Viral modulation of the immune response

Research summary:

www.cbm.uam.es/antonio_alcami

We are characterizing viral mechanisms to modulate the host anti-viral immune response and the inflammatory response. We work on herpesvirus and poxvirus proteins that are secreted from infected cells and interact with cytokines or chemokines, and modulate their activity. The contribution of viral proteins to pathogenesis is tested in mouse models of infection. We are characterizing glycoprotein G from herpes simplex virus, a protein that interacts with both chemokines and neurotrophic factors to facilitate viral invasion of the nervous system. We have further characterized unique anti-inflammatory properties of soluble tumour necrosis factor receptors encoded by poxviruses. We have shown that addition of a viral chemokine binding domain to the human tumour necrosis factor receptor used in the clinic to treat autoimmune diseases enhances its anti-inflammatory activity, and a mutation in the human receptor restricts its ligand specificity. We also described that the Schlafen poxvirus protein is a potent inhibitor of the DNA sensing pathway, which controls the early production of type I interferon and limits the activation of protective anti-viral responses. The DNA sensing pathway has a major role in the initiation of the inflammatory response, and the viral protein has the potential to inhibit uncontrolled inflammatory responses leading to autoimmune diseases. Understanding how viruses have optimized their immune modulatory activities may help us to identify new therapeutic approaches to treat human inflammatory diseases.

Viral metagenomics is offering us the opportunity of identifying complex viral communities present in natural environments. Using next generation sequencing we are characterizing at the genetic level complex viral communities adapted to the extreme environmental conditions of from Polar regions, Antarctica and the Arctic. We are expanding this research to the study of Alpine ecosystems in the Ordesa and Monte Perdido National Park in the Pyrenees.

Lastly, our group has optimized the methodology to capture microorganisms and viruses in the air (airbiota) to identify at the genetic level the presence of airborne pathogens. Since the COVID-19 pandemic started, we have adapted this methodology to identify SARS-CoV-2 in aerosols. In collaboration with clinicians we characterized the aerosol transmission of SARS-CoV-2 in hospitals and the impact of air transmission in the COVID-19 pandemic.

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Inhibition of the DNA sensing pathway by the poxvirus protein Schlafen. The blockade of this pathway prevents the early production of type IFN leading to inhibition of the anti-viral and inflammatory responses.

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Last nameNameLaboratoryExt.*e-mailProfessional category
Alcamí PertejoAntonio2034560aalcami(at)cbm.csic.esE. Profesores de Investigación de Organismos Públicos de Investigación
Alonso SánchezMaría Isabel2034590ialonso(at)cbm.csic.esContrato Predoctoral
Alvarez de Miranda RodríguezFrancisco Javier2034590fj.alvarez(at)cbm.csic.esTitulado Sup. Actividades Tecn. y Prof.GP1
Donaire CarpioSamuel2034590Estudiante
Fernández MoyanoMª Carmen2034590mcfernandez(at)cbm.csic.esE.Ayudantes De Invest. De Los Oo.Publicos De Investigacion
González SerranoRafael2034560Titulado Sup. Actividades Tecn. y Prof.GP1
Hernáez de la PlazaBruno2034590bhernaez(at)cbm.csic.esTitulado Sup. Actividades Tecn. y Prof.GP1 Indef.
Martín HernándezMª Rocío2034590mrmartin(at)cbm.csic.esTécnico Sup. Actividades Tecn. y Prof.GP3 Indef.
Mejias MartínezLorena2034590lmejias(at)cbm.csic.esEstudiante
Rastrojo LastrasAlberto2034590arastrojo(at)cbm.csic.esProfesor Contratado Universidad, GA
Sánchez CarrilloSergio2034590Titulado Sup. Actividades Tecn. y Prof.GP1
Sánchez FernándezCarolina2034590carolina_s(at)cbm.csic.esTécnico Sup. Actividades Tec. y Profes.GP3
Sánchiz GiraldoÁfrica3024590asanchiz(at)cbm.csic.esTitulado Sup. Actividades Tecn. y Prof.GP1
Vázquez CalvoAngela2034590avazquez(at)cbm.csic.esTitulado Sup. Actividades Tecn. y Prof.GP1

Relevant publications:

  • Pontejo, S. M., Sánchez, C., Ruiz-Argüello, B. and Alcamí, A. (2019) Insights into ligand binding by a viral tumor necrosis factor (TNF) decoy receptor yield a selective soluble human type 2 TNF receptor. J. Biol. Chem. 294(13):5214-5227. doi: 10.1074/jbc.RA118.005828.

  • Martínez-Vicente, P., Farré, D., Sánchez, C., Alcamí, A., Engel, P. and Angulo, A. (2019) Subversion of natural killer cell responses by a cytomegalovirus-encoded soluble CD48 decoy receptor. PLoS Pathog.15(4):e1007658. doi: 10.1371/journal.ppat.1007658.

  • Alejo, A., Sánchez, C., Amu, S., Fallon, P. G. and Alcamí, A. (2019) Addition of a Viral Immunomodulatory Domain to Etanercept Generates a Bifunctional Chemokine and TNF Inhibitor. J. Clin. Med. 9(1):25. doi: 10.3390/jcm9010025.

  • Hurtado-Guerrero, I., Hernáez, B., Pinto-Medel, M. J., Calonge, E., Rodriguez-Bada, J. L., Urbaneja, P., Alonso, A., Mena-Vázquez, N., Aliaga, P., Issazadeh-Navikas, S., Pavia, J., Leyva, L., Alcamí, J., Alcamí, A., Fernández, Ó. and Oliver-Martos, B. (2020) Antiviral, Immunomodulatory and Antiproliferative Activities of Recombinant Soluble IFNAR2 without IFN-ß Mediation. J. Clin. Med. 9(4):959. doi: 10.3390/jcm9040959.

  • Yaron, J. R., Zhang, L., Guo, Q., Burgin, M., Schutz, L. N., Awo, E., Wise, L., Krause, K. L., Ildefonso, C. J., Kwiecien, J. M., Juby, M., Rahman, M. M., Chen, H., Moyer, R. W., Alcami, A., McFadden, G. and Lucas, A. R. (2020) Deriving Immune Modulating Drugs from Viruses-A New Class of Biologics. J. Clin. Med. 9(4):972. doi: 10.3390/jcm9040972.

  • Hernáez, B. and Alcamí, A. (2020) Virus-encoded cytokine and chemokine decoy receptors. Curr. Opin. Immunol. 66:50-56. doi: 10.1016/j.coi.2020.04.008.

  • Rojas, J. M., Alejo, A., Avia, J. M., Rodríguez-Martín, D., Sánchez, C., Alcamí, A., Sevilla, N. and Martín, V. (2020) Activation of OX40 and CD27 Costimulatory Signalling in Sheep through Recombinant Ovine Ligands. Vaccines 8(2):333. doi: 10.3390/vaccines8020333.

  • Kropp, K. A., López-Muñoz, A. D., Ritter, B., Martín, R., Rastrojo, A., Srivaratharajan, S., Döhner, K., Dhingra, A., Czechowicz, J. S., Nagel, C. H., Sodeik, B., Alcamí, A. and Viejo-Borbolla, A. (2020) Herpes Simplex Virus 2 Counteracts Neurite Outgrowth Repulsion during Infection in a Nerve Growth Factor-Dependent Manner. J. Virol. 94(20):e01370-20. doi: 10.1128/JVI.01370-20.

  • Desdín-Micó, G., Soto-Heredero, G., Aranda, J. F., Oller, J., Carrasco, E., Gabandé-Rodríguez, E., Blanco, E. M., Alfranca, A., Cussó, L., Desco, M., Ibañez, B., Gortazar, A. R., Fernández-Marcos, P., Navarro, M. N., Hernáez, B., Alcamí, A., Baixauli, F., and Mittelbrunn, M. (2020) T cells with dysfunctional mitochondria induce multimorbidity and premature senescence. Science 368(6497):1371-1376. doi: 10.1126/science.aax0860.

  • Hernáez, B., Alonso, G., Georgana, I., El-Jesr, M., Martín, R., Shair, K. H. Y., Fischer, C., Sauer, S., Maluquer de Motes, C. and Alcamí, A. (2020) Viral cGAMP nuclease reveals the essential role of DNA sensing in protection against acute lethal virus infection. Sci. Adv. 6(38):eabb4565. doi: 10.1126/sciadv.abb4565.

  • Olagnier, D., Farahani, E., Thyrsted, J., Blay-Cadanet, J., Herengt, A., Idorn, M., Hait, A., Hernaez, B., Knudsen, A., Iversen, M. B., Schilling, M., Jørgensen, S. E., Thomsen, M., Reinert, L. S., Lappe, M., Hoang, H. D., Gilchrist, V. H., Hansen, A. L., Ottosen, R., Nielsen, C. G., Møller, C., van der Horst, D., Peri, S., Balachandran, S., Huang, J., Jakobsen, M., Svenningsen, E. B., Poulsen, T. B., Bartsch, L., Thielke, A. L., Luo, Y, Alain, T., Rehwinkel, J., Alcamí, A., Hiscott, J., Mogensen, T. H., Paludan, S. R. and Holm, C. K. (2020) SARS-CoV2-mediated suppression of NRF2-signaling reveals potent antiviral and anti-inflammatory activity of 4-octyl-itaconate and dimethyl fumarate. Nat. Commun. 11(1):4938. doi: 10.1038/s41467-020-18764-3.

  • Kropp, K. A., Srivaratharajan, S., Ritter, B., Yu, P., Krooss, S., Polten, F., Pich, A., Alcamí, A. and Viejo-Borbolla, A. (2020) Identification of the Cleavage Domain within Glycoprotein G of Herpes Simplex Virus Type 2. Viruses 12(12):1428. doi: 10.3390/v12121428.

  • Al Rumaih, Z., Tuazon Kels, M. J., Ng, E., Pandey, P., Pontejo, S. M., Alejo, A., Alcamí, A., Chaudhri, G. and Karupiah, G. (2020) Poxvirus-encoded TNF receptor homolog dampens inflammation and protects from uncontrolled lung pathology during respiratory infection. Proc. Natl. Acad. Sci.U. S. A. 117(43):26885-26894. doi: 10.1073/pnas.2004688117.

  • Alcamí, A. (2020) Was smallpox a widespread mild disease? Science 369(6502):376-377. doi: 10.1126/science.abd1214

Doctoral theses:

  • Graciela Alonso (2019). Relevancia de la actividad viral anti-linfotoxina y el gen viral Schalfen en la patogénesis del virus ectromelia. Universidad Autónoma de Madrid. Co-supervisada: Antonio Alcamí y Bruno Hernáez.
  • Alberto Domingo López (2019). Papel de la glicoproteína G del virus herpes simplex en patogénesis. Universidad Autónoma de Madrid. Co-supervisada: Antonio Alcamí y Alberto Rastrojo.
  • Sergio Martín Pontejo (2012). Características moleculares y funcionales de los receptores solubles del TNF con capacidad anti-quimioquinas de poxvirus. Universidad Autónoma de Madrid. Directores: Begoña Ruiz Argüello y Antonio Alcamí.
  • Marcos Palomo (2012). Caracterización de inhibidores solubles de interferón codificados por poxvirus. Universidad Autónoma de Madrid. Director: Antonio Alcamí.
  • Nadia Martínez Martín (2012). Herpes simples virus glycoprotein G enhances chemotaxis and axonal growth through modification of plasma membrane microdomains and receptor trafficking. Universidad Autónoma de Madrid. Directores: Abel Viejo Borbolla y Antonio Alcamí.

Patents:

  • S. M. Pontejo, C. Sánchez and A. Alcamí. A variant form of etanercept with increased specificity for TNF. PCT/EP2019/079492. International Patent Application 29/10/2019. Owner: CSIC.
  • A. Rastrojo and A. Alcamí. Device and method for capturing and analysing airborne organisms. EP20382510.4. European Patent Application 12/06/2020. Owner: CSIC.
  • Martín-Pontejo, S. y Alcami, A. Unión a glicosaminoglicanos de proteínas con dominio SECRET codificadas por poxvirus. Número de prioridad: P201230540. País: España. Fechas de prioridad: 11 abril 2012. Propietario: CSIC.
  • Cabrera, J. R., Viejo-Borbolla, A., Martínez-Martín, N., Wandosell, F. y Alcami, A.. 'Proteína viral recombinante SgG2 y/o complejos binarios SgG2-FNs para su uso en crecimiento y/o regeneración axonal'. Número de prioridad: P201231654. País: España. Fecha de prioridad: 26 octubre 2012. Propietario: CSIC.

Other activities:

  • Organizer. 3rd European Chemokine and Cell Migration Conference. Salamanca, Spain. 06/2019.
  • Advisor to the World Health Organization Advisory Committee on Variola Virus Research
  • Member of the Editorial Board of Virology.
  • Member of the Editorial Board of Journal of Virology.
  • Advisor to the World Health Organization Advisory Committee on Variola Virus Research.
  • Organizer, together with R. Blasco and E. Villar, of the XIX International Poxvirus, Asfarvirus and Iridovirus Conference. Salamanca, June 2012.
  • The Group participates in the Spanish Network of Multiple Sclerosis (www.reem.es).

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