Luis Enjuanes
Group Leader
Isabel Sola
Group Co-leader
Research summary
The main focus of our research is the study of the molecular basis of coronavirus (CoV) replication and virulence, and the identification of signalling pathways modified by the virus, to control disease. The information from these basic projects will be used to design protection strategies against CoV-induced diseases, particularly human severe pneumonia that can end in acute respiratory distress syndrome (ARDS).
Publications
Morales L, Oliveros JC, Fernandez-Delgado R, tenOever BR, Enjuanes L, Sola I. SARS-CoV-Encoded Small RNAs Contribute to Infection-Associated Lung Pathology. Cell Host Microbe. 2017;21(3):344-355
Canton J, Fehr AR, Fernandez-Delgado R, Gutierrez-Alvarez FJ, Sanchez-Aparicio MT, Garcia-Sastre A, Perlman S, Enjuanes L, Sola I.MERS-CoV 4b protein interferes with the NF-kappaB-dependent innate immune response during infection. PLoS Pathog 2018; 14: e1006838.
Castaño-Rodriguez C, Honrubia JM, Gutierrez-Alvarez J, DeDiego ML, Nieto-Torres JL, Jimenez-Guardeno JM, Regla-Nava JA, Fernandez-Delgado R, Verdia-Baguena C, Queralt-Martin M, Kochan G, Perlman S, Aguilella V, Sola I, Enjuanes, LRole of severe acute respiratory syndrome coronavirus viroporins E, 3a and 8a in replication and pathogenesis. mBio 2018 9: e02325-17
Stalin Raj V, Okba NMA, Gutierrez-Alvarez J, Drabek D, van Dieren B, Widagdo W, Lamers MM, Widjaja I, Fernandez-Delgado R, Sola I, Bensaid A, Koopmans MP, Segales J, Osterhaus A, Bosch BJ, Enjuanes L, Haagmans BLChimeric camel/human heavy-chain antibodies protect against MERS-CoV infection. . Sci Adv 2018; 4: eaas9667
Letko M, Miazgowicz K, McMinn R, Seifert SN, Sola I, Enjuanes L, Carmody A, van Doremalen N, Munster V Adaptive evolution of MERS-CoV to species variation in DPP4.. Cell Rep 2018; 24: 1730-1737.
Human infections causing pneumonia and acute respiratory distress syndrome (ARDS) are a growing health problem. In 2015, respiratory diseases were the third most common cause of death in the EU. The problem is even greater in the elderly population, which responds with significant lower efficacy to vaccination. Viruses are responsible for most respiratory infections. Among them, human coronaviruses (CoV) are the cause of up to 15% of all respiratory problems. Seven human CoVs have been described, HCoV-229E, HCoV-OC43, HCoV-NL63, HCoV-HKU1, SARS-CoV, MERS-CoV, and 2019-nCoV, the last three leading to deadly infections. Our laboratory focuses on the design of vaccines and selection of antivirals to protect against human respiratory CoV infections by modulating the innate immune response in young and elderly populations.
The main aims of our research are:
• To identify CoV genes responsible for virus virulence, to delete or modify these genes using reverse genetics in order to develop new generation vaccines such as replication-competent propagation-deficient RNA replicons, which are safe and promising vaccine candidates, and to determine their effectiveness in animal model systems. The expression of micro-RNAs with immunomodulating capacities will provide enhanced efficiency in older adults.
• To identify cell-signalling pathways involved in CoV replication and pathology, and to select antiviral drugs that inhibit these pathways interfering with virus replication or pathology. In particular, we study PBM-PDZ protein-protein interactions involved in the innate immune and inflammatory responses, since overstimulation of these pathways seems responsible for an increase in fatalities during SARS-CoV, MERS-CoV and 2019-nCoV epidemics
• To determine the contribution of host miRNAs and virus-derived small RNAs to the inflammatory lung pathology induced by CoV infection. These small non-coding RNAs represent targets for antivirals
• To study the effect of specific IFN-stimulated genes on the replication and innate immune responses of respiratory viruses, such as influenza and CoVs, which induce diseases associated with excessive immune signalling.
Marta López de Diego
Atracción de Talento Investigador from Comunidad de Madrid call 2017
Project´s name: Effect of viral and host factors on innate immunity, respiratory virus replication and pathogenesis
Summary: Influenza viruses and coronaviruses are respiratory pathogens with drastic health and economic consequences for many animal species, including humans. Seasonal Influenza viruses produce severe infections in 3-5 million people and around 500.000 deaths annually. In addition, sporadically these viruses produce pandemics of unpredictable consequences. On the other hand, coronaviruses produce 10 to 30% of common colds in humans and more severe infections, such as the pandemic we are suffering now caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2).
In our group we are interested in analyzing virus host-interactions, particularly the innate immune responses induced after respiratory virus infections, since these host responses affect viral replication and pathogenesis. Our final goal is to use the knowledge generated in our research to develop new antivirals to fight these and other viral infections, and to analyze viral and host genetic factors affecting the severity of respiratory virus diseases. As such we are aiming at (i) studying the cellular functions of interferon-stimulated genes and the effect of these genes on virus replication, on the induction of innate immune responses and virus pathogenesis, (ii) studying the functional effects of mutations on influenza virulence genes on virus replication, and pathogenesis, (iii) evaluating the effect of genetic polymorphisms on innate immune response genes in the severity of the diseases induced by influenza and coronaviruses, and (iv) developing antivirals mainly targeting innate immune response proteins and viral proteins.
Schematic representation of the effect of IFI44 protein on IFN responses. PRRs such as RIG-I, MDA5 and TLRs recognize viral products. This recognition leads to the activation of IKKe, which phosphorylates and activates the transcription factors IRF-3 and IRF-7, and IKKa and IKKb, which phosphorylate IkBa, leading to the activation of NF-κB. IRF-3, IRF-7 and NF-κB are critical for the induction of type I (IFNa and b) and type III (IFNl) IFNs expression. (B) Type I and III IFNs signal through IFNa/b (IFNAR) and IFNl (IFNLR1) receptors, leading to the induction of expression of ISGs inducing an antiviral state, including IFI44. IFI44 interacts with FKBP5, which in turn interacts with IKKa, IKKb, and IKKe kinases. This interaction decreases the ability of IKKe to phosphorylate IRF-3 (and likely IRF-7 and STAT1), and the ability of IKKb to phosphorylate IkBa.
Laboratory Members
Name |
Position |
Contact |
| Marta López de Diego | Talent Attraction researcher | |
| Laura Villamayor Coronado | Postdoctoral Scientist | |
| Sandra Gómez López | Technician | |
| Darío López García | Graduate Student JAE-INTRO, |
Funding
Role of host proteins on the induction of innate immune responses and on modulating the virulence of respiratory viruses. Grant Atracción de Talento Investigador, from Comunidad de Madrid. 2018-2022. PI: Marta L. DeDiego.
Role of influenza virus proteins on innate immune responses and virus pathogenicity. Spanish Ministry of Science, Innovation and Universities (RTI2018-094213-A-I00), from 2019 to 2021 p>
Publications
Nogales A, DeDiego ML. Host Single Nucleotide Polymorphisms Modulating Influenza A Virus Disease in Humans. Pathogens. 2019 Sep 30;8(4):168. doi: 10.3390/pathogens8040168.
DeDiego ML, Nogales A, Martinez-Sobrido L, Topham DJ. Interferon-Induced Protein 44 Interacts with Cellular FK506-Binding Protein 5, Negatively Regulates Host Antiviral Responses, and Supports Virus Replication. mBio. 2019 Aug 27;10(4):e01839-19. doi: 10.1128/mBio.01839-19.
DeDiego ML, Martinez-Sobrido L, Topham DJ. Novel Functions of IFI44L as a Feedback Regulator of Host Antiviral Responses. J Virol. 2019 Oct 15;93(21):e01159-19. doi: 10.1128/JVI.01159-19. .
Nogales A, Ávila-Pérez G, Rangel-Moreno J, Chiem K, DeDiego ML, Martínez- Sobrido L. A Novel Fluorescent and Bioluminescent Bireporter Influenza A Virus To Evaluate Viral Infections. J Virol. 2019 May 1;93(10):e00032-19. doi: 10.1128/JVI.00032-19.
Nogales A, Martinez-Sobrido L, Chiem K, Topham DJ, DeDiego ML. Functional Evolution of the 2009 Pandemic H1N1 Influenza Virus NS1 and PA in Humans. J Virol. 2018 Sep 12;92(19):e01206-18. doi: 10.1128/JVI.01206-18.
A complete list of publication can be obtained from Pubmed
