Puesta a punto de un modelo de rinosinusitis crónica asociada a poliposis nasal monitorizado mediante técnicas de análisis de imágenes micro CT-PET

[ES] La rinosinusitis es un proceso inflamatorio que afecta a la cavidad y senos nasales obstruyéndolos. Se denomina rinosinusitis crónica (RSC) cuando la enfermedad perdura más allá de las 12 semanas. La RSC puede verse asociada a pólipos nasales (RSC-PN) o no (RSC-SP), siendo la poliposis nasal una enfermedad con una morbilidad muy alta caracterizada por la existencia de estructuras neoplásicas que provocan la obstrucción de las vías aéreas. Los pólipos están formados por el infiltrado de células inflamatorias. Los tratamientos actuales no son efectivos en gran parte de los pacientes, teniendo que someterse a repetidas intervenciones quirúrgicas siendo necesario el desarrollo de nuevos fármacos más efectivos. La investigación en modelos animales se encuentra actualmente limitada por la inexistencia de métodos diagnósticos y de seguimiento de la enfermedad que no impliquen sacrificar los animales. Este estudio evalúa la eficacia del análisis de imágenes realizado empleando las técnicas de tomografía computarizada (CT) y tomografía por emisión de positrones (PET) en el diagnóstico de la RSC-PN y el seguimiento se su evolución sobre un modelo animal de la enfermedad desarrollado mediante instilaciones con ovoalbúmina como sensibilizador y enterotoxina B de Staphylococcus aureus como agente inductor de la misma. La técnica CT se basa en la capacidad de penetración de los rayos X para detectar cambios en la densidad de los tejidos, mientras que la técnica PET tiene la capacidad de calcular la captación de la glucosa mediante un radiomarcador homólogo. Ambas propiedades se ven alteradas en el transcurso de un proceso inflamatorio severo. Los resultados obtenidos avalan la validez de estas técnicas para determinar la existencia de un proceso inflamatorio y estructuras neoplásicas en el modelo de la enfermedad desarrollado. Los resultados obtenidos por las técnicas de análisis histológico post-mortem corroboraron esta conclusión, permitiendo afirmar que la monitorización mediante las técnicas de CT y PET es un método efectivo para la determinación y seguimiento de la evolución de la RSC-PN en los modelos animales in vivo y posibilitando la investigación de tratamientos eficaces de la enfermedad.[EN] Rhinosinusitis is an inflammatory and obstructive process that affects the nasal cavity and sinuses. It’s called chronic rhinosinusitis (CRS) when the disease lasts beyond 12 weeks. CRS can be associated with nasal polyps (CRSwNP) or not (CRSsNP). CRSwNP is a disease with high morbidity characterized by the existence of neoplastic structures that cause airways obstruction. Polyps are formed by the infiltration of inflammatory cells. Current treatments are ineffective in many of the patients having to undergo repeated surgical procedures therefore the developing of new and more effective drugs are necessary. Research in animal models is currently limited by the lack of diagnostic and disease monitoring methods without sacrificing animals. This study evaluates the effectiveness of the analysis of images carried out by computed tomography (CT) and positron emission tomography (PET) techniques in the diagnosis and monitoring of CSR-PN in an animal model. This animal model of the disease was obtained by an instillations protocol with ovalbumin as a sensitizer and Staphylococcus aureus enterotoxin B as inducing agent. CT technique is based on the ability of penetration of x-rays for detecting changes in tissue density. PET technique has the ability to calculate the glucose uptake by a homologous radiolabel. Tissue density and glucose uptake are properties that are altered in the course of a severe inflammatory process. The results obtained confirm the validity of these techniques to determine the existence of an inflammatory process and neoplastic structures in the developed disease model. The results obtained by the histological post-mortem analysis techniques corroborated this conclusion. It can be said that the use of CT and PET techniques is an effective method for determining and monitoring the evolution of CSRwPN in animal models in vivo, allowing the research into effective treatments for the disease.Rius Rocabert, S. (2014). Puesta a punto de un modelo de rinosinusitis crónica asociada a poliposis nasal monitorizado mediante técnicas de análisis de imágenes micro CT-PET. http://hdl.handle.net/10251/46181.Archivo delegad

Oncolytic Virotherapy in Glioma Tumors.

Glioma tumors are one of the most devastating cancer types. Glioblastoma is the most advanced stage with the worst prognosis. Current therapies are still unable to provide an e ective cure. Recent advances in oncolytic immunotherapy have generated great expectations in the cancer therapy field. The use of oncolytic viruses (OVs) in cancer treatment is one such immune-related therapeutic alternative. OVs have a double oncolytic action by both directly destroying the cancer cells and stimulating a tumor specific immune response to return the ability of tumors to escape the control of the immune system. OVs are one promising alternative to conventional therapies in glioma tumor treatment. Several clinical trials have proven the feasibility of using some viruses to specifically infect tumors, eluding undesired toxic e ects in the patient. Here, we revisited the literature to describe the main OVs proposed up to the present moment as therapeutic alternatives in order to destroy glioma cells in vitro and trigger tumor destruction in vivo. Oncolytic viruses were divided with respect to the genome in DNA and RNA viruses. Here, we highlight the results obtained in various clinical trials, which are exploring the use of these agents as an alternative where other approaches provide limited hope.post-print832 K

The Many Ways to Deal with STING

The stimulator of interferon genes (STING) is an adaptor protein involved in the activation of IFN-β and many other genes associated with the immune response activation in vertebrates. STING induction has gained attention from different angles such as the potential to trigger an early immune response against different signs of infection and cell damage, or to be used as an adjuvant in cancer immune treatments. Pharmacological control of aberrant STING activation can be used to mitigate the pathology of some autoimmune diseases. The STING structure has a well-defined ligand binding site that can harbor natural ligands such as specific purine cyclic di-nucleotides (CDN). In addition to a canonical stimulation by CDNs, other non-canonical stimuli have also been described, whose exact mechanism has not been well defined. Understanding the molecular insights underlying the activation of STING is important to realize the different angles that need to be considered when designing new STING-binding molecules as therapeutic drugs since STING acts as a versatile platform for immune modulators. This review analyzes the different determinants of STING regulation from the structural, molecular, and cell biology points of view.This work was supported by Ministerio de Ciencia e Innovación PID2019-105761RBI00/AEI/10.13039/501100011033. J.A-H. was supported by the PFIS fellowship co-funded by the FEDER/FSE and the ISCIII.S

Newcastle Disease Virus (NDV) Oncolytic Activity in Human Glioma Tumors Is Dependent on CDKN2A-Type I IFN Gene Cluster Codeletion.

Glioblastoma (GBM) is the most aggressive and frequent primary brain tumor in adults with a median overall survival of 15 months. Tumor recurrence and poor prognosis are related to cancer stem cells (CSCs), which drive resistance to therapies. A common characteristic in GBM is CDKN2A gene loss, located close to the cluster of type I IFN genes at Ch9p21. Newcastle disease virus (NDV) is an avian paramyxovirus with oncolytic and immunostimulatory properties that has been proposed for the treatment of GBM. We have analyzed the CDKN2A-IFN I gene cluster in 1018 glioma tumors and evaluated the NDV oncolytic e ect in six GBM CSCs ex vivo and in a mouse model. Our results indicate that more than 50% of GBM patients have some IFN deletion. Moreover, GBM susceptibility to NDV is dependent on the loss of the type I IFN. Infection of GBM with an NDV-expressing influenza virus NS1 protein can overcome the resistance to oncolysis by NDV of type I-competent cells. These results highlight the potential of using NDV vectors in antitumor therapies.post-print3309 K

Broad virus inactivation using inorganic micro/nano-particulate materials

Inorganic materials can provide a set of tools to decontaminate solid, liquid or air containing viral particles. The use of disinfectants can be limited or not practical in scenarios where continuous cleaning is not feasible. Physicochemical differences between viruses raise the need for effective formulations for all kind of viruses. In the present work we describe two types of antimicrobial inorganic materials: i) a novel soda-lime glass (G3), and ii) kaolin containing metals nanoparticles (Ag or CuO), as materials to disable virus infectivity. Strong antiviral properties can be observed in G3 glass, and kaolin-containing nanoparticle materials showing a reduction of viral infectivity close to 99%. in the first 10 ​min of contact of vesicular stomatitis virus (VSV). A potent virucidal activity is also present in G3 and kaolin containing Ag or CuO nanoparticles against all kinds of viruses tested, reducing more than 99% the amount of HSV-1, Adenovirus, VSV, Influenza virus and SARS-CoV-2 exposed to them. Virucidal properties could be explained by a direct interaction of materials with viruses as well as inactivation by the presence of virucidal elements in the material lixiviates. Kaolin-based materials guarantee a controlled release of active nanoparticles with antiviral activity. Current coronavirus crisis highlights the need for new strategies to remove viruses from contaminated areas. We propose these low-cost inorganic materials as useful disinfecting antivirals in the actual or future pandemic threats.This research was performed with support from The Spanish National Research Council (CSIC) (Project No 202060E109). M.F. is grateful to the Comunidad Autonoma de Madrid for research project No. 2017-T1/BIO-4992 (“Atracción de Talento” Action) cofunded by Universidad Complutense de Madrid. This publication was also supported by the European Virus Archive GLOBAL (EVA-GLOBAL) project that has received funding from the European Union's Horizon 2020 research and innovation program ​under grant agreement 871029. S. R.-R. was supported by the the FPI fellowship funded by Universidad San Pablo CEU. J.A-H. was supported by the PFIS fellowship co-funded by the FEDER/FSE and the ISCIII

Sendai Virus, a Strong Inducer of Anti-Lentiviral State in Ovine Cells

Small ruminant lentiviruses (SRLVs) are widely spread in the ovine and caprine populations, causing an incurable disease affecting animal health and production. Vaccine development is hindered owing to the high genetic heterogeneity of lentiviruses and the selection of T-cell and antibody escape mutants, requiring antigen delivery optimization. Sendai virus (SeV) is a respiratory paramyxovirus in mice that has been recognized as a potent inducer of innate immune responses in several species, including mouse and human. The aim of this study was to stimulate an innate antiviral response in ovine cells and evaluate the potential inhibitory effect upon small ruminant lentivirus (SRLV) infections. Ovine alveolar macrophages (AMs), blood-derived macrophages (BDMs), and skin fibroblasts (OSFs) were stimulated through infection with SeV encoding green fluorescent protein (GFP). SeV efficiently infected ovine cells, inducing an antiviral state in AM from SRLV naturally-infected animals, as well as in in vitro SRLV-infected BDM and OSF from non-infected animals. Supernatants from SeV-infected AM induced an antiviral state when transferred to fresh cells challenged with SRLV. Similar to SRLV, infectivity of an HIV-1-GFP lentiviral vector was also restricted in ovine cells infected with SeV. In myeloid cells, an M1-like proinflammatory polarization was observed together with an APOBEC3Z1 induction, among other lentiviral restriction factors. Our observations may boost new approximations in ameliorating the SRLV burden by stimulation of the innate immune response using SeV-based vaccine vectors.This research was funded by Spanish Ministry of Science, Innovation, and Universities, grant number RTI2018-096172-B-C31; Consejo Superior de Investigaciones Científicas, i-Coop and EMHE Program; and by Government of Navarra (CONECTIM) and by Project NIETO-CM B2017/BMD-3731 to E.N.-V. “The APC was funded by the CSIC Open Access Publication Support Initiative through its Unit of Information Resources for Research (URICI).” L.d.P.-M. and I.E. were funded by Universidad Pública de Navarra. S.R.-R. was funded by an FPI fellowship granted by Universidad San Pablo CEU. R.R. was supported by the Spanish Ministry of Science and Innovation “Ramón y Cajal” contract.Peer reviewe

Influenza A virus infection alters the resistance profile of gut microbiota to clinically relevant antibiotics

Influenza virus infection affects both lung and intestinal bacterial community composition. Most of the published analyses focus on the characterization of the microbiota composition changes. Here we assess functional alterations of gut microbiota such as nutrient and antibiotic resistance changes during an acute respiratory tract infection. Upon influenza A virus (IAV) infection, cecal microbiota drops accompanied by a decrease in the ability to metabolize some common nutrients under aerobic conditions. At the same time, the cecal community presents an increase in resistance against clinically relevant antibiotics, particularly cephalosporins. Functional characterization of complex communities presents an additional and necessary element of analysis that nowadays is mainly limited to taxonomic description. The consequences of these functional alterations could affect treatment strategies, especially in multimicrobial infections

Determinants of poor clinical outcome in patients with influenza pneumonia: A systematic review and meta-analysis

Background: The clinical burden of influenza is increasing worldwide. Aging, immunosuppression, and underlying respiratory illness are determinants of poor clinical outcomes, including greater mortality. Bacterial infections seem to be the main reason. Updated information on the role of bacterial infection as the cause of complications would be of value in improving the prognosis of patients with influenza. Methods: A systematic review and meta-analysis were performed by using the PubMed repository using keywords like: Influenza, H1N1, Streptococcus pneumoniae, bacterial coinfection, secondary coinfection, bacterial complications in pneumonia, and seasonal influenza. Only articles written in English were included in publications from 2010 to 2020. The analyses were conducted following the preferred reporting items for systematic review and meta-analyses guidelines. The results were independently validated using a TrinetX database cohort of roughly 4 million patients. Results: We included 135 studies that contained data from 48,259 patients hospitalized with influenza of any age. Bacterial infections were diagnosed in 5391 (11.2%). Streptococcus pneumoniae (30.7%) and Staphylococcus aureus (30.4%) were the most frequent microorganisms, followed by Haemophilus influenzae (7.1%) and Pseudomonas aeruginosa (5.9%). The random-effects model of the meta-analysis indicated that bacterial infections posed a 3.4-fold increased risk of death compared with influenza infection alone. Unexpectedly, asthma was protective (odds ratio 0.8). Conclusion: Bacterial infections diagnosed in 11.2% of patients with influenza increase 3.4-fold the mortality risk. S. pneumoniae, S. aureus, H. influenzae, and P. aeruginosa account for nearly 75% of the cases. Earlier diagnosis and use of antibiotics should improve outcomes in this population

Repurposing the yellow fever vaccine for intratumoral immunotherapy

Abstract Live 17D is widely used as a prophylactic vaccine strain for yellow fever virus that induces potent neutralizing humoral and cellular immunity against the wild‐type pathogen. 17D replicates and kills mouse and human tumor cell lines but not non‐transformed human cells. Intratumoral injections with viable 17D markedly delay transplanted tumor progression in a CD8 T‐cell‐dependent manner. In mice bearing bilateral tumors in which only one is intratumorally injected, contralateral therapeutic effects are observed consistent with more prominent CD8 T‐cell infiltrates and a treatment‐related reduction of Tregs. Additive efficacy effects were observed upon co‐treatment with intratumoral 17D and systemic anti‐CD137 and anti‐PD‐1 immunostimulatory monoclonal antibodies. Importantly, when mice were preimmunized with 17D, intratumoral 17D treatment achieved better local and distant antitumor immunity. Such beneficial effects of prevaccination are in part explained by the potentiation of CD4 and CD8 T‐cell infiltration in the treated tumor. The repurposed use of a GMP‐grade vaccine to be given via the intratumoral route in prevaccinated patients constitutes a clinically feasible and safe immunotherapy approach