RESUMEN
SARS-CoV-2 spike (S) protein mediates virus attachment to the cells and fusion between viral and cell membranes. Membrane fusion is driven by mutual interaction between the highly conserved heptad-repeat regions 1 and 2 (HR1 and HR2) of the S2 subunit of the spike. For this reason, these S2 regions are interesting therapeutic targets for COVID-19. Although HR1 and HR2 have been described as transiently exposed during the fusion process, no significant antibody responses against these S2 regions have been reported. Here we designed chimeric proteins that imitate highly stable HR1 helical trimers and strongly bind to HR2. The proteins have broad inhibitory activity against WT B.1 and BA.1 viruses. Sera from COVID-19 convalescent donors showed significant levels of reactive antibodies (IgG and IgA) against the HR1 mimetic proteins, whereas these antibody responses were absent in sera from uninfected donors. Moreover, both inhibitory activity and antigenicity of the proteins correlate positively with their structural stability but not with the number of amino acid changes in their HR1 sequences, indicating a conformational and conserved nature of the involved epitopes. Our results reveal previously undetected spike epitopes that may guide the design of new robust COVID-19 vaccines and therapies.
Asunto(s)
COVID-19 , SARS-CoV-2 , Humanos , Glicoproteína de la Espiga del Coronavirus/química , Proteínas del Envoltorio Viral/química , Epítopos , Vacunas contra la COVID-19 , Glicoproteínas de Membrana/química , Proteínas Recombinantes de Fusión/genéticaRESUMEN
BACKGROUND: Differences in physiology of ARDS have been described between COVID-19 and non-COVID-19 patients. This study aimed to compare initial values and longitudinal changes in respiratory system compliance (CRS), oxygenation parameters and ventilatory ratio (VR) in patients with COVID-19 and non-COVID-19 pulmonary ARDS matched on oxygenation. METHODS: 135 patients with COVID-19 ARDS from two centers were included in a physiological study; 767 non-COVID-19 ARDS from a clinical trial were used for the purpose of at least 1:2 matching. A propensity-matching was based on age, severity score, oxygenation, positive end-expiratory pressure (PEEP) and pulmonary cause of ARDS and allowed to include 112 COVID-19 and 198 non-COVID pulmonary ARDS. RESULTS: The two groups were similar on initial oxygenation. COVID-19 patients had a higher body mass index, higher CRS at day 1 (median [IQR], 35 [28-44] vs 32 [26-38] ml cmH2O-1, p = 0.037). At day 1, CRS was correlated with oxygenation only in non-COVID-19 patients; 61.6% and 68.2% of COVID-19 and non-COVID-19 pulmonary ARDS were still ventilated at day 7 (p = 0.241). Oxygenation became lower in COVID-19 than in non-COVID-19 patients at days 3 and 7, while CRS became similar. VR was lower at day 1 in COVID-19 than in non-COVID-19 patients but increased from day 1 to 7 only in COVID-19 patients. VR was higher at days 1, 3 and 7 in the COVID-19 patients ventilated using heat and moisture exchangers compared to heated humidifiers. After adjustment on PaO2/FiO2, PEEP and humidification device, CRS and VR were found not different between COVID-19 and non-COVID-19 patients at day 7. Day-28 mortality did not differ between COVID-19 and non-COVID-19 patients (25.9% and 23.7%, respectively, p = 0.666). CONCLUSIONS: For a similar initial oxygenation, COVID-19 ARDS initially differs from classical ARDS by a higher CRS, dissociated from oxygenation. CRS become similar for patients remaining on mechanical ventilation during the first week of evolution, but oxygenation becomes lower in COVID-19 patients. TRIAL REGISTRATION: clinicaltrials.gov NCT04385004.
Asunto(s)
COVID-19/terapia , Respiración con Presión Positiva/métodos , Síndrome de Dificultad Respiratoria/terapia , Anciano , Análisis de los Gases de la Sangre , Índice de Masa Corporal , COVID-19/fisiopatología , Femenino , Humanos , Unidades de Cuidados Intensivos , Masculino , Persona de Mediana Edad , Puntaje de Propensión , Intercambio Gaseoso Pulmonar/fisiología , Respiración Artificial/métodos , Síndrome de Dificultad Respiratoria/fisiopatología , Pruebas de Función Respiratoria , Mecánica Respiratoria/fisiología , SARS-CoV-2RESUMEN
CASE PRESENTATION: A 78-year-old woman was admitted to the ED with a 10-day history of diarrhea and recent onset of dry cough, fever, and asthenia. She had a medical history of obesity (BMI 32) and arterial hypertension treated with irbesartan. In the context of a large-scale lockdown in France during the COVID-19 pandemic, she only had physical contact with her husband, who did not report any symptoms. She required mechanical ventilation because of severe hypoxemia within 1 hour after admission to the ED.