RESUMEN
BACKGROUND: Societal measures to contain the spread of COVID-19 (eg, lockdown and contact restrictions) have been associated with decreased health and well-being. A multitude of prepandemic studies identified the beneficial effects of physical exercise on both physical and mental health. OBJECTIVE: We report on the feasibility of a remote physical exercise intervention and its stress-buffering potential in 2 untrained cohorts: a pre-COVID-19 cohort that completed the intervention in 2019 and a lockdown cohort that started the intervention shortly before pandemic-related restrictions were implemented. METHODS: In a randomized controlled trial, participants were assigned to either an intervention group (IG; pre-COVID-19 cohort: n=7 and lockdown cohort: n=9) or a control group (CG; pre-COVID-19 cohort: n=6 and lockdown cohort: n=6). IG participants received weekly individualized training recommendations delivered via web-based support. The intervention period was initially planned for 8 weeks, which was adhered to in the pre-COVID-19 cohort (mean 8.3, SD 0.5 weeks) but was extended to an average of 17.7 (SD 2.0) weeks in the lockdown cohort. Participants' health parameters were assessed before and after the intervention: aerobic capacity was measured as peak oxygen uptake (VO2peak) via cardiopulmonary exercise testing. Depressive symptoms were scored via the depression subscale of the Brief Symptom Inventory-18. RESULTS: Dropout rates were low in both cohorts in the IG (pre-COVID-19 cohort: n=0, 0% and lockdown cohort: n=2, 16.7%) and the CG (pre-COVID-19 cohort: n=0, 0% and lockdown cohort: n=2, 20%). The mean adherence to the training sessions of the IG for both cohorts was 84% (pre-COVID-19 cohort: SD 5.5% and lockdown cohort: SD 11.6%). Aligned rank transform ANOVAs in the lockdown cohort indicated deterioration of VO2peak and depressive symptoms from before to after the intervention in the CG but no longitudinal changes in the IG. Analyses in the pre-COVID-19 cohort revealed significant increases in VO2peak for the IG compared to the CG (P=.04) but no intervention effects on depressive symptoms. CONCLUSIONS: With low dropout rates and high adherence, the remote intervention was feasible for healthy adults under regular conditions and in the face of pandemic-related stressors. Moreover, our results hint at a stress-buffering effect as well as a buffering of a lockdown-induced deconditioning of remote physical exercise interventions in the pandemic scenario, which can be used in future studies to overcome equally stressful periods of life. However, due to limited statistical power, these findings should be replicated in similar scenarios. TRIAL REGISTRATION: German Clinical Trials Register DRKS00018078; https://drks.de/search/en/trial/DRKS00018078.
Asunto(s)
COVID-19 , Humanos , COVID-19/prevención & control , COVID-19/epidemiología , Masculino , Femenino , Adulto , Pandemias , Ejercicio Físico , Persona de Mediana Edad , Terapia por Ejercicio/métodos , SARS-CoV-2 , Estudios de Factibilidad , Estudios de Cohortes , DepresiónRESUMEN
For the control of immunity in COVID-19 survivors and vaccinated subjects, there is an urgent need for reliable and rapid serological assays. Based on samples from 63 COVID-19 survivors up to 7 months after symptom onset, and on 50 serum samples taken before the beginning of the pandemic, we compared the performances of three commercial immunoassays for the detection of SARS-CoV-2 IgA and IgG antibodies (Euroimmun SARS-COV-2 IgA/IgG, Mikrogen recomWell SARS-CoV-2 IgA/IgG, and Serion ELISA agile SARS-CoV-2 IgA/IgG) and three rapid lateral flow (immunochromatographic) tests (Abbott PanBio COVID-19 IgG/IgM, Nadal COVID-19 IgG/IgM, and Cleartest Corona 2019-nCOV IgG/IgM) with a 50% plaque-reduction neutralization test (PRNT50) representing the gold standard. Fifty-seven out of 63 PCR-confirmed COVID-19 patients (90%) showed neutralizing antibodies. The sensitivity of the seven assays ranged from 7.0% to 98.3%, and the specificity ranged from 86.0% to 100.0%. Only one commercial immunoassay showed a sensitivity and specificity of greater than 98%.
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COVID-19 , SARS-CoV-2 , Anticuerpos Antivirales , Humanos , Inmunoensayo , Inmunoglobulina M , Pandemias , Sensibilidad y EspecificidadRESUMEN
Immune checkpoint blockade therapy is beneficial and even curative for some cancer patients. However, the majority don't respond to immune therapy. Across different tumor types, pre-existing T cell infiltrates predict response to checkpoint-based immunotherapy. Based on in vitro pharmacological studies, mouse models and analyses of human melanoma patients, we show that the cytokine GDF-15 impairs LFA-1/ß2-integrin-mediated adhesion of T cells to activated endothelial cells, which is a pre-requisite of T cell extravasation. In melanoma patients, GDF-15 serum levels strongly correlate with failure of PD-1-based immune checkpoint blockade therapy. Neutralization of GDF-15 improves both T cell trafficking and therapy efficiency in murine tumor models. Thus GDF-15, beside its known role in cancer-related anorexia and cachexia, emerges as a regulator of T cell extravasation into the tumor microenvironment, which provides an even stronger rationale for therapeutic anti-GDF-15 antibody development.
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Melanoma , Linfocitos T , Humanos , Ratones , Animales , Linfocitos T/patología , Antígeno-1 Asociado a Función de Linfocito , Células Endoteliales/patología , Inhibidores de Puntos de Control Inmunológico/farmacología , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Melanoma/patología , Inmunoterapia , Microambiente TumoralRESUMEN
BACKGROUND: The viral load and tissue distribution of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) remain important questions. The current study investigated SARS-CoV-2 viral load, biodistribution and anti-SARS-CoV-2 antibody formation in patients suffering from severe corona virus disease 2019 (COVID-19) induced acute respiratory distress syndrome (ARDS). METHODS: This is a retrospective single-center study in 23 patients with COVID-19-induced ARDS. Data were collected within routine intensive care. SARS-CoV-2 viral load was assessed via reverse transcription quantitative polymerase chain reaction (RT-qPCR). Overall, 478 virology samples were taken. Anti-SARS-CoV-2-Spike-receptor binding domain (RBD) antibody detection of blood samples was performed with an enzyme-linked immunosorbent assay. RESULTS: Most patients (91%) suffered from severe ARDS during ICU treatment with a 30-day mortality of 30%. None of the patients received antiviral treatment. Tracheal aspirates tested positive for SARS-CoV-2 in 100% of the cases, oropharyngeal swabs only in 77%. Blood samples were positive in 26% of the patients. No difference of viral load was found in tracheal or blood samples with regard to 30-day survival or disease severity. SARS-CoV-2 was never found in dialysate. Serologic testing revealed significantly lower concentrations of SARS-CoV-2 neutralizing IgM and IgA antibodies in survivors compared to non-survivors (p = 0.009). CONCLUSIONS: COVID-19 induced ARDS is accompanied by a high viral load of SARS-CoV-2 in tracheal aspirates, which remained detectable in the majority throughout intensive care treatment. Remarkably, SARS-CoV-2 RNA was never detected in dialysate even in patients with RNAemia. Viral load or the buildup of neutralizing antibodies was not associated with 30-day survival or disease severity.
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Anticuerpos Neutralizantes/inmunología , Anticuerpos Antivirales/inmunología , Prueba Serológica para COVID-19/métodos , COVID-19/complicaciones , COVID-19/inmunología , Síndrome de Dificultad Respiratoria/etiología , Síndrome de Dificultad Respiratoria/inmunología , SARS-CoV-2/inmunología , Anciano , Anticuerpos Neutralizantes/sangre , Anticuerpos Antivirales/sangre , COVID-19/epidemiología , COVID-19/virología , Ensayo de Inmunoadsorción Enzimática , Femenino , Alemania/epidemiología , Humanos , Inmunoglobulina A/sangre , Inmunoglobulina A/inmunología , Inmunoglobulina G/sangre , Inmunoglobulina G/inmunología , Inmunoglobulina M/sangre , Inmunoglobulina M/inmunología , Masculino , Persona de Mediana Edad , Dominios Proteicos/inmunología , ARN Viral/genética , Síndrome de Dificultad Respiratoria/virología , Estudios Retrospectivos , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , SARS-CoV-2/genética , Glicoproteína de la Espiga del Coronavirus/inmunología , Carga Viral/genéticaRESUMEN
Objectives: The severity of Coronavirus Disease 2019 (COVID-19) is largely determined by the immune response. First studies indicate altered lymphocyte counts and function. However, interactions of pro- and anti-inflammatory mechanisms remain elusive. In the current study we characterized the immune responses in patients suffering from severe COVID-19-induced acute respiratory distress syndrome (ARDS). Methods: This was a single-center retrospective study in patients admitted to the intensive care unit (ICU) with confirmed COVID-19 between March 14th and May 28th 2020 (n = 39). Longitudinal data were collected within routine clinical care, including flow-cytometry of lymphocyte subsets, cytokine analysis and growth differentiation factor 15 (GDF-15). Antibody responses against the receptor binding domain (RBD) of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Spike protein were analyzed. Results: All patients suffered from severe ARDS, 30.8% died. Interleukin (IL)-6 was massively elevated at every time-point. The anti-inflammatory cytokine IL-10 was concomitantly upregulated with IL-6. The cellular response was characterized by lymphocytopenia with low counts of CD8+ T cells, natural killer (NK) and naïve T helper cells. CD8+ T and NK cells recovered after 8 to 14 days. The B cell system was largely unimpeded. This coincided with a slight increase in anti-SARS-CoV-2-Spike-RBD immunoglobulin (Ig) G and a decrease in anti-SARS-CoV-2-Spike-RBD IgM. GDF-15 levels were elevated throughout ICU treatment. Conclusions: Massively elevated levels of IL-6 and a delayed cytotoxic immune defense characterized severe COVID-19-induced ARDS. The B cell response and antibody production were largely unimpeded. No obvious imbalance of pro- and anti-inflammatory mechanisms was observed, with elevated GDF-15 levels suggesting increased tissue resilience.
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Betacoronavirus/inmunología , Infecciones por Coronavirus/patología , Síndrome de Liberación de Citoquinas/patología , Neumonía Viral/patología , Síndrome Respiratorio Agudo Grave/patología , Anciano , Anticuerpos Antivirales/sangre , Anticuerpos Antivirales/inmunología , COVID-19 , Infecciones por Coronavirus/inmunología , Síndrome de Liberación de Citoquinas/inmunología , Femenino , Factor 15 de Diferenciación de Crecimiento/sangre , Humanos , Inmunoglobulina G/sangre , Inmunoglobulina G/inmunología , Unidades de Cuidados Intensivos , Interleucina-10/sangre , Interleucina-6/sangre , Estudios Longitudinales , Linfopenia , Masculino , Persona de Mediana Edad , Pandemias , Proyectos Piloto , Neumonía Viral/inmunología , Estudios Retrospectivos , SARS-CoV-2 , Síndrome Respiratorio Agudo Grave/inmunología , Glicoproteína de la Espiga del Coronavirus/inmunologíaRESUMEN
Asymptomatic infections with polyomaviruses in humans are common, but these small viruses can cause severe diseases in immunocompromised hosts. New Jersey polyomavirus (NJPyV) was identified via a muscle biopsy in an organ transplant recipient with systemic vasculitis, myositis, and retinal blindness, and human polyomavirus 12 (HPyV12) was detected in human liver tissue. The evolutionary origins and potential diseases are not well understood for either virus. In order to define their receptor engagement strategies, we first used nuclear magnetic resonance (NMR) spectroscopy to establish that the major capsid proteins (VP1) of both viruses bind to sialic acid in solution. We then solved crystal structures of NJPyV and HPyV12 VP1 alone and in complex with sialylated glycans. NJPyV employs a novel binding site for a α2,3-linked sialic acid, whereas HPyV12 engages terminal α2,3- or α2,6-linked sialic acids in an exposed site similar to that found in Trichodysplasia spinulosa-associated polyomavirus (TSPyV). Gangliosides or glycoproteins, featuring in mammals usually terminal sialic acids, are therefore receptor candidates for both viruses. Structural analyses show that the sialic acid-binding site of NJPyV is conserved in chimpanzee polyomavirus (ChPyV) and that the sialic acid-binding site of HPyV12 is widely used across the entire polyomavirus family, including mammalian and avian polyomaviruses. A comparison with other polyomavirus-receptor complex structures shows that their capsids have evolved to generate several physically distinct virus-specific receptor-binding sites that can all specifically engage sialylated glycans through a limited number of contacts. Small changes in each site may have enabled host-switching events during the evolution of polyomaviruses.IMPORTANCE Virus attachment to cell surface receptors is critical for productive infection. In this study, we have used a structure-based approach to investigate the cell surface recognition event for New Jersey polyomavirus (NJPyV) and human polyomavirus 12 (HPyV12). These viruses belong to the polyomavirus family, whose members target different tissues and hosts, including mammals, birds, fish, and invertebrates. Polyomaviruses are nonenveloped viruses, and the receptor-binding site is located in their capsid protein VP1. The NJPyV capsid features a novel sialic acid-binding site that is shifted in comparison to other structurally characterized polyomaviruses but shared with a closely related simian virus. In contrast, HPyV12 VP1 engages terminal sialic acids in a manner similar to the human Trichodysplasia spinulosa-associated polyomavirus. Our structure-based phylogenetic analysis highlights that even distantly related avian polyomaviruses possess the same exposed sialic acid-binding site. These findings complement phylogenetic models of host-virus codivergence and may also reflect past host-switching events.
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Proteínas de la Cápside/química , Poliomavirus/genética , Polisacáridos/química , Receptores Virales/química , Sitios de Unión , Proteínas de la Cápside/genética , Cristalografía , Evolución Molecular , Humanos , Ácido N-Acetilneuramínico/metabolismo , Filogenia , Poliomavirus/química , Poliomavirus/clasificación , Infecciones por Polyomavirus/virología , Unión Proteica , Conformación Proteica , Receptores Virales/genética , Acoplamiento ViralRESUMEN
Glioblastoma is an aggressive primary brain tumor with bad prognosis. On the other hand, oncolytic measles virus (MeV) therapy is an experimental glioma treatment strategy with clinical safety and first evidence of anti-tumoral efficacy. Therefore, we investigated the combination of MeV with conventional therapies by cytotoxic survival assays in long-term glioma cell lines LN229, LNZ308, and glioma stem-like GS8 cells, as well as the basal viral infectivity in primary glioblastoma cultures T81/16, T1094/17, and T708/16. We employed Chou-Talalay analysis to identify the synergistic treatment sequence chemotherapy, virotherapy, and finally radiotherapy (CT-VT-RT). RNA sequencing and immunopeptidome analyses were used to delineate treatment-induced molecular and immunological profiles. CT-VT-RT displayed synergistic anti-glioma activity and initiated a type 1 interferon response, along with canonical Janus kinase-signal transducers and activators of transcription (JAK-STAT) signaling, and downstream interferon-stimulated genes were induced, resulting in apoptotic cascades. Furthermore, antigen presentation along with immunostimulatory chemokines was increased in CT-VT-RT-treated glioma cells, indicating a treatment-induced pro-inflammatory phenotype. We identified novel treatment-induced viral and tumor-associated peptides through HLA ligandome analysis. Our data delineate an actionable treatment-induced molecular and immunological signature of CT-VT-RT, and they could be exploited for the design of novel tailored treatment strategies involving virotherapy and immunotherapy.