The Bacterial Mucosal Immunotherapy MV130 Protects Against SARS-CoV-2 Infection and Improves COVID-19 Vaccines Immunogenicity

COVID-19-specific vaccines are efficient prophylactic weapons against SARS-CoV-2 virus. However, boosting innate responses may represent an innovative way to immediately fight future emerging viral infections or boost vaccines. MV130 is a mucosal immunotherapy, based on a mixture of whole heat-inactivated bacteria, that has shown clinical efficacy against recurrent viral respiratory infections. Herein, we show that the prophylactic intranasal administration of this immunotherapy confers heterologous protection against SARS-CoV-2 infection in susceptible K18-hACE2 mice. Furthermore, in C57BL/6 mice, prophylactic administration of MV130 improves the immunogenicity of two different COVID-19 vaccine formulations targeting the SARS-CoV-2 spike (S) protein, inoculated either intramuscularly or intranasally. Independently of the vaccine candidate and vaccination route used, intranasal prophylaxis with MV130 boosted S-specific responses, including CD8+-T cell activation and the production of S-specific mucosal IgA antibodies. Therefore, the bacterial mucosal immunotherapy MV130 protects against SARS-CoV-2 infection and improves COVID-19 vaccines immunogenicity.CF was supported by AECC Foundation (INVES192DELF) and is currently funded by the Miguel Servet program (ID: CP20/00106) (ISCIII). IH-M receives the support of a fellowship from la Caixa Foundation (ID 100010434, fellowship code: LCF/BQ/IN17/11620074) and from the European Union’s Horizon 2020 research and innovation program under the Marie Skłodowska-Curie grant agreement no. 713673. AJ-C is a postgraduate fellow of the City Council of Madrid at the Residencia de Estudiantes (2020–2021). GD is supported by an European Molecular Biology Organization (EMBO) Long-term fellowship (ALTF 379-2019). This project has received funding from the European Union's Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement No. Project number 892965. OL and JA-C acknowledge Comunidad de Madrid (Tec4Bio-CM, S2018/NMT-4443, FEDER). Work in OL laboratory was funded by CNIO with the support of the projects Y2018/BIO4747 and P2018/NMT4443 from Comunidad de Madrid and co-funded by the European Social Fund and the European Regional Development Fund. The CNIO is supported by the Instituto de Salud Carlos III (ISCIII). Work at CNB and CISA is funded by the Spanish Health Ministry, Instituto de Salud Carlos III (ISCIII), Fondo COVID-19 grant COV20/00151, and Fondo Supera COVID-19 (Crue Universidades-Banco Santander) (to JG-A). Work in the DS laboratory is funded by the CNIC; by the European Research Council (ERC-2016-Consolidator Grant 725091); by Agencia Estatal de Investigación (PID2019-108157RB); by Comunidad de Madrid (B2017/BMD-3733 Immunothercan-CM); by Fondo Solidario Juntos (Banco Santander); by a research agreement with Inmunotek S.L.; and by Fundació La Marató de TV3 (201723). The CNIC is supported by the Instituto de Salud Carlos III (ISCIII), the MICINN, and the Pro CNIC Foundation.Peer reviewe

Trained immunity induction by the inactivated mucosal vaccine MV130 protects against experimental viral respiratory infections.

MV130 is an inactivated polybacterial mucosal vaccine that confers protection to patients against recurrent respiratory infections, including those of viral etiology. However, its mechanism of action remains poorly understood. Here, we find that intranasal prophylaxis with MV130 modulates the lung immune landscape and provides long-term heterologous protection against viral respiratory infections in mice. Intranasal administration of MV130 provides protection against systemic candidiasis in wild-type and Rag1-deficient mice lacking functional lymphocytes, indicative of innate immune-mediated protection. Moreover, pharmacological inhibition of trained immunity with metformin abrogates the protection conferred by MV130 against influenza A virus respiratory infection. MV130 induces reprogramming of both mouse bone marrow progenitor cells and in vitro human monocytes, promoting an enhanced cytokine production that relies on a metabolic shift. Our results unveil that the mucosal administration of a fully inactivated bacterial vaccine provides protection against viral infections by a mechanism associated with the induction of trained immunity.We are grateful to members of the D.S. laboratory for discussions and critical reading of the manuscript. We thank the CNIC facilities and personnel for assistance. P.B. is funded by grant BES-2014-069933 (‘‘Ayudas para Contratos Predoctorales para la Formacio´ n de Doctores 2014’’) from the Spanish Ministry of Economy, Industry and Competitiveness (MINECO). L.C. was a recipient of a European Respiratory Society Fellowship (RESPIRE2-2013- 3708). G.D. is supported by a European Molecular Biology Organization Long-term Fellowship (ALTF 379-2019). This project has received funding from the European Union’s Horizon 2020 research and innovation programme under the Marie Sk1odowska-Curie grant agreement No. 892965. Work in the D.S. laboratory is funded by the CNIC; by the European Research Council (ERC-2016-consolidator grant 725091); by the European Commission (635122-PROCROP H2020); by Ministerio de Ciencia e Innovacio´ n (MICINN), Agencia Estatal de Investigacio´ n (AEI), and Fondo Europeo de Desarrollo Regional (FEDER) (SAF2016-79040-R); by AEI (PID2019-108157RB); by Comunidad de Madrid (B2017/BMD-3733 Immunothercan-CM); by FIS-Instituto de Salud Carlos III, MICINN and FEDER (RD16/0015/0018-REEM); by a collaboration agreement with Inmunotek; by Atresmedia (Constantes y Vitales prize); by Fundacio´ La Marato´ de TV3 (201723); and by Fondo Solidario Juntos (Banco Santander). The CNIC is supported by the Instituto de Salud Carlos III, the MICINN, and the Pro CNIC Foundation.S

Residual pulmonary infiltrates, symptoms and diffusion impairment at one‐year after severe COVID‐19 infection have different associated factors

Menendez R, Mendez R, Latorre A, Gonzalez-Jimenez P, Peces-Barba G, Molina M, et al. Residual pulmonary infiltrates, symptoms and diffusion impairment at 1-year after severe COVID-19 infection have different associated factors. J Intern Med. 2023;00:1-13. Introduction. After severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pneumonia, patients may show lung sequelae on radiology and functional impairment at the 1-year followup. We aimed to describe the persistence of symptoms, radiological alterations, or reduced diffusing capacity of the lung for carbon monoxide (DLCO) at 1-year follow-up in patients from the Spanish Registry RECOVID. Methods. RECOVID collected symptom and radiological and functional lung tests data on hospitalized patients with coronavirus disease 2019 during the acute phase and at the 6- and 12-month follow-up visits. Results. Of the 2500 enrolled survivors (90% admitted to the ward), 1874 had follow-up visits for up to a year. Of these, 42% continued to present with symptoms, 27% had radiological sequelae and 31% had reduced DLCO. Independently associated factors included female sex, asthma and the requirement for invasive or non-invasive mechanical ventilation. Complete radiological resolution was 72.2% at 12 months; associated factors with incomplete recovery were age, male sex, oxygen or respiratory support, corticosteroids and an initial SpO(2)/FiO(2) = 2. Reduced D-LCO was observed in 31% of patients at 12 months; associated factors were older age, female sex, smoking habit, SpO(2)/FiO(2) = 2 and the requirement of respiratory support.At 12 months, a proportion of the asymptomatic patients showed reduced D-LCO (9.5%), radiological findings (25%) or both (11%). Conclusions. The factors associated with symptom persistence, incomplete radiological resolution and D-LCO <80% differed according to age, sex, comorbidities and respiratory support. The burden of symptoms, reduced D-LCO and incomplete radiological resolution were considerable in patients with SARS-CoV-2 pneumonia at the 1-year follow-up after hospitalisation

SDHA gain-of-function engages inflammatory mitochondrial retrograde signaling via KEAP1-Nrf2.

Whether screening the metabolic activity of immune cells facilitates discovery of molecular pathology remains unknown. Here we prospectively screened the extracellular acidification rate as a measure of glycolysis and the oxygen consumption rate as a measure of mitochondrial respiration in B cells from patients with primary antibody deficiency. The highest oxygen consumption rate values were detected in three study participants with persistent polyclonal B cell lymphocytosis (PPBL). Exome sequencing identified germline mutations in SDHA, which encodes succinate dehydrogenase subunit A, in all three patients with PPBL. SDHA gain-of-function led to an accumulation of fumarate in PPBL B cells, which engaged the KEAP1-Nrf2 system to drive the transcription of genes encoding inflammatory cytokines. In a single patient trial, blocking the activity of the cytokine interleukin-6 in vivo prevented systemic inflammation and ameliorated clinical disease. Overall, our study has identified pathological mitochondrial retrograde signaling as a disease modifier in primary antibody deficiency

Aplicaciones electroquímicas al tratamiento de aguas residuales

El presente libro tiene como finalidad compilar numerosas investigaciones en el campo de la tecnología electroquímica y sus aplicaciones ambientales, contando con la colaboración de un gran número de investigadores tanto nacionales como extranjeros, proponiendo con ello una visión amplia dentro de la aplicación de la electroquímica. Los temas que integran esta obra se escogieron cuidadosamente considerando desde los principios básicos de la electroquímica aplicada al tratamiento de aguas residuales hasta los parámetros a considerar durante el diseño, operación y evaluación de dichos sistemas, sin dejar de lado las aplicaciones utilizadas en la actualidad en la industria, la docencia y la investigación. Este libro reúne diversas temáticas por lo que puede considerarse como un compendio de aquellos elementos que el lector requiere para poder tener una visión amplia de las aplicaciones de la electroquímica en el campo del tratamiento de agua residual.En el Capítulo 1 se presenta una primera impresión de los Fundamentes de la Electroquímica Ambiental, en donde los autores explican cómo esta disciplina es una nueva área de la ciencia en donde se emplean conocimientos de Electroquímica, Ingeniería Química y Ciencia de Materiales, así como las aplicaciones específicas para la remediación ambiental. En el Capítulo 2 los autores ofrecen una descripción de los principales parámetros fisicoquímicos y biológicos que se emplean para definir a la calidad del agua. Este capítulo describe en función de qué características físicas, químicas y biológicas se puede evaluar a un agua residual así como también la aplicación de estas características como variables de control de un proceso de tratamiento y también como el empleo de ellas para limitar las concentraciones máximas permisibles de descarga de aguas residuales. El Capítulo 3 se refiere a uno de los procesos más empleados en el tratamiento de agua: la coagulación-floculación. Se aborda desde una óptica teórica hasta la descripción de un ejemplo de aplicación en la industria. Resulta importante incluir este capítulo ya que uno de los métodos más prometedores en la electroquímica ambiental es la electrocoagulación, la cual se narra en el Capítulo 6. Las bases de las celdas de laboratorio y reactores industriales electroquímicos se relatan en el Capítulo 4. En particular, se refieren las implicaciones que tienen las principales características físicas y de diseño de celdas de laboratorio y reactores electroquímicos industriales que permiten obtener transformaciones eficientes gracias a un correcto control del potencial de electrodo en estos sistemas. La implementación de procesos electroquímicos para su aplicación a nivel industrial, requiere del diseño eficiente del dispositivo central: el reactor electroquímico. Por lo que, en el Capítulo 5 se presentan los elementos de análisis de reactores electroquímicos para su diseño y caracterización. El Capítulo 7 describe bajo qué circunstancias se puede llevar a cabo el proceso de electroflotación. Los autores muestran cómo este proceso está influenciado por el pH de la solución acuosa, la densidad de corriente y el tipo de electrodos que se emplean. El lector encontrará en el Capítulo 8 las bases teóricas de uno de los procesos que involucra la química de la reacción de Fenton, así como las aplicaciones ambientales para el tratamiento de soluciones sintéticas y reales con diferentes contaminantes refractarios, tales como plaguicidas, colorantes, productos de cuidado personal, fármacos y residuos químicos industriales. En el Capítulo 9 se presentan algunos conceptos fundamentales sobre la Electrooxidación, también conocida como oxidación electroquímica, la cual está enfocada a realizar la oxidación de contaminantes presentes en aguas residuales sobre la superficie de electrodos. La tecnología para la electrogeneración de peróxido de hidrógeno y su empleo en el tratamiento de agua residual se describe en el Capítulo 10. Uno de los metales pesados que tienen un alto grado de toxicidad en el ambiente es el Cr(VI), el cual no puede ser removido por métodos convencionales por lo que una tecnología que puede emplearse en este tratamiento se relata en el Capítulo 11. En el Capítulo 12 se presentan los avances más recientes cuando se emplean los métodos electroquímicos con algún otro tipo de tratamiento, lo que ha resultado en la obtención de sinergias en los procesos, lo que implica una reducción en los costos de operación. Finalmente, en el Capítulo 13, se presenta el tema de usos y aplicaciones de sensores químicos y electroquímicos para la detección de contaminantes en agua y agua residual

Soy Niña

Este libro pretende contribuir al reencuentro de la educación con esas finalidades que verdaderamente importan a una niña o un niño: ser feliz, jugar, vivir juntos y (no) aprender. Para ello hemos puesto el arte, nuestras experiencias y el saber acumulado al servicio del disfrute, el cuestionamiento, el análisis crítico y la construcción común de un presente deseable. Un texto colaborativo coordinado por Ignacio Calderón Almendros y realizado por alumnado de Educación y Cambio Social en el Grado en Educación Infantil de la Universidad de Málaga

DNGR-1 in dendritic cells limits tissue damage by dampening neutrophil recruitment

Host injury triggers feedback mechanisms that limit tissue damage. Conventional type 1 dendritic cells (cDC1s) express dendritic cell natural killer lectin group receptor-1 (DNGR-1), encoded by the gene Clec9a, which senses tissue damage and favors cross-presentation of dead-cell material to CD8+ T cells. Here we find that DNGR-1 additionally reduces host-damaging inflammatory responses induced by sterile and infectious tissue injury in mice. DNGR-1 deficiency leads to exacerbated caerulein-induced necrotizing pancreatitis and increased pathology during systemic Candida albicans infection without affecting fungal burden. This effect is B and T cell–independent and attributable to increased neutrophilia in DNGR-1–deficient settings. Mechanistically, DNGR-1 engagement activates SHP-1 and inhibits MIP-2 (encoded by Cxcl2) production by cDC1s during Candida infection. This consequently restrains neutrophil recruitment and promotes disease tolerance. Thus, DNGR-1–mediated sensing of injury by cDC1s serves as a rheostat for the control of tissue damage, innate immunity, and immunopathology.C.d.F. is supported by the AECC Foundation as the recipient of an “Ayuda Fundación Científica AECC a personal investigador en cancer.” P.S.-L. is funded by grant BES-2015-072699 from the Spanish Ministerio de Ciencia, Innovación y Universidades (MCIU). M.E. is the recipient of a CNIC International Ph.D. Programme fellowship “la Caixa”-Severo Ochoa OSLC-CNIC-2013-04. S.K.W. is supported by a European Molecular Biology Organization (EMBO) Long-Term Fellowship (grant ALTF 438-2016) and a CNIC-International Postdoctoral Programme Fellowship (grant 17230-2016). Work in the D.S. laboratory is funded by the CNIC and grant SAF2016-79040-R from MCIU, Agencia Estatal de Investigación, and Fondos Europeos de Desarrollo Regional (FEDER); B2017/BMD-3733 Immunothercan-CM from Comunidad de Madrid; RD16/0015/0018-REEM from FIS-Instituto de Salud Carlos III, MICINN, and FEDER; Acteria Foundation; Constantes y Vitales prize (Atresmedia); La Marató de TV3 Foundation (201723); the European Commission (635122-PROCROP H2020); and the European Research Council (ERC-2016-Consolidator Grant 725091). The CNIC is supported by the MCIU and the Pro-CNIC Foundation and is a Severo Ochoa Center of Excellence (SEV-2015-0505).Peer reviewe

Persistent Respiratory Failure and Re-Admission in Patients with Chronic Obstructive Pulmonary Disease Following Hospitalization for COVID-19

Background: Chronic obstructive pulmonary disease (COPD) has been associated with worse clinical evolution/survival during a hospitalization for SARS-CoV2 (COVID-19). The objective of this study was to learn the situation of these patients at discharge as well as the risk of re-admission/mortality in the following 12 months.Methods: We carried out a subanalysis of the RECOVID registry. A multicenter, observational study that retrospectively collected data on severe acute COVID-19 episodes and follow-up visits for up to a year in survivors. The data collection protocol includes general demographic data, smoking, comorbidities, pharmacological treatment, infection severity, complications during hospitalization and required treatment. At discharge, resting oxygen saturation (SpO2), dyspnea according to the mMRC (modified Medical Research Council) scale and long-term oxygen therapy prescription were recorded. The follow-up database included the clinical management visits at 6 and 12 months, where re-admission and mortality were recorded.Results: A total of 2047 patients were included (5.6% had a COPD diagnosis). At discharge, patients with COPD had greater dyspnea and a greater need for prescription home oxygen. After adjusting for age, sex and Charlson comorbidity index, patients with COPD had a greater risk of hospital re-admission due to respiratory causes (HR 2.57 [1.35-4.89], p = 0.004), with no significant differences in survival.Conclusion: Patients with COPD who overcome a serious SARS-CoV2 infection show a worse clinical situation at discharge and a greater risk of re-admission for respiratory causes

Mitochondrial respiratory-chain adaptations in macrophages contribute to antibacterial host defense

Macrophages tightly scale their core metabolism upon activation, but the precise regulation of the mitochondrial electron transport chain (ETC) and its functional implications are currently unknown. Here we show that recognition of live bacteria by macrophages transiently decreased the assembly of ETC complex I (CI) and CI-containing supercomplexes and switched the relative contribution of CI and CII to mitochondrial respiration. This was mediated by the phagosomal NADPH-oxidase and the reactive oxygen species (ROS)-dependent tyrosine-kinase Fgr. It required Toll-like receptor signalling and the NLRP3 inflammasome, which were both connected to bacterial viability-specific immune responses. Inhibition of CII during E. coli infection normalized serum levels of interleukin 1β (IL-1β) and IL-10 to levels found in mice treated with dead bacteria, and impaired control of bacteria. We thus identified ETC adaptations as an early immune-metabolic checkpoint that adjusts innate immune responses to bacterial infection