SARS-CoV-2 infects adipose tissue in a fat depot- and viral lineage-dependent manner.

Visceral adiposity is a risk factor for severe COVID-19, and a link between adipose tissue infection and disease progression has been proposed. Here we demonstrate that SARS-CoV-2 infects human adipose tissue and undergoes productive infection in fat cells. However, susceptibility to infection and the cellular response depends on the anatomical origin of the cells and the viral lineage. Visceral fat cells express more ACE2 and are more susceptible to SARS-CoV-2 infection than their subcutaneous counterparts. SARS-CoV-2 infection leads to inhibition of lipolysis in subcutaneous fat cells, while in visceral fat cells, it results in higher expression of pro-inflammatory cytokines. Viral load and cellular response are attenuated when visceral fat cells are infected with the SARS-CoV-2 gamma variant. A similar degree of cell death occurs 4-days after SARS-CoV-2 infection, regardless of the cell origin or viral lineage. Hence, SARS-CoV-2 infects human fat cells, replicating and altering cell function and viability in a depot- and viral lineage-dependent fashion.

Gasdermin-D activation by SARS-CoV-2 triggers NET and mediate COVID-19 immunopathology.

BACKGROUND: The release of neutrophil extracellular traps (NETs) is associated with inflammation, coagulopathy, and organ damage found in severe cases of COVID-19. However, the molecular mechanisms underlying the release of NETs in COVID-19 remain unclear. OBJECTIVES: We aim to investigate the role of the Gasdermin-D (GSDMD) pathway on NETs release and the development of organ damage during COVID-19. METHODS: We performed a single-cell transcriptome analysis in public data of bronchoalveolar lavage. Then, we enrolled 63 hospitalized patients with moderate and severe COVID-19. We analyze in blood and lung tissue samples the expression of GSDMD, presence of NETs, and signaling pathways upstreaming. Furthermore, we analyzed the treatment with disulfiram in a mouse model of SARS-CoV-2 infection. RESULTS: We found that the SARS-CoV-2 virus directly activates the pore-forming protein GSDMD that triggers NET production and organ damage in COVID-19. Single-cell transcriptome analysis revealed that the expression of GSDMD and inflammasome-related genes were increased in COVID-19 patients. High expression of active GSDMD associated with NETs structures was found in the lung tissue of COVID-19 patients. Furthermore, we showed that activation of GSDMD in neutrophils requires active caspase1/4 and live SARS-CoV-2, which infects neutrophils. In a mouse model of SARS-CoV-2 infection, the treatment with disulfiram inhibited NETs release and reduced organ damage. CONCLUSION: These results demonstrated that GSDMD-dependent NETosis plays a critical role in COVID-19 immunopathology and suggests GSDMD as a novel potential target for improving the COVID-19 therapeutic strategy.

Clinical, radiological, and transbronchial biopsy findings in patients with long COVID-19: a case series.

This brief communication demonstrates the correlation of persistent respiratory symptoms with functional, tomographic, and transbronchial pulmonary biopsy findings in patients with COVID-19 who had a long follow-up period. We report a series of six COVID-19 patients with pulmonary involvement who presented with persistent dyspnea within 4-15 months of discharge. We performed transbronchial biopsies, and the histopathological pattern consistently demonstrated peribronchial remodeling with interstitial pulmonary fibrosis. Therefore, lung biopsy may be useful in the approach of patients with long COVID-19, although the type of procedure, its precise indication, and the moment to perform it are yet to be clarified. (Brazilian Registry of Clinical Trials-ReBEC; identifier: RBR-8j9kqy [http://www.ensaiosclinicos.gov.br]).

SARS-Cov-2 pneumonia phenotyping on imaging exams of patients submitted to minimally invasive autopsy.

Background: Correlation between pathology and imaging of the new SARS-Cov-2 disease (COVID-19) is scarce. This study aimed to characterize SARS-Cov-2 pneumonia on imaging of patients submitted to minimally invasive autopsy (MIA). Methods: This unicentric retrospective observational study included 46 consecutive patients with confirmed COVID-19 who underwent MIA. All clinical chest images were reviewed and classified for the presence and grade of viral pneumonia, as well as disease evolution. On CT, phenotypes were described as consistent with mild, moderate, or severe viral pneumonia, with or without radiological signs of organizing pneumonia (OP). In severe pneumonia, CT could also be classified as diffuse progressive OP or radiological diffuse alveolar damage (DAD). Specific features on CT were noted, including fibroproliferative signs that could indicate potential or initial fibrosis. Results: MIA showed a heterogeneous panel of alterations, with a high prevalence of OP and acute fibrinous and organizing pneumonia (AFOP). Also, signs of interstitial fibrosis corresponded to the most prevalent pathological feature. Initial chest radiography (CXR) findings were mainly consistent with moderate or severe viral pneumonia. Most patients showed stability or improvement (reduction of opacities) on imaging. CTs were performed on 15 patients. Consolidations were found in most patients, frequently showing features consistent with an OP phenotype. Fibroproliferative changes were also prevalent on CT. Conclusions: In this study, SARS-Cov-2 pneumonia showed heterogeneous radiological and pathological patterns. Signs of organization and potential or initial fibrosis were prevalent on both imaging and pathology. Imaging phenotyping may help to predict post-infection fibrosing interstitial pneumonitis in COVID-19.

Pulmonary fibrosis secondary to COVID-19: a narrative review.

Introduction: Coronavirus disease 2019 (COVID-19) is still increasing worldwide, and as a result, the number of patients with pulmonary fibrosis secondary to COVID-19 will expand over time. Risk factors, histopathological characterization, pathophysiology, prevalence, and management of post-COVID-19 pulmonary fibrosis are poorly understood, and few studies have addressed these issues.Areas covered:This article reviews the current evidence regarding post-COVID-19 pulmonary fibrosis, with an emphasis on the potential risk factors, histopathology, pathophysiology, functional and tomographic features, and potential therapeutic modalities. A search on the issue was performed in the MEDLINE, Embase, and SciELO databases and the Cochrane library between 1 December 2019, and 25 January 2021. Studies were reviewed and relevant topics were incorporated into this narrative review. Expert opinion: Pulmonary sequelae may occur secondary to COVID-19, which needs to be included as a potential etiology in the current differential diagnosis of pulmonary fibrosis. Therefore, serial clinical, tomographic, and functional screening for pulmonary fibrosis is recommended after COVID-19, mainly in patients with pulmonary involvement in the acute phase of the disease. Further studies are necessary to determine the risk factors, markers, pathophysiology, and appropriate management of post-COVID-19 pulmonary fibrosis.

From dermatological conditions to COVID-19: Reasoning for anticoagulation, suppression of inflammation, and hyperbaric oxygen therapy.

COVID-19 generates a complex systemic inflammatory response that can lead to death due to wide macrophage activation, endothelial damage, and coagulation in critically ill patients. SARS-CoV-2-induced lung injury due to inflammatory mediated thrombosis could be similar to the livedoid vasculopathy in the skin, supporting a translational comparison of these clinical settings. In this article, we discuss anticoagulation, suppression of inflammatory response, and hyperbaric oxygen therapy in the context of severe COVID-19 and livedoid vasculopathy.

Pulmonary pathology of ARDS in COVID-19: A pathological review for clinicians.

COVID-19 has quickly reached pandemic levels since it was first reported in December 2019. The virus responsible for the disease, named SARS-CoV-2, is enveloped positive-stranded RNA viruses. During its replication in the cytoplasm of host cells, the viral genome is transcribed into proteins, such as the structural protein spike domain S1, which is responsible for binding to the cell receptor of the host cells. Infected patients have initially flu-like symptoms, rapidly evolving to severe acute lung injury, known as acute respiratory distress syndrome (ARDS). ARDS is characterized by an acute and diffuse inflammatory damage into the alveolar-capillary barrier associated with a vascular permeability increase and reduced compliance, compromising gas exchange and causing hypoxemia. Histopathologically, this condition is known as diffuse alveolar damage which consists of permanent damage to the alveoli epithelial cells and capillary endothelial cells, with consequent hyaline membrane formation and eventually intracapillary thrombosis. All of these mechanisms associated with COVID-19 involve the phenotypic expression from different proteins transcription modulated by viral infection in specific pulmonary microenvironments. Therefore, this knowledge is fundamentally important for a better pathophysiological understanding and identification of the main molecular pathways associated with the disease evolution. Evidently, clinical findings, signs and symptoms of a patient are the phenotypic expression of these pathophysiological and molecular mechanisms of SARS-CoV-2 infection. Therefore, no findings alone, whether molecular, clinical, radiological or pathological axis are sufficient for an accurate diagnosis. However, their intersection and/or correlation are extremely critical for clinicians establish the diagnosis and new treatment perspectives.