Prevención de Pandemias Virales. (PrePan)

Introducción

RNA respiratory viruses like Influenza or Coronavirus are the causative agents of pandemics in the 21st century. Preventing these pandemics is one of the greatest challenges for human health. Vaccines are the best cost-effective therapeutical option and usually rely on the viral surface glycoprotein (Spike glycoprotein in Coronavirus and Hemagglutinin in Influenza virus). However, viral glycoproteins accumulate most of the RNA viruses' escape mutations, threatening the vaccines' effectiveness. Therefore, broad-spectrum vaccines that neutralize known and emerging viral strains are urgently required. Here, we propose an alternative approach using conserved structural proteins with slower mutational rates, such as viral nucleoproteins (NPs), as targets for medical intervention.

NPs are located inside the virus particles, encapsidating the viral RNA genome by combining two activities: self-polymerization and RNA interaction. In addition to protecting the viral genome from degradation, viral NPs serve as molecular machines for viral replication and transcription. NPs are highly conserved across Influenza and Coronavirus families and are the most abundant protein in infected cells. NPs are ideal targets for antivirals, but they were traditionally not considered antigens for vaccines because of their location inside the viral particle "hidden" from the immune system. However, recent discoveries from our lab and others demonstrated that NPs also regulate the innate and adaptative immune response through distinct mechanisms: (i) strong T cell activation by digested peptides exposed in the cell surface of the infected cells, (ii) direct binding to inflammatory chemokines in the cell surface of infected cells, and (iii) specific monoclonal antibodies (mAbs) for viral NPs that reduce inflammation and pathology in the lung.

This project offers the opportunity to generate universal treatments that target conserved internal proteins of the virus that provide a more mutation-resistant therapeutic option for current epidemics and expected future waves of Coronaviruses and Influenza viruses. Here, we describe a stepwise method using purified NPs to generate a panel of specific monoclonal antibodies (mAbs) in mice. We will characterize the affinity and the epitope binging of these mAbs by combining epitope binning assays and electron microscopy analysis (EM). Based on these results, we will test the therapeutic potential of these mAbs in vivo and propose a candidate immunotherapy. To expand our knowledge of the immune response triggered by the viral NPs, we will combine molecular and visualization techniques to unravel the molecular mechanism of transport of the viral NPs to the cell surface. The resulting information will provide insights into the antigenic principles of Influenza and Coronavirus NPs, which can guide the design of universal vaccines.

Investigador principal

Sara Landeras Bueno

Miembros del Grupo

Investigadores en formación

Iris Barragán Martín

Líneas de investigación

Viral nucleoproteins: Ideal candidates to prevent future pandemics caused by RNA human viruses.

Título del proyecto: Structure of the SARS-CoV-2 Nucleocapsid: building block to viral capsid

Investigadora Principal: Erica Ollmann Saphire

Co-Investigadora: Sara Landeras Bueno

Entidad financiadora: US National Institutes of Health (NIH)

Referencia: R21 AI118016-01A1

Duración (desde/hasta): 07/08/2023-07/08/2025

Cuantía económica: $515,000

Título del proyecto: Combating Emerging Ebola virus threats with affordable cures

Investigadora Principal: Sara Landeras Bueno

Entidad financiadora: La Jolla Institute for Immunology

Referencia: SPARK award for innovations in Immunology

Duración (desde/hasta): 01/02/2020 – 02/02/2021

Cuantía económica: $25,000

Título del proyecto: Rational design of SARS-CoV-2 therapeutics

Investigadora Principal: Erica Ollmann Saphire and Sara Landeras Bueno

Entidad financiadora: La Jolla Institute for Immunology

Referencia: COVID-19 Advancement by postdoctoral research

Duración (desde/hasta): 01/08/2019 - 31/07/2021

Cuantía económica: $50,000

Autores: Norris MJ, Husby ML, Kiosses WB, Yin J, Saxena R, Rennick LJ, Heiner A,

Harkins SS, Pokhrel R, Schendel SL, Hastie KM, Landeras-Bueno S, Salie ZL, Lee

B, Chapagain PP, Maisner A, Duprex WP, Stahelin RV, Saphire EO.

Año de publicación: 2022

Título: Measles and Nipah virus assembly: Specific lipid binding drives matrix polymerization.

Revista: Science Advances

Clave: A

DOI: doi: 10.1126/sciadv.abn1440.

Índice de impacto: 13.6 (Wos)/20.4 (Scopus)

Cuartil en su área: Q1

Autores: Regla-Nava JA, Wang YT, Fontes-Garfias CR, Liu Y, Syed T, Susantono M,

Gonzalez A, Viramontes KM, Verma SK, Kim K, Landeras-Bueno S, Huang CT,

Prigozhin DM, Gleeson JG, Terskikh AV, Shi PY, Shresta S.

Año de publicación: 2022

Título: A Zika virus mutation enhances transmission potential and confers escape from protective dengue virus

immunity.

Revista: Cell Rep.

Clave: A

DOI: 10.1016/j.celrep.2022.110655

Índice de impacto: 8.8 (WoS)/14,9 (Scopus)

Cuartil en su área: Q1

Autores: Nieto-Torres JL, Shanahan SL, Chassefeyre R, Chaiamarit T, Zaretski S,

Landeras-Bueno S, Verhelle A, Encalada SE, Hansen M.

Año de publicación: 2021

Título: LC3B phosphorylation regulates FYCO1 binding and directional transport of autophagosomes.

Revista: Curr Biol.

Clave: A

DOI: 10.1016/j.cub.2021.05.052

Índice de impacto: 9,2 (WoS)/12,1(Scopus)

Cuartil en su área: Q1

Autores: Landeras-Bueno S, Wasserman H, Oliveira G, VanAernum ZL, Busch F, Salie ZL,

Wysocki VH, Andersen K, Saphire EO.

Año de publicación: 2021

Título: Cellular mRNA triggers structural transformation of Ebola virus matrix protein VP40 to its essential regulatory form.

Revista: Cell Rep.

Clave: A

DOI: 10.1016/j.celrep.2021.108986.

Índice de impacto: 8.8 (WoS)/14,9 (Scopus)

Cuartil en su área: Q1

Autores: Wang YT, Landeras-Bueno S, Hsieh LE, Terada Y, Kim K, Ley K, Shresta S,

Saphire EO, Regla-Nava JA.

Año de publicación: 2020

Título: Spiking Pandemic Potential: Structural and Immunological Aspects of SARS-CoV-2.

Revista: Trends Microbiol.

Clave: A

DOI: 10.1016/j.tim.2020.05.012.

Índice de impacto: 15,9 (WoS)/27,4 (Scopus)

Cuartil en su área: Q1

Autores: Landeras-Bueno S, Oda SI, Norris MJ, Li Salie Z, Guenaga J, Wyatt RT, Saphire

EO.

Año de publicación: 2019

Título: Sudan Ebolavirus VP35-NP Crystal Structure Reveals a Potential Target for

Pan-Filovirus Treatment.

Revista: mBio.

Clave: A

DOI: 10.1128/mBio.00734-19

Índice de impacto: 6,4 (WoS)/10,8 (Scopus)

Cuartil en su área: Q1

Autores: Marcos-Villar L, Díaz-Colunga J, Sandoval J, Zamarreño N, Landeras-Bueno S,

Esteller M, Falcón A, Nieto A.

Año de publicación: 2018

Título: Epigenetic control of influenza virus: role of

H3K79 methylation in interferon-induced antiviral response.

Revista: Sci Rep.

Clave: A

DOI: 10.1038/s41598-018-19370-6

Índice de impacto: 4,6 (WoS)/ 4,9 (Scopus)

Cuartil en su área: Q2 (WoS)/ Q1 (Scopus)

Autores: Landeras-Bueno S, Fernández Y, Falcón A, Oliveros JC, Ortín J.

Año de publicación: 2016

Título: Chemical Genomics Identifies the PERK-Mediated Unfolded Protein Stress Response as a Cellular Target for Influenza Virus Inhibition.

Revista: mBio.

Clave: A

DOI: 10.1128/mBio.00085-16

Índice de impacto: 6,4 (WoS)/10,8 (Scopus)

Cuartil en su área: Q1

Autores: Rodriguez-Frandsen A, de Lucas S, Pérez-González A, Pérez-Cidoncha M,

Roldan-Gomendio A, Pazo A, Marcos-Villar L, Landeras-Bueno S, Ortín J, Nieto A.

Año de publicación: 2016

Título: hCLE/C14orf166, a cellular protein required for viral replication, is incorporated into influenza virus particles.

Revista: Sci Rep.

Clave: A

DOI: 10.1038/srep20744

Índice de impacto: 4,6 (WoS)/ 4,9 (Scopus)

Cuartil en su área: Q2 (WoS)/ Q1 (Scopus)

Autores: Landeras-Bueno S, Ortín J.

Año de publicación: 2016

Título: Regulation of influenza virus infection by long non-coding RNAs.

Revista: Virus Research

Clave: A

DOI: 10.1016/j.virusres.2015.08.008

Índice de impacto: 5 (WoS)/ 8,9 (Scopus)

Cuartil en su área: Q2 (WoS)/ Q1 (Scopus)

Autores: Ver LS, Marcos-Villar L, Landeras-Bueno S, Nieto A, Ortín J.

Año de publicación: 2015

Título: The Cellular Factor NXP2/MORC3 Is a Positive Regulator of Influenza Virus Multiplication.

Revista: J Virol.

Clave: A

DOI: 10.1128/JVI.01530-15

Índice de impacto: 5,4 (WoS)/ 10,4 (Scopus)

Cuartil en su área: Q2 (WoS)/ Q1 (Scopus)

Autores: Landeras-Bueno S, Jorba N, Pérez-Cidoncha M, Ortín J.

Año de publicación: 2011

Título: The splicing factor proline-glutamine rich (SFPQ/PSF) is involved in influenza virus transcription.

Revista: PLoS Pathog

Clave: A

DOI: 10.1371/journal.ppat.1002397

Índice de impacto: 6,7 (WoS)/ 11,2 (Scopus)

Cuartil en su área: Q1