Abstract
Background and purpose: There is a need for effective anti-COVID-19 treatments, mainly for individuals at risk of severe disease such as the elderly and the immunosuppressed. Drug repositioning has proved effective in identifying drugs that can find a new application for the control of coronavirus disease, in particular COVID-19. The purpose of the present study was to find synergistic antiviral combinations for COVID-19 based on lethal mutagenesis.
Experimental approach: The effect of combinations of remdesivir and ribavirin on the infectivity of SARS-CoV-2 in cell culture has been tested. Viral populations were monitored by ultra-deep sequencing, and the decrease of infectivity as a result of the treatment was measured.
Key results: Remdesivir and ribavirin exerted a synergistic inhibitory activity against SARS-CoV-2, quantified both by CompuSyn (Chou-Talalay method) and Synergy Finder (ZIP-score model). In serial passage experiments, virus extinction was readily achieved with remdesivir-ribavirin combinations at concentrations well below their cytotoxic 50 value, but not with the drugs used individually. Deep sequencing of treated viral populations showed that remdesivir, ribavirin, and their combinations evoked significant increases of the number of viral mutations and haplotypes, as well as modification of diversity indices that characterize viral quasi-species.
Conclusion and implications: SARS-CoV-2 extinction can be achieved by synergistic combination treatments based on lethal mutagenesis. In addition, the results offer prospects of triple drug treatments for effective SARS-CoV-2 suppression.
DOI: 10.1111/bph.16344.
NPJ Vaccines. 2024 Mar 6;9(1):53.
L Marcos-Villar#, B Perdiguero#, .... M Esteban, CE Gómez
Abstract
Vaccines based on mRNA technology have revolutionized the field. In fact, lipid nanoparticles (LNP) formulated with mRNA are the preferential vaccine platform used in the fight against SARS-CoV-2 infection, with wider application against other diseases. The high demand and property right protection of the most potent cationic/ionizable lipids used for LNP formulation of COVID-19 mRNA vaccines have promoted the design of alternative nanocarriers for nucleic acid delivery. In this study we have evaluated the immunogenicity and efficacy of different rationally designed lipid and polymeric-based nanoparticle prototypes against SARS-CoV-2 infection. An mRNA coding for a trimeric soluble form of the receptor binding domain (RBD) of the spike (S) protein from SARS-CoV-2 was encapsulated using different components to form nanoemulsions (NE), nanocapsules (NC) and lipid nanoparticles (LNP). The toxicity and biological activity of these prototypes were evaluated in cultured cells after transfection and in mice following homologous prime/boost immunization. Our findings reveal good levels of RBD protein expression with most of the formulations. In C57BL/6 mice immunized intramuscularly with two doses of formulated RBD-mRNA, the modified lipid nanoparticle (mLNP) and the classical lipid nanoparticle (LNP-1) were the most effective delivery nanocarriers at inducing binding and neutralizing antibodies against SARS-CoV-2. Both prototypes fully protected susceptible K18-hACE2 transgenic mice from morbidity and mortality following a SARS-CoV-2 challenge. These results highlight that modulation of mRNAs immunogenicity can be achieved by using alternative nanocarriers and support further assessment of mLNP and LNP-1 prototypes as delivery vehicles for mRNA vaccines.
Front Immunol. 2024 Feb 12:15:1273942.
D Fernández-Soto, AF García-Jiménez, JM Casasnovas, M Valés-Gómez, HT Reyburn
Introduction: It is now clear that coronavirus disease 19 (COVID-19) severity is associated with a dysregulated immune response, but the relative contributions of different immune cells is still not fully understood. SARS CoV-2 infection triggers marked changes in NK cell populations, but there are contradictory reports as to whether these effector lymphocytes play a protective or pathogenic role in immunity to SARS-CoV-2.
Methods: To address this question we have analysed differences in the phenotype and function of NK cells in SARS-CoV-2 infected individuals who developed either very mild, or life-threatening COVID-19 disease.
Results: Although NK cells from patients with severe disease appeared more activated and the frequency of adaptive NK cells was increased, they were less potent mediators of ADCC than NK cells from patients with mild disease. Further analysis of peripheral blood NK cells in these patients revealed that a population of NK cells that had lost expression of the activating receptor NKG2D were a feature of patients with severe disease and this correlated with elevated levels of cell free NKG2D ligands, especially ULBP2 and ULBP3 in the plasma of critically ill patients. In vitro, culture in NKG2DL containing patient sera reduced the ADCC function of healthy donor NK cells and this could be blocked by NKG2DL-specific antibodies.
Discussion: These observations of reduced NK function in severe disease are consistent with the hypothesis that defects in immune surveillance by NK cells permit higher levels of viral replication, rather than that aberrant NK cell function contributes to immune system dysregulation and immunopathogenicity.
- El estudio ha revelado la aparición incipiente de variantes de coronavirus con propiedades biológicas alteradas en pacientes de COVID-19
- Estas mutaciones, hasta ahora inadvertidas por su baja proporción en los pacientes infectados, han sido detectadas gracias a una técnica de secuenciación ultra-profunda
Equipos del Consejo Superior de Investigaciones Científicas (CSIC), de la Universidad Politécnica de Madrid y de la Fundación Jiménez Díaz han revelado en pacientes de COVID-19 la aparición incipiente de variantes de coronavirus con propiedades biológicas alteradas.
El estudio utilizó muestras de virus aislados de pacientes de la primera ola de COVID-19 en Madrid, sobre las que se aplica una técnica de secuenciación ultra-profunda para identificar mutaciones presentes en muy baja proporción. En cada paciente infectado se hallaron multitud de mutaciones cuya relación de parentesco se analizó mediante mapas de redes neuronales. Este procedimiento, basado en técnicas de computación avanzada, permite visualizar en forma de mapas tridimensionales las secuencias con distintas mutaciones, la distancia evolutiva entre secuencias y la frecuencia con la que se encuentran en cada paciente.
- Un acuerdo con la organización de salud pública Medicines Patent Pool (MPP), respaldado por las Naciones Unidas y supervisado por la OMS, facilitará que esta tecnología llegue a los países de bajos recursos
- El CSIC no cobrará regalías por la explotación de su vacuna siempre que se fabrique para países incluidos en la lista de países con ingresos bajos o medios
- Tras los test serológicos, es la segunda vez que el CSIC pone una tecnología a disposición de la iniciativa C-TAP de la OMS para compartirla y producirla a precio asequible
El Consejo Superior de Investigaciones Científicas (CSIC), organismo dependiente del Ministerio de Ciencia e Innovación, pone a disposición de los países en vías de desarrollo su prototipo de vacuna covid-19 basada en el virus vaccinia MVA como vector desarrollada por investigadores del CNB-CSIC. La institución ha firmado un segundo acuerdo con la organización de salud pública Medicines Patent Pool (MPP), respaldada por la Organización de las Naciones Unidas (ONU), y bajo supervisión de la Organización Mundial de la Salud (OMS) que facilitará que esta tecnología avance a ensayos clínicos y llegue a los países más necesitados. Tras los test serológicos de covid-19, es la segunda vez que el CSIC cede una tecnología a través de la iniciativa COVID-19 Technology Access Pool (C-TAP) de la OMS para facilitar al acceso igualitario a tecnologías sanitarias de covid-19.
La firma se enmarca en la iniciativa (C-TAP), creada por la OMS en mayo de 2020 para facilitar el acceso oportuno, igualitario y asequible a productos sanitarios de la covid-19 a través del impulso a su producción. C-TAP proporciona una ventana única mundial a las entidades que desarrollan tecnologías para hacer frente a la covid-19, como terapias, vacunas y sistemas de diagnóstico, con el objetivo de que compartan su propiedad intelectual (patentes), conocimiento y datos, con fabricantes de probada calidad mediante licencias transparentes, no-exclusivas y con voluntad de servir a la sanidad pública.
J Nanobiotechnology. 2022 Jul 30;20(1):352.
M L DeDiego , Y Portilla, N Daviu, D López-García, L Villamayor, VMulens-Arias, JG Ovejero, Á Gallo-Cordova, S Veintemillas-Verdaguer, MP Morales, DF Barber
Abstract
Background: Coronaviruses usually cause mild respiratory disease in humans but as seen recently, some human coronaviruses can cause more severe diseases, such as the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), the global spread of which has resulted in the ongoing coronavirus pandemic.
Results: In this study we analyzed the potential of using iron oxide nanoparticles (IONPs) coated with biocompatible molecules like dimercaptosuccinic acid (DMSA), 3-aminopropyl triethoxysilane (APS) or carboxydextran (FeraSpin™ R), as well as iron oxyhydroxide nanoparticles (IOHNPs) coated with sucrose (Venofer®), or iron salts (ferric ammonium citrate -FAC), to treat and/or prevent SARS-CoV-2 infection. At non-cytotoxic doses, IONPs and IOHNPs impaired virus replication and transcription, and the production of infectious viruses in vitro, either when the cells were treated prior to or after infection, although with different efficiencies. Moreover, our data suggest that SARS-CoV-2 infection affects the expression of genes involved in cellular iron metabolism. Furthermore, the treatment of cells with IONPs and IOHNPs affects oxidative stress and iron metabolism to different extents, likely influencing virus replication and production. Interestingly, some of the nanoparticles used in this work have already been approved for their use in humans as anti-anemic treatments, such as the IOHNP Venofer®, and as contrast agents for magnetic resonance imaging in small animals like mice, such as the FeraSpin™ R IONP.
Conclusions: Therefore, our results suggest that IONPs and IOHNPs may be repurposed to be used as prophylactic or therapeutic treatments in order to combat SARS-CoV-2 infection.
Keywords: Anti-anemic; Iron metabolism; Iron oxide nanoparticles; Iron oxyhydroxide nanoparticles; MRI contrast agents; Oxidative stress; SARS-CoV-2; Viral infection; Viral replication.
DOI: 10.1186/s12951-022-01542-2
- Investigadores del CSIC han identificado que las nanopartículas de óxido, usadas en tratamientos médicos, disminuyen la replicación celular del virus
- Los resultados destacan que medicamentos antianémicos y agentes de contraste de resonancia magnética basados en nanopartículas de hierro podrían usarse como antivirales
Investigadores del Consejo Superior de Investigaciones Científicas (CSIC) han encontrado actividad antiviral contra el SARS-Cov-2 en las nanopartículas de óxido y oxihidróxido de hierro. Los resultados, publicados en Journal of Nanobiotechnology, sugieren que el estrés oxidativo y la interferencia con el metabolismo intracelular del hierro que producen podría ser la causa de su efecto antiviral. Esto invita a pensar, además, que la replicación del virus podría depender de los niveles intracelulares de hierro.
Estudios previos habían identificado que las nanopartículas de óxido de hierro tenían un efecto antiviral contra el virus de la gripe, por lo que investigadores del CSIC en el Centro Nacional de Biotecnología (CNB-CSIC) y el Instituto de Ciencia de Materiales de Madrid, (ICMM-CSIC) iniciaron una colaboración para estudiar si las nanopartículas de óxido y oxihidróxido de hierro también podrían tener actividad antiviral contra el SARS-CoV-2
- Estos anticuerpos, basados en el sistema inmunitario de los dromedarios, tienen potencial terapéutico en pacientes inmunodeficientes o no protegidos por las vacunas
- El estudio ha demostrado en modelos animales que son activos frente a las variantes más virulentas de SARS-CoV-2 y que pueden proteger hasta el 100% de los infectados
Investigadores del CSIC han obtenido anticuerpos neutralizantes eficaces frente a las variantes más virulentas del SARS-CoV-2 y que pueden utilizarse como terapia en pacientes de covid-19. Los investigadores, que han publicado el estudio en Frontiers in Immunology, han producido los anticuerpos mediante cultivos celulares en el laboratorio y afirman que la producción ya puede escalarse para su aplicación clínica. Además, estos anticuerpos tienen un gran potencial para la detección del virus, por lo que pueden ser de gran utilidad para diferentes formatos de test antigénicos del SARS-CoV-2. El CSIC ha patentado esta tecnología y busca empresas interesadas en llevar estos anticuerpos al mercado.
Los investigadores del Centro Nacional de Biotecnología (CNB-CSIC) dirigidos por Luis Ángel Fernández y José María Casasnovas seleccionaron los nanoanticuerpos que mejor se unían a la región de la proteína viral S (spike) del SARS-CoV-2 y que bloqueaban la entrada del virus en la célula. Los ensayos in vitro en células infectadas con SARS-CoV-2 identificaron aquellos con una mayor actividad neutralizante del virus en la plataforma de antivirales del instituto del CSIC, dirigida por los investigadores Urtzi Garaigorta y Pablo Gastaminza.
Investigadores del CSIC, en colaboración con la Fundación Jiménez Díaz, han descubierto que pacientes vacunados e infectados con la variante alfa durante la tercera ola de la pandemia de covid19 (entre enero y marzo de 2021) ya presentaban mutaciones características de las variantes delta plus, iota y omicron. Este estudio interdisciplinar, publicado en Journal of Clinical Investigation, ha analizado en detalle por primera vez en España muestras de hisopos nasofaríngeos correspondientes a pacientes vacunados y posteriormente infectados durante la tercera ola de la pandemia.
Este estudio ha podido desarrollarse gracias al trabajo previo de puesta a punto de una potente metodología de secuenciación ultra profunda que permite detectar secuencias víricas mutadas que se hallan en proporciones muy bajas que no son detectables por las técnicas de secuenciación habituales de poca profundidad. “De cada muestra analizada y de cada trozo del virus analizado obtenemos muchos miles de secuencias. Esto nos permite detectar mutaciones a distintos niveles de frecuencia coexistiendo dentro del paciente infectado”, explica Celia Perales, investigadora del Centro Nacional de Biotecnología (CNB-CSIC) y del Instituto de Investigación Sanitaria de la Fundación Jiménez Díaz.
- El director del Centro Nacional de Biotecnología (CNB-CSIC) pilota un centro que busca vacunas, antivirales y anticuerpos para la covid-19, sin olvidar la investigación del cáncer, los antibióticos y la contaminación
El inmunólogo Mario Mellado, director del Centro Nacional de Biotecnología (CNB-CSIC), lleva en el cargo casi tanto tiempo como el SARS-CoV-2 con nosotros. Él se considera “un tipo positivo” y confía en que podamos acabar con la situación actual. Mellado pone su propio grano de arena al frente de un centro que se ha convertido en referente en la investigación por y para la pandemia. Mientras, continúa con sus propios proyectos científicos centrados en el sistema inmune.
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