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1.
Signal Transduct Target Ther ; 7(1): 29, 2022 01 28.
Article in English | MEDLINE | ID: covidwho-1655546

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is transmitted on mink farms between minks and humans in many countries. However, the systemic pathological features of SARS-CoV-2-infected minks are mostly unknown. Here, we demonstrated that minks were largely permissive to SARS-CoV-2, characterized by severe and diffuse alveolar damage, and lasted at least 14 days post inoculation (dpi). We first reported that infected minks displayed multiple organ-system lesions accompanied by an increased inflammatory response and widespread viral distribution in the cardiovascular, hepatobiliary, urinary, endocrine, digestive, and immune systems. The viral protein partially co-localized with activated Mac-2+ macrophages throughout the body. Moreover, we first found that the alterations in lipids and metabolites were correlated with the histological lesions in infected minks, especially at 6 dpi, and were similar to that of patients with severe and fatal COVID-19. Particularly, altered metabolic pathways, abnormal digestion, and absorption of vitamins, lipids, cholesterol, steroids, amino acids, and proteins, consistent with hepatic dysfunction, highlight metabolic and immune dysregulation. Enriched kynurenine in infected minks contributed to significant activation of the kynurenine pathway and was related to macrophage activation. Melatonin, which has significant anti-inflammatory and immunomodulating effects, was significantly downregulated at 6 dpi and displayed potential as a targeted medicine. Our data first illustrate systematic analyses of infected minks to recapitulate those observations in severe and fetal COVID-19 patients, delineating a useful animal model to mimic SARS-CoV-2-induced systematic and severe pathophysiological features and provide a reliable tool for the development of effective and targeted treatment strategies, vaccine research, and potential biomarkers.


Subject(s)
COVID-19/metabolism , Lung/metabolism , Macrophages, Alveolar/metabolism , Metabolome , Mink/virology , SARS-CoV-2/metabolism , Amino Acids/metabolism , Animals , Antiviral Agents/pharmacology , COVID-19/drug therapy , COVID-19/genetics , COVID-19/pathology , Disease Models, Animal , Female , Humans , Lung/pathology , Lung/virology , Macrophages, Alveolar/pathology , Macrophages, Alveolar/virology , Melatonin/metabolism , Metabolic Networks and Pathways/genetics , Molecular Targeted Therapy/methods , SARS-CoV-2/drug effects , SARS-CoV-2/genetics , SARS-CoV-2/pathogenicity , Sterols/metabolism , Virulence , Virus Replication/genetics
4.
Cell Stress Chaperones ; 26(5): 859-868, 2021 09.
Article in English | MEDLINE | ID: covidwho-1353732

ABSTRACT

Vaccinations are widely credited with reducing death rates from COVID-19, but the underlying host-viral mechanisms/interactions for morbidity and mortality of SARS-CoV-2 infection remain poorly understood. Acute respiratory distress syndrome (ARDS) describes the severe lung injury, which is pathologically associated with alveolar damage, inflammation, non-cardiogenic edema, and hyaline membrane formation. Because proteostatic pathways play central roles in cellular protection, immune modulation, protein degradation, and tissue repair, we examined the pathological features for the unfolded protein response (UPR) using the surrogate biomarker glucose-regulated protein 78 (GRP78) and co-receptor for SARS-CoV-2. At autopsy, immunostaining of COVID-19 lungs showed highly elevated expression of GRP78 in both pneumocytes and macrophages compared with that of non-COVID control lungs. GRP78 expression was detected in both SARS-CoV-2-infected and un-infected pneumocytes as determined by multiplexed immunostaining for nucleocapsid protein. In macrophages, immunohistochemical staining for GRP78 from deceased COVID-19 patients was increased but overlapped with GRP78 expression taken from surgical resections of non-COVID-19 controls. In contrast, the robust in situ GRP78 immunostaining of pneumocytes from COVID-19 autopsies exhibited no overlap and was independent of age, race/ethnicity, and gender compared with that from non-COVID-19 controls. Our findings bring new insights for stress-response pathways involving the proteostatic network implicated for host resilience and suggest that targeting of GRP78 expression with existing therapeutics might afford an alternative therapeutic strategy to modulate host-viral interactions during SARS-CoV-2 infections.


Subject(s)
Alveolar Epithelial Cells/metabolism , COVID-19/metabolism , Endoplasmic Reticulum Stress , Heat-Shock Proteins/analysis , Receptors, Coronavirus/analysis , SARS-CoV-2/pathogenicity , Adult , Aged , Aged, 80 and over , Alveolar Epithelial Cells/pathology , Alveolar Epithelial Cells/virology , Autopsy , COVID-19/mortality , COVID-19/pathology , COVID-19/virology , Case-Control Studies , Female , Host-Pathogen Interactions , Humans , Macrophages, Alveolar/metabolism , Macrophages, Alveolar/virology , Male , Middle Aged , Proteostasis , Up-Regulation , Young Adult
5.
J Clin Invest ; 131(14)2021 07 15.
Article in English | MEDLINE | ID: covidwho-1311200

ABSTRACT

The coronavirus disease 2019 (COVID-19) pandemic is among the most important public health crises of our generation. Despite the promise of prevention offered by effective vaccines, patients with severe COVID-19 will continue to populate hospitals and intensive care units for the foreseeable future. The most common clinical presentation of severe COVID-19 is hypoxemia and respiratory failure, typical of the acute respiratory distress syndrome (ARDS). Whether the clinical features and pathobiology of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pneumonia differ from those of pneumonia secondary to other pathogens is unclear. This uncertainty has created variability in the application of historically proven therapies for ARDS to patients with COVID-19. We review the available literature and find many similarities between patients with ARDS from pneumonia attributable to SARS-CoV-2 versus other respiratory pathogens. A notable exception is the long duration of illness among patients with COVID-19, which could result from its unique pathobiology. Available data support the use of care pathways and therapies proven effective for patients with ARDS, while pointing to unique features that might be therapeutically targeted for patients with severe SARS-CoV-2 pneumonia.


Subject(s)
COVID-19/etiology , Pneumonia, Viral/etiology , Respiratory Distress Syndrome/etiology , SARS-CoV-2 , Angiotensin-Converting Enzyme 2/physiology , Autopsy , COVID-19/epidemiology , COVID-19/pathology , Cytokines/biosynthesis , Humans , Lung/immunology , Lung/pathology , Lung/virology , Macrophages, Alveolar/immunology , Macrophages, Alveolar/virology , Models, Biological , Pandemics , Pneumonia, Viral/immunology , Pneumonia, Viral/pathology , Receptors, Virus/physiology , Respiratory Distress Syndrome/immunology , Respiratory Distress Syndrome/pathology , SARS-CoV-2/immunology , SARS-CoV-2/pathogenicity , SARS-CoV-2/physiology , Severity of Illness Index
7.
Nature ; 595(7865): 114-119, 2021 07.
Article in English | MEDLINE | ID: covidwho-1207147

ABSTRACT

Respiratory failure is the leading cause of death in patients with severe SARS-CoV-2 infection1,2, but the host response at the lung tissue level is poorly understood. Here we performed single-nucleus RNA sequencing of about 116,000 nuclei from the lungs of nineteen individuals who died of COVID-19 and underwent rapid autopsy and seven control individuals. Integrated analyses identified substantial alterations in cellular composition, transcriptional cell states, and cell-to-cell interactions, thereby providing insight into the biology of lethal COVID-19. The lungs from individuals with COVID-19 were highly inflamed, with dense infiltration of aberrantly activated monocyte-derived macrophages and alveolar macrophages, but had impaired T cell responses. Monocyte/macrophage-derived interleukin-1ß and epithelial cell-derived interleukin-6 were unique features of SARS-CoV-2 infection compared to other viral and bacterial causes of pneumonia. Alveolar type 2 cells adopted an inflammation-associated transient progenitor cell state and failed to undergo full transition into alveolar type 1 cells, resulting in impaired lung regeneration. Furthermore, we identified expansion of recently described CTHRC1+ pathological fibroblasts3 contributing to rapidly ensuing pulmonary fibrosis in COVID-19. Inference of protein activity and ligand-receptor interactions identified putative drug targets to disrupt deleterious circuits. This atlas enables the dissection of lethal COVID-19, may inform our understanding of long-term complications of COVID-19 survivors, and provides an important resource for therapeutic development.


Subject(s)
COVID-19/pathology , COVID-19/virology , Lung/pathology , SARS-CoV-2/pathogenicity , Single-Cell Analysis , Aged , Aged, 80 and over , Alveolar Epithelial Cells/pathology , Alveolar Epithelial Cells/virology , Atlases as Topic , Autopsy , COVID-19/immunology , Case-Control Studies , Female , Fibroblasts/pathology , Fibrosis/pathology , Fibrosis/virology , Humans , Inflammation/pathology , Inflammation/virology , Macrophages/pathology , Macrophages/virology , Macrophages, Alveolar/pathology , Macrophages, Alveolar/virology , Male , Middle Aged , Plasma Cells/immunology , T-Lymphocytes/immunology
8.
Nature ; 590(7847): 635-641, 2021 02.
Article in English | MEDLINE | ID: covidwho-1019856

ABSTRACT

Some patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) develop severe pneumonia and acute respiratory distress syndrome1 (ARDS). Distinct clinical features in these patients have led to speculation that the immune response to virus in the SARS-CoV-2-infected alveolus differs from that in other types of pneumonia2. Here we investigate SARS-CoV-2 pathobiology by characterizing the immune response in the alveoli of patients infected with the virus. We collected bronchoalveolar lavage fluid samples from 88 patients with SARS-CoV-2-induced respiratory failure and 211 patients with known or suspected pneumonia from other pathogens, and analysed them using flow cytometry and bulk transcriptomic profiling. We performed single-cell RNA sequencing on 10 bronchoalveolar lavage fluid samples collected from patients with severe coronavirus disease 2019 (COVID-19) within 48 h of intubation. In the majority of patients with SARS-CoV-2 infection, the alveolar space was persistently enriched in T cells and monocytes. Bulk and single-cell transcriptomic profiling suggested that SARS-CoV-2 infects alveolar macrophages, which in turn respond by producing T cell chemoattractants. These T cells produce interferon-γ to induce inflammatory cytokine release from alveolar macrophages and further promote T cell activation. Collectively, our results suggest that SARS-CoV-2 causes a slowly unfolding, spatially limited alveolitis in which alveolar macrophages containing SARS-CoV-2 and T cells form a positive feedback loop that drives persistent alveolar inflammation.


Subject(s)
COVID-19/immunology , COVID-19/virology , Macrophages, Alveolar/immunology , Pneumonia, Viral/immunology , Pneumonia, Viral/virology , SARS-CoV-2/pathogenicity , T-Lymphocytes/immunology , Bronchoalveolar Lavage Fluid/chemistry , Bronchoalveolar Lavage Fluid/immunology , COVID-19/genetics , Cohort Studies , Humans , Interferon-gamma/immunology , Interferons/immunology , Interferons/metabolism , Macrophages, Alveolar/metabolism , Macrophages, Alveolar/virology , Pneumonia, Viral/genetics , RNA-Seq , SARS-CoV-2/immunology , Signal Transduction/immunology , Single-Cell Analysis , T-Lymphocytes/metabolism , Time Factors
9.
Eur J Clin Invest ; 51(1): e13443, 2021 Jan.
Article in English | MEDLINE | ID: covidwho-901035

ABSTRACT

BACKGROUND: To reveal detailed histopathological changes, virus distributions, immunologic properties and multi-omic features caused by SARS-CoV-2 in the explanted lungs from the world's first successful lung transplantation of a COVID-19 patient. MATERIALS AND METHODS: A total of 36 samples were collected from the lungs. Histopathological features and virus distribution were observed by optical microscope and transmission electron microscope (TEM). Immune cells were detected by flow cytometry and immunohistochemistry. Transcriptome and proteome approaches were used to investigate main biological processes involved in COVID-19-associated pulmonary fibrosis. RESULTS: The histopathological changes of the lung tissues were characterized by extensive pulmonary interstitial fibrosis and haemorrhage. Viral particles were observed in the cytoplasm of macrophages. CD3+ CD4- T cells, neutrophils, NK cells, γ/δ T cells and monocytes, but not B cells, were abundant in the lungs. Higher levels of proinflammatory cytokines iNOS, IL-1ß and IL-6 were in the area of mild fibrosis. Multi-omics analyses revealed a total of 126 out of 20,356 significant different transcription and 114 out of 8,493 protein expression in lung samples with mild and severe fibrosis, most of which were related to fibrosis and inflammation. CONCLUSIONS: Our results provide novel insight that the significant neutrophil/ CD3+ CD4- T cell/ macrophage activation leads to cytokine storm and severe fibrosis in the lungs of COVID-19 patient and may contribute to a better understanding of COVID-19 pathogenesis.


Subject(s)
COVID-19/pathology , Hemorrhage/pathology , Lung Transplantation , Lung/pathology , Lymph Nodes/pathology , Pulmonary Fibrosis/pathology , B-Lymphocytes/pathology , B-Lymphocytes/ultrastructure , B-Lymphocytes/virology , COVID-19/genetics , COVID-19/metabolism , COVID-19/surgery , Chromatography, Liquid , Flow Cytometry , Gene Expression Profiling , Humans , Interleukin-1beta/metabolism , Interleukin-6/metabolism , Killer Cells, Natural/pathology , Killer Cells, Natural/ultrastructure , Killer Cells, Natural/virology , Lung/metabolism , Lung/ultrastructure , Lung/virology , Lymph Nodes/metabolism , Lymph Nodes/ultrastructure , Lymph Nodes/virology , Macrophages, Alveolar/pathology , Macrophages, Alveolar/ultrastructure , Macrophages, Alveolar/virology , Male , Middle Aged , Monocytes/pathology , Monocytes/ultrastructure , Monocytes/virology , Neutrophils/pathology , Neutrophils/ultrastructure , Neutrophils/virology , Nitric Oxide Synthase Type II/metabolism , Proteomics , Pulmonary Fibrosis/genetics , Pulmonary Fibrosis/metabolism , Pulmonary Fibrosis/surgery , RNA-Seq , SARS-CoV-2 , Severity of Illness Index , T-Lymphocytes/pathology , T-Lymphocytes/ultrastructure , T-Lymphocytes/virology , Tandem Mass Spectrometry
10.
EMBO Rep ; 21(12): e51252, 2020 12 03.
Article in English | MEDLINE | ID: covidwho-895751

ABSTRACT

Respiratory infections, like the current COVID-19 pandemic, target epithelial cells in the respiratory tract. Alveolar macrophages (AMs) are tissue-resident macrophages located within the lung. They play a key role in the early phases of an immune response to respiratory viruses. AMs are likely the first immune cells to encounter SARS-CoV-2 during an infection, and their reaction to the virus will have a profound impact on the outcome of the infection. Interferons (IFNs) are antiviral cytokines and among the first cytokines produced upon viral infection. In this study, AMs from non-infectious donors are challenged with SARS-CoV-2. We demonstrate that challenged AMs are incapable of sensing SARS-CoV-2 and of producing an IFN response in contrast to other respiratory viruses, like influenza A virus and Sendai virus, which trigger a robust IFN response. The absence of IFN production in AMs upon challenge with SARS-CoV-2 could explain the initial asymptotic phase observed during COVID-19 and argues against AMs being the sources of pro-inflammatory cytokines later during infection.


Subject(s)
COVID-19/immunology , Macrophages, Alveolar/immunology , Macrophages, Alveolar/virology , SARS-CoV-2/immunology , Antiviral Agents/immunology , COVID-19/virology , Cells, Cultured , Cytokines/immunology , Epithelial Cells/immunology , Epithelial Cells/virology , Humans , Immune Evasion , Interferon Type I/immunology , Lung/immunology , Lung/virology , Pandemics
11.
Rev Med Virol ; 30(5): e2140, 2020 09.
Article in English | MEDLINE | ID: covidwho-848179

ABSTRACT

A knowledge-based cybernetic framework model representing the dynamics of SARS-CoV-2 inside the human body has been studied analytically and in silico to explore the pathophysiologic regulations. The following modeling methodology was developed as a platform to introduce a predictive tool supporting a therapeutic approach to Covid-19 disease. A time-dependent nonlinear system of ordinary differential equations model was constructed involving type-I cells, type-II cells, SARS-CoV-2 virus, inflammatory mediators, interleukins along with host pulmonary gas exchange rate, thermostat control, and mean pressure difference. This formalism introduced about 17 unknown parameters. Estimating these unknown parameters requires a mathematical association with the in vivo sparse data and the dynamic sensitivities of the model. The cybernetic model can simulate a dynamic response to the reduced pulmonary alveolar gas exchange rate, thermostat control, and mean pressure difference under a very critical condition based on equilibrium (steady state) values of the inflammatory mediators and system parameters. In silico analysis of the current cybernetical approach with system dynamical modeling can provide an intellectual framework to help experimentalists identify more active therapeutic approaches.


Subject(s)
Betacoronavirus/pathogenicity , Coronavirus Infections/immunology , Host-Pathogen Interactions/immunology , Lung/immunology , Nonlinear Dynamics , Pneumonia, Viral/immunology , Acute-Phase Proteins/antagonists & inhibitors , Acute-Phase Proteins/genetics , Acute-Phase Proteins/immunology , Angiotensin-Converting Enzyme 2 , Anti-Inflammatory Agents/therapeutic use , Antiviral Agents/therapeutic use , Betacoronavirus/drug effects , Betacoronavirus/growth & development , Body Temperature , COVID-19 , Coronavirus Infections/drug therapy , Coronavirus Infections/pathology , Coronavirus Infections/virology , Cytokines/antagonists & inhibitors , Cytokines/genetics , Cytokines/immunology , Epithelial Cells/drug effects , Epithelial Cells/immunology , Epithelial Cells/virology , Gene Expression Regulation , Host-Pathogen Interactions/drug effects , Host-Pathogen Interactions/genetics , Humans , Lung/drug effects , Lung/virology , Macrophages, Alveolar/drug effects , Macrophages, Alveolar/immunology , Macrophages, Alveolar/virology , Pandemics , Peptidyl-Dipeptidase A/genetics , Peptidyl-Dipeptidase A/immunology , Pneumonia, Viral/drug therapy , Pneumonia, Viral/pathology , Pneumonia, Viral/virology , Pulmonary Gas Exchange/drug effects , Pulmonary Gas Exchange/immunology , SARS-CoV-2 , Spike Glycoprotein, Coronavirus/antagonists & inhibitors , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/immunology
12.
Front Immunol ; 11: 1312, 2020.
Article in English | MEDLINE | ID: covidwho-615475

ABSTRACT

Respiratory, circulatory, and renal failure are among the gravest features of COVID-19 and are associated with a very high mortality rate. A common denominator of all affected organs is the expression of angiotensin-converting enzyme 2 (ACE2), a protease responsible for the conversion of Angiotensin 1-8 (Ang II) to Angiotensin 1-7 (Ang 1-7). Ang 1-7 acts on these tissues and in other target organs via Mas receptor (MasR), where it exerts beneficial effects, including vasodilation and suppression of inflammation and fibrosis, along an attenuation of cardiac and vascular remodeling. Unfortunately, ACE2 also serves as the binding receptor of SARS viral spike glycoprotein, enabling its attachment to host cells, with subsequent viral internalization and replication. Although numerous reports have linked the devastating organ injuries to viral homing and attachment to organ-specific cells widely expressing ACE2, little attention has been given to ACE-2 expressed by the immune system. Herein we outline potential adverse effects of SARS-CoV2 on macrophages and dendritic cells, key cells of the immune system expressing ACE2. Specifically, we propose a new hypothesis that, while macrophages play an important role in antiviral defense mechanisms, in the case of SARS-CoV, they may also serve as a Trojan horse, enabling viral anchoring specifically within the pulmonary parenchyma. It is tempting to assume that diverse expression of ACE2 in macrophages among individuals might govern the severity of SARS-CoV-2 infection. Moreover, reallocation of viral-containing macrophages migrating out of the lung to other tissues is theoretically plausible in the context of viral spread with the involvement of other organs.


Subject(s)
Betacoronavirus/metabolism , Dendritic Cells/metabolism , Lung/pathology , Macrophages, Alveolar/metabolism , Peptidyl-Dipeptidase A/metabolism , Angiotensin-Converting Enzyme 2 , Betacoronavirus/immunology , COVID-19 , Coronavirus Infections/immunology , Coronavirus Infections/pathology , Dendritic Cells/immunology , Dendritic Cells/virology , Humans , Lung/virology , Macrophages, Alveolar/immunology , Macrophages, Alveolar/virology , Pandemics , Parenchymal Tissue/pathology , Parenchymal Tissue/virology , Pneumonia, Viral/immunology , Pneumonia, Viral/pathology , Receptors, Virus/metabolism , SARS-CoV-2 , Spike Glycoprotein, Coronavirus/metabolism
13.
Nature ; 583(7818): 830-833, 2020 07.
Article in English | MEDLINE | ID: covidwho-220333

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the cause of coronavirus disease 2019 (COVID-19), which has become a public health emergency of international concern1. Angiotensin-converting enzyme 2 (ACE2) is the cell-entry receptor for severe acute respiratory syndrome coronavirus (SARS-CoV)2. Here we infected transgenic mice that express human ACE2 (hereafter, hACE2 mice) with SARS-CoV-2 and studied the pathogenicity of the virus. We observed weight loss as well as virus replication in the lungs of hACE2 mice infected with SARS-CoV-2. The typical histopathology was interstitial pneumonia with infiltration of considerable numbers of macrophages and lymphocytes into the alveolar interstitium, and the accumulation of macrophages in alveolar cavities. We observed viral antigens in bronchial epithelial cells, macrophages and alveolar epithelia. These phenomena were not found in wild-type mice infected with SARS-CoV-2. Notably, we have confirmed the pathogenicity of SARS-CoV-2 in hACE2 mice. This mouse model of SARS-CoV-2 infection will be valuable for evaluating antiviral therapeutic agents and vaccines, as well as understanding the pathogenesis of COVID-19.


Subject(s)
Betacoronavirus/pathogenicity , Coronavirus Infections/pathology , Coronavirus Infections/virology , Lung/pathology , Peptidyl-Dipeptidase A/genetics , Peptidyl-Dipeptidase A/metabolism , Pneumonia, Viral/pathology , Pneumonia, Viral/virology , Transgenes , Angiotensin-Converting Enzyme 2 , Animals , Antigens, Viral/immunology , Antigens, Viral/metabolism , Betacoronavirus/immunology , Betacoronavirus/metabolism , Bronchi/pathology , Bronchi/virology , COVID-19 , Coronavirus Infections/immunology , Disease Models, Animal , Epithelial Cells/pathology , Epithelial Cells/virology , Female , Humans , Immunoglobulin G/immunology , Lung/immunology , Lung/virology , Lymphocytes/immunology , Macrophages, Alveolar/immunology , Macrophages, Alveolar/virology , Male , Mice , Mice, Transgenic , Pandemics , Pneumonia, Viral/immunology , Receptors, Complement 3d/genetics , Receptors, Complement 3d/metabolism , SARS-CoV-2 , Virus Replication , Weight Loss
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