RESUMEN
To discover new drugs to combat COVID-19, an understanding of the molecular basis of SARS-CoV-2 infection is urgently needed. Here, for the first time, we report the crucial role of cathepsin L (CTSL) in patients with COVID-19. The circulating level of CTSL was elevated after SARS-CoV-2 infection and was positively correlated with disease course and severity. Correspondingly, SARS-CoV-2 pseudovirus infection increased CTSL expression in human cells in vitro and human ACE2 transgenic mice in vivo, while CTSL overexpression, in turn, enhanced pseudovirus infection in human cells. CTSL functionally cleaved the SARS-CoV-2 spike protein and enhanced virus entry, as evidenced by CTSL overexpression and knockdown in vitro and application of CTSL inhibitor drugs in vivo. Furthermore, amantadine, a licensed anti-influenza drug, significantly inhibited CTSL activity after SARS-CoV-2 pseudovirus infection and prevented infection both in vitro and in vivo. Therefore, CTSL is a promising target for new anti-COVID-19 drug development.
Asunto(s)
Antivirales/farmacología , COVID-19/metabolismo , Catepsina L , Inhibidores de Cisteína Proteinasa/farmacología , Desarrollo de Medicamentos , SARS-CoV-2/metabolismo , Glicoproteína de la Espiga del Coronavirus/metabolismo , Internalización del Virus/efectos de los fármacos , Adolescente , Adulto , Anciano , Animales , COVID-19/genética , Catepsina L/antagonistas & inhibidores , Catepsina L/genética , Catepsina L/metabolismo , Femenino , Humanos , Masculino , Ratones , Ratones Transgénicos , Persona de Mediana Edad , SARS-CoV-2/genética , Glicoproteína de la Espiga del Coronavirus/genética , Tratamiento Farmacológico de COVID-19RESUMEN
BACKGROUND: There is still no clinical evidence available to support or to oppose corticosteroid treatment for coronavirus disease 2019 (COVID-19) pneumonia. OBJECTIVE: To investigate the efficacy and safety of corticosteroid given to the hospitalized patients with COVID-19 pneumonia. METHODS: This was a prospective, multicenter, single-blind, randomized control trial. Adult patients with COVID-19 pneumonia who were admitted to the general ward were randomly assigned to either receive methylprednisolone or not for 7 days. The primary end point was the incidence of clinical deterioration 14 days after randomization. RESULTS: We terminated this trial early because the number of patients with COVID-19 pneumonia in all the centers decreased in late March. Finally, a total of 86 COVID-19 patients underwent randomization. There was no difference of the incidence of clinical deterioration between the methylprednisolone group and control group (4.8 vs. 4.8%, p = 1.000). The duration of throat viral RNA detectability in the methylprednisolone group was 11 days (interquartile range, 6-16 days), which was significantly longer than that in the control group (8 days [2-12 days], p = 0.030). There were no significant differences between the 2 groups in other secondary outcomes. Mass cytometry discovered CD3+ T cells, CD8+ T cells, and NK cells in the methylprednisolone group which were significantly lower than those in the control group after randomization (p < 0.05). CONCLUSIONS: From this prematurely closed trial, we found that the short-term early use of corticosteroid could suppress the immune cells, which may prolong severe acute respiratory syndrome coronavirus 2 shedding in patients with COVID-19 pneumonia. TRIAL REGISTRATION: ClinicalTrials.gov, NCT04273321.
Asunto(s)
Tratamiento Farmacológico de COVID-19 , Glucocorticoides/uso terapéutico , Hospitalización , Metilprednisolona/uso terapéutico , Faringe/química , ARN Viral/aislamiento & purificación , Esparcimiento de Virus , Adulto , Anciano , Antibacterianos/uso terapéutico , Antivirales/uso terapéutico , Complejo CD3 , Linfocitos T CD8-positivos , COVID-19/sangre , COVID-19/terapia , COVID-19/transmisión , Prueba de Ácido Nucleico para COVID-19 , Progresión de la Enfermedad , Intervención Médica Temprana , Oxigenación por Membrana Extracorpórea , Femenino , Humanos , Células Asesinas Naturales , Recuento de Linfocitos , Masculino , Persona de Mediana Edad , Terapia por Inhalación de Oxígeno , Habitaciones de Pacientes , Faringe/virología , Modelos de Riesgos Proporcionales , Respiración Artificial , SARS-CoV-2 , Método Simple Ciego , Subgrupos de Linfocitos T , Linfocitos T , Factores de Tiempo , Resultado del TratamientoRESUMEN
Cytokine storm resulting from SARS-CoV-2 infection is one of the leading causes of acute respiratory distress syndrome (ARDS) and lung fibrosis. We investigated the effect of inflammatory molecules to identify any marker that is related to lung fibrosis in coronavirus disease 2019 (COVID-19). Seventy-six COVID-19 patients who were admitted to Youan Hospital between January 21 and March 20, 2020 and recovered were recruited for this study. Pulmonary fibrosis, represented as fibrotic volume on chest CT images, was computed by an artificial intelligence (AI)-assisted program. Plasma samples were collected from the participants shortly after admission, to measure the basal inflammatory molecules levels. At discharge, fibrosis was present in 46 (60.5%) patients whose plasma interferon-γ (IFN-γ) levels were twofold lower than those without fibrosis (p > 0.05). The multivariate-adjusted logistic regression analysis demonstrated the inverse association risk of having lung fibrosis and basal circulating IFN-γ levels with an estimate of 0.43 (p = 0.02). Per the 1-SD increase of basal IFN-γ level in circulation, the fibrosis volume decreased by 0.070% (p = 0.04) at the discharge of participants. The basal circulating IFN-γ levels were comparable with c-reactive protein in the discrimination of the occurrence of lung fibrosis among COVID-19 patients at discharge, unlike circulating IL-6 levels. In conclusion, these data indicate that decreased circulating IFN-γ is a risk factor of lung fibrosis in COVID-19.