mats as substrates, obtaining very low amounts of detached AgNPs in all cases. Under simulated operational conditions, a material loss less than 1% of nanostructured silver was measured. SEM micrographs demonstrated high silver distribution homogeneity on the polymer fibers. The antiviral coatings were tested against SARS-CoV-2, obtaining inactivation yields greater than 99.9%. We believe our results will be beneficial in the fight against the current COVID-19 pandemic and in controlling other infectious airborne pathogens

Published
2022

12. Concentration of IgG against the Spike Receptor-Binding Domain predicts the viral neutralization activity of convalescent plasma and serum against SARS-CoV-2

Author

Santiago, Llipsy, Uranga Murillo, Iratxe, Arias, Maykel, Moreo, Eduardo, Hidalgo, Sandra, Gálvez Buerba, Eva Mª, Ramírez-Labrada, Ariel, Miguel, Diego de, Paño, José Ramón, Pardo, Julián, Santiago, Llipsy, Uranga Murillo, Iratxe, Arias, Maykel, Moreo, Eduardo, Hidalgo, Sandra, Gálvez Buerba, Eva Mª, Ramírez-Labrada, Ariel, Miguel, Diego de, Paño, José Ramón, and Pardo, Julián

Abstract

SARS-CoV-2 is the virus responsible for the Covid-19 pandemic, due to its rapid propagation and the initial lack of vaccines or appropriate treatments. Nowadays, despite different vaccines available, the main treatments are palliative, focused on supplemental oxygen and anti-inflammatory therapy. Passive immunization could be an effective and economic treatment once standarized. It consists of the transfer of pathogen-specific antibodies to patients whose immune system has not originated a response yet. The donors’ antibodies neutralize and attenuate pathogen replication. Besides, an antibody against the Receptor-Binding Domain of Spike (RBD) would block the interaction of the virus with ACE2 and its entry in the cell. Here, an in-house RBG IgG ELISA test has been validated using a cohort of more than 320 samples of convalescent plasma and serum and adapted to quantify the concentration of plasma RBD IgG and its correlation with the SARS-CoV-2 neutralizing activity in vitro.

Published
2021

13. Determination of the concentration of igg against the spike receptor-binding domain that predicts the viral neutralizing activity of convalescent plasma and serum against sars-cov-2

Author

Santiago, Llipsy, Uranga-Murillo, Iratxe, Arias, Maykel, González-Ramírez, Andrés Manuel, Macías-León, Javier, Moreo, Eduardo, Redrado, Sergio, García-García, Ana, Taleb, Víctor, Lira-Navarrete, Erandi, Hurtado-Guerrero, Ramón, Aguilo, Nacho, Encabo-Berzosa, Maria Del Mar, Hidalgo, Sandra, Galvez, Eva M., Ramirez-Labrada, Ariel, de Miguel, Diego, Benito, Rafael, Miranda, Patricia, Fernández, Antonio, Domingo, José María, Serrano, Laura, Yuste, Cristina, Villanueva-Saz, Sergio, Paño-Pardo, José Ramón, Pardo, Julián, Santiago, Llipsy, Uranga-Murillo, Iratxe, Arias, Maykel, González-Ramírez, Andrés Manuel, Macías-León, Javier, Moreo, Eduardo, Redrado, Sergio, García-García, Ana, Taleb, Víctor, Lira-Navarrete, Erandi, Hurtado-Guerrero, Ramón, Aguilo, Nacho, Encabo-Berzosa, Maria Del Mar, Hidalgo, Sandra, Galvez, Eva M., Ramirez-Labrada, Ariel, de Miguel, Diego, Benito, Rafael, Miranda, Patricia, Fernández, Antonio, Domingo, José María, Serrano, Laura, Yuste, Cristina, Villanueva-Saz, Sergio, Paño-Pardo, José Ramón, and Pardo, Julián

Abstract

Several hundred millions of people have been diagnosed of coronavirus disease 2019 (COVID-19), causing millions of deaths and a high socioeconomic burden. SARS-CoV-2, the causative agent of COVID-19, induces both specific T-and B-cell responses, being antibodies against the virus detected a few days after infection. Passive immunization with hyperimmune plasma from convalescent patients has been proposed as a potentially useful treatment for COVID-19. Using an in-house quantitative ELISA test, we found that plasma from 177 convalescent donors contained IgG antibodies specific to the spike receptor-binding domain (RBD) of SARS-CoV-2, although at very different concentrations which correlated with previous disease severity and gender. Anti-RBD IgG plasma concentrations significantly correlated with the plasma viral neutralizing activity (VN) against SARS-CoV-2 in vitro. Similar results were found using an independent cohort of serum from 168 convalescent health workers. These results validate an in-house RBD IgG ELISA test in a large cohort of COVID-19 convalescent patients and indicate that plasma from all convalescent donors does not contain a high enough amount of anti-SARS-CoV-2-RBD neutralizing IgG to prevent SARS-CoV-2 infection in vitro. The use of quantitative anti-RBD IgG detection systems might help to predict the efficacy of the passive immunization using plasma from patients recovered from SARS-CoV-2.

Published
2021

14. Analysis of the inflammatory cytokine and cell immunity profile in blood that predicts disease severity in COVID-19 patients

Author

Hidalgo, Sandra, Morte Romea, Elena, Pesini, Cecilia, Uranga Murillo, Iratxe, Sierra Monzón, José L., Martínez Lázaro, Beatriz, Paño, José Ramón, Gálvez Buerba, Eva Mª, Pardo, Julián, Hidalgo, Sandra, Morte Romea, Elena, Pesini, Cecilia, Uranga Murillo, Iratxe, Sierra Monzón, José L., Martínez Lázaro, Beatriz, Paño, José Ramón, Gálvez Buerba, Eva Mª, and Pardo, Julián

Published
2021

15. Determination of the concentration of igg against the spike receptor-binding domain that predicts the viral neutralizing activity of convalescent plasma and serum against sars-cov-2

Author

Santiago, Llipsy, Uranga-Murillo, Iratxe, Arias, Maykel, González-Ramírez, Andrés Manuel, Macías-León, Javier, Moreo, Eduardo, Redrado, Sergio, García-García, Ana, Taleb, Víctor, Lira-Navarrete, Erandi, Hurtado-Guerrero, Ramón, Aguilo, Nacho, Encabo-Berzosa, Maria Del Mar, Hidalgo, Sandra, Galvez, Eva M., Ramirez-Labrada, Ariel, de Miguel, Diego, Benito, Rafael, Miranda, Patricia, Fernández, Antonio, Domingo, José María, Serrano, Laura, Yuste, Cristina, Villanueva-Saz, Sergio, Paño-Pardo, José Ramón, Pardo, Julián, Santiago, Llipsy, Uranga-Murillo, Iratxe, Arias, Maykel, González-Ramírez, Andrés Manuel, Macías-León, Javier, Moreo, Eduardo, Redrado, Sergio, García-García, Ana, Taleb, Víctor, Lira-Navarrete, Erandi, Hurtado-Guerrero, Ramón, Aguilo, Nacho, Encabo-Berzosa, Maria Del Mar, Hidalgo, Sandra, Galvez, Eva M., Ramirez-Labrada, Ariel, de Miguel, Diego, Benito, Rafael, Miranda, Patricia, Fernández, Antonio, Domingo, José María, Serrano, Laura, Yuste, Cristina, Villanueva-Saz, Sergio, Paño-Pardo, José Ramón, and Pardo, Julián

Abstract

Several hundred millions of people have been diagnosed of coronavirus disease 2019 (COVID-19), causing millions of deaths and a high socioeconomic burden. SARS-CoV-2, the causative agent of COVID-19, induces both specific T-and B-cell responses, being antibodies against the virus detected a few days after infection. Passive immunization with hyperimmune plasma from convalescent patients has been proposed as a potentially useful treatment for COVID-19. Using an in-house quantitative ELISA test, we found that plasma from 177 convalescent donors contained IgG antibodies specific to the spike receptor-binding domain (RBD) of SARS-CoV-2, although at very different concentrations which correlated with previous disease severity and gender. Anti-RBD IgG plasma concentrations significantly correlated with the plasma viral neutralizing activity (VN) against SARS-CoV-2 in vitro. Similar results were found using an independent cohort of serum from 168 convalescent health workers. These results validate an in-house RBD IgG ELISA test in a large cohort of COVID-19 convalescent patients and indicate that plasma from all convalescent donors does not contain a high enough amount of anti-SARS-CoV-2-RBD neutralizing IgG to prevent SARS-CoV-2 infection in vitro. The use of quantitative anti-RBD IgG detection systems might help to predict the efficacy of the passive immunization using plasma from patients recovered from SARS-CoV-2.

Published
2021

16. Nuevas dianas terapéuticas en sepsis

Author

Arias, Maykel, Garzón, Marcela, Comas, Laura, Uranga Murillo, Iratxe, Santiago, Llipsy, Pardo, Julián, Gálvez Buerba, Eva Mª, Arias, Maykel, Garzón, Marcela, Comas, Laura, Uranga Murillo, Iratxe, Santiago, Llipsy, Pardo, Julián, and Gálvez Buerba, Eva Mª

Published
2020

17. Efecto de nanopartículas de oro sobre el microambiente inmunológico tumoral

Author

Comas, Laura, Uranga Murillo, Iratxe, Artiga, Álvaro, Serrano, Inés, Arias, Maykel, Fuente, Jesús M. de la, Pardo, Julián, Gálvez Buerba, Eva Mª, Comas, Laura, Uranga Murillo, Iratxe, Artiga, Álvaro, Serrano, Inés, Arias, Maykel, Fuente, Jesús M. de la, Pardo, Julián, and Gálvez Buerba, Eva Mª

Published
2020

18. Serpinb6b inhibits Granzyme A-mediated macrophage inflammatory response and improves sepsis and inflammatory colorectal cancer

Author

Santiago, Llipsy, Garzón, Marcela, Comas, Laura, Uranga Murillo, Iratxe, Ramírez-Labrada, Ariel, Arias, Maykel, Bird, Phillip I., Gálvez Buerba, Eva Mª, Pardo, Julián, Santiago, Llipsy, Garzón, Marcela, Comas, Laura, Uranga Murillo, Iratxe, Ramírez-Labrada, Ariel, Arias, Maykel, Bird, Phillip I., Gálvez Buerba, Eva Mª, and Pardo, Julián

Published
2019

20. Antigen-specific primed cytotoxic T cells eliminate tumour cells in vivo and prevent tumour development, regardless of the presence of anti-apoptotic mutations conferring drug resistance

Author

Ministerio de Economía y Competitividad (España), European Commission, Universidad de Zaragoza, Gobierno de Aragón, Ministerio de Educación, Cultura y Deporte (España), Fundación Banco Santander, ARAID Foundation, Ministerio de Ciencia e Innovación (España), Agencia Estatal de Investigación (España), Ministerio de Ciencia, Innovación y Universidades (España), Jaime-Sánchez, Paula, Catalán, Elena, Uranga Murillo, Iratxe, Aguiló, Nacho, Santiago, Llipsy, Lanuza, Pilar M., Miguel, Diego de, Arias, Maykel, Pardo, Julián, Ministerio de Economía y Competitividad (España), European Commission, Universidad de Zaragoza, Gobierno de Aragón, Ministerio de Educación, Cultura y Deporte (España), Fundación Banco Santander, ARAID Foundation, Ministerio de Ciencia e Innovación (España), Agencia Estatal de Investigación (España), Ministerio de Ciencia, Innovación y Universidades (España), Jaime-Sánchez, Paula, Catalán, Elena, Uranga Murillo, Iratxe, Aguiló, Nacho, Santiago, Llipsy, Lanuza, Pilar M., Miguel, Diego de, Arias, Maykel, and Pardo, Julián

Abstract

Cytotoxic CD8+ T (Tc) cells are the main executors of transformed and cancer cells during cancer immunotherapy. The latest clinical results evidence a high efficacy of novel immunotherapy agents that modulate Tc cell activity against bad prognosis cancers. However, it has not been determined yet whether the efficacy of these treatments can be affected by selection of tumoural cells with mutations in the cell death machinery, known to promote drug resistance and cancer recurrence. Here, using a model of prophylactic tumour vaccination based on the LCMV-gp33 antigen and the mouse EL4 T lymphoma, we analysed the molecular mechanism employed by Tc cells to eliminate cancer cells in vivo and the impact of mutations in the apoptotic machinery on tumour development. First of all, we found that Tc cells, and perf and gzmB are required to efficiently eliminate EL4.gp33 cells after LCMV immunisation during short-term assays (1-4 h), and to prevent tumour development in the long term. Furthermore, we show that antigen-pulsed chemoresistant EL4 cells overexpressing Bcl-XL or a dominant negative form of caspase-3 are specifically eliminated from the peritoneum of infected animals, as fast as parental EL4 cells. Notably, antigen-specific Tc cells control the tumour growth of the mutated cells, as efficiently as in the case of parental cells. Altogether, expression of the anti-apoptotic mutations does not confer any advantage for tumour cells neither in the short-term survival nor in long-term tumour formation. Although the mechanism involved in the elimination of the apoptosis-resistant tumour cells is not completely elucidated, neither necroptosis nor pyroptosis seem to be involved. Our results provide the first experimental proof that chemoresistant cancer cells with mutations in the main cell death pathways are efficiently eliminated by Ag-specific Tc cells in vivo during immunotherapy and, thus, provide the molecular basis to treat chemoresistant cancer cells with CD8 Tc-base

Published
2018

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