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1.
EuropePMC; 2022.
Preprint in English | EuropePMC | ID: ppcovidwho-330174

ABSTRACT

Severe injuries following viral infection cause lung epithelial destruction with the presence of ectopic basal progenitor cells (EBCs), although the exact function of EBCs remains controversial. We and others previously showed the presence of ectopic tuft cells in the disrupted alveolar region following severe influenza infection. Here, we further revealed that the ectopic tuft cells are derived from EBCs. This process is amplified by Wnt signaling inhibition but suppressed by Notch inhibition. Further analysis revealed that p63-CreER labeled population de novo arising during regeneration includes alveolar epithelial cells when Tamoxifen was administrated after viral infection. The generation of the p63-CreER labeled alveolar cells is independent of tuft cells, demonstrating segregated differentiation paths of EBCs in lung repair. EBCs and ectopic tuft cells can also be found in the lung parenchyma post SARS-CoV-2 infection, suggesting a similar response to severe injuries in humans.

3.
EuropePMC; 2020.
Preprint in English | EuropePMC | ID: ppcovidwho-325385

ABSTRACT

Background: Novel coronavirus disease 2019 (COVID-19) is a global public health emergency. Here, we developed and validated a practical model based on the data from a multi-center cohort in China for early identification and prediction of which patients will be admitted to the intensive care unit (ICU). Methods: Data of 1087 patients with laboratory-confirmed COVID-19 were collected from 49 sites between January 2 and February 28, 2020, in Sichuan and Wuhan. Patients were randomly categorized into the training and validation cohorts (7:3). The least absolute shrinkage and selection operator and logistic regression analyzes were used to develop the nomogram. The performance of the nomogram was evaluated for the C-index, calibration, discrimination, and clinical usefulness. Further, the nomogram was externally validated in a different cohort. Results: The individualized prediction nomogram included 6 predictors: age, respiratory rate, systolic blood pressure, smoking status, fever, and chronic kidney disease. The model demonstrated a high discriminative ability in the training cohort (C-index = 0.829), which was confirmed in the external validation cohort (C-index = 0.776). In addition, the calibration plots confirmed good concordance for predicting the risk of ICU admission. Decision curve analysis revealed that the prediction nomogram was clinically useful. Conclusion: We established an early prediction model incorporating clinical characteristics that could be quickly obtained on hospital admission, even in community health centers. This model can be conveniently used to predict the individual risk for ICU admission of patients with COVID-19 and optimize the use of limited resources.

6.
Adv Sci (Weinh) ; 9(7): e2104192, 2022 03.
Article in English | MEDLINE | ID: covidwho-1589262

ABSTRACT

Coronavirus disease 2019 (COVID-19) patients with impact on skin and hair loss are reported. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is detected in the skin of some patients; however, the detailed pathological features of skin tissues from patients infected with SARS-CoV-2 at a molecular level are limited. Especially, the ability of SARS-CoV-2 to infect skin cells and impact their function is not well understood. A proteome map of COVID-19 skin is established here and the susceptibility of human-induced pluripotent stem cell (hiPSC)-derived skin organoids with hair follicles and nervous system is investigated, to SARS-CoV-2 infection. It is shown that KRT17+ hair follicles can be infected by SARS-CoV-2 and are associated with the impaired development of hair follicles and epidermis. Different types of nervous system cells are also found to be infected, which can lead to neuron death. Findings from the present work provide evidence for the association between COVID-19 and hair loss. hiPSC-derived skin organoids are also presented as an experimental model which can be used to investigate the susceptibility of skin cells to SARS-CoV-2 infection and can help identify various pathological mechanisms and drug screening strategies.


Subject(s)
COVID-19/physiopathology , Induced Pluripotent Stem Cells/cytology , Models, Biological , Organoids/cytology , Skin/cytology , COVID-19/virology , Hair Follicle/virology , Humans , Nervous System/virology , Proteomics , SARS-CoV-2/isolation & purification
7.
Cell Discov ; 6(1): 84, 2020 Nov 13.
Article in English | MEDLINE | ID: covidwho-1387260
9.
MAbs ; 13(1): 1930636, 2021.
Article in English | MEDLINE | ID: covidwho-1258715

ABSTRACT

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), which causes coronavirus disease-2019 (COVID-19), interacts with the host cell receptor angiotensin-converting enzyme 2 (hACE2) via its spike 1 protein during infection. After the virus sequence was published, we identified two potent antibodies against the SARS-CoV-2 receptor binding domain (RBD) from antibody libraries using a phage-to-yeast (PtY) display platform in only 10 days. Our lead antibody JMB2002, now in a Phase 1 clinical trial (ChiCTR2100042150), showed broad-spectrum in vitro blocking activity against hACE2 binding to the RBD of multiple SARS-CoV-2 variants, including B.1.351 that was reportedly much more resistant to neutralization by convalescent plasma, vaccine sera and some clinical-stage neutralizing antibodies. Furthermore, JMB2002 has demonstrated complete prophylactic and potent therapeutic efficacy in a rhesus macaque disease model. Prophylactic and therapeutic countermeasure intervention of SARS-CoV-2 using JMB2002 would likely slow down the transmission of currently emerged SARS-CoV-2 variants and result in more efficient control of the COVID-19 pandemic.


Subject(s)
Angiotensin-Converting Enzyme 2/antagonists & inhibitors , Antibodies, Neutralizing/pharmacology , Antiviral Agents/pharmacology , COVID-19/drug therapy , COVID-19/prevention & control , SARS-CoV-2/drug effects , Angiotensin-Converting Enzyme 2/genetics , Angiotensin-Converting Enzyme 2/immunology , Animals , Antibody Specificity , Binding Sites, Antibody , CHO Cells , COVID-19/immunology , COVID-19/metabolism , COVID-19/virology , Chlorocebus aethiops , Cricetulus , Disease Models, Animal , Epitopes , Macaca mulatta , SARS-CoV-2/immunology , SARS-CoV-2/pathogenicity , Vero Cells
10.
Virol Sin ; 36(5): 879-889, 2021 Oct.
Article in English | MEDLINE | ID: covidwho-1174014

ABSTRACT

The ongoing coronavirus disease 2019 (COVID-19) pandemic caused more than 96 million infections and over 2 million deaths worldwide so far. However, there is no approved vaccine available for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the disease causative agent. Vaccine is the most effective approach to eradicate a pathogen. The tests of safety and efficacy in animals are pivotal for developing a vaccine and before the vaccine is applied to human populations. Here we evaluated the safety, immunogenicity, and efficacy of an inactivated vaccine based on the whole viral particles in human ACE2 transgenic mouse and in non-human primates. Our data showed that the inactivated vaccine successfully induced SARS-CoV-2-specific neutralizing antibodies in mice and non-human primates, and subsequently provided partial (in low dose) or full (in high dose) protection of challenge in the tested animals. In addition, passive serum transferred from vaccine-immunized mice could also provide full protection from SARS-CoV-2 infection in mice. These results warranted positive outcomes in future clinical trials in humans.


Subject(s)
COVID-19 Vaccines/immunology , COVID-19 , Animals , Antibodies, Neutralizing/blood , Antibodies, Viral/blood , COVID-19/prevention & control , Mice , Mice, Transgenic , Primates , SARS-CoV-2 , Spike Glycoprotein, Coronavirus , Vaccines, Inactivated/immunology
11.
Medicine (Baltimore) ; 100(12): e25232, 2021 Mar 26.
Article in English | MEDLINE | ID: covidwho-1150010

ABSTRACT

ABSTRACT: We aimed to investigate the relationship of radiological features and the corresponding pulmonary pathology of patients with Coronavirus Disease (COVID-19) pneumonia.In this multicenter study, serial chest CT and radiographic images from 9 patients (51-85 years old, 56% male) were reviewed and analyzed. Postmortem lungs were sampled and studied from these autopsies, with a special focus on several corresponding sites based on imaging features.The predominant pattern of pulmonary injury in these 9 cases was diffuse alveolar damage (DAD) and interstitial inflammation. Moreover, acute fibrinous exudates, organization, inflammatory cell infiltration, hyaline membranes, pulmonary edema, pneumocyte hyperplasia, and fibrosis were all observed. The histopathology features varied according to the site and severity of each lesion. In most of the 9 cases, opacities started from a subpleural area and peripheral structures were more severely damaged based on gross views and pathological examinations. Fibrosis could occur in early stages of infection and this was supported by radiological and pathological findings. The radiological features of COVID-19 pneumonia, at the critically ill stage, were diffuse ground-glass opacities with consolidation, interstitial thickening, and fibrous stripes, which was based in the fibrous tissue proliferation in the alveolar and interlobular septa, and filled alveoli with organizing exudation. Fungal and bacterial co-infections were also observed in 6 cases.Typical imaging features can be correlated with underlying pathological findings. Combining assessments of imaging features with pathological findings therefore can enhance our understanding of the histopathological mechanism of COVID-19 pneumonia, and facilitate early radiological diagnosis and prognosis estimation of COVID-19 pneumonia, which has important implications for the development of clinical targeted treatments and research related to COVID-19 pneumonia.


Subject(s)
COVID-19/pathology , Aged , Aged, 80 and over , Autopsy , Female , Humans , Lung/pathology , Male , Middle Aged , SARS-CoV-2
12.
Natl Sci Rev ; 7(12): 1868-1878, 2020 Dec.
Article in English | MEDLINE | ID: covidwho-1087785

ABSTRACT

Systematic autopsy and comprehensive pathological analyses of COVID-19 decedents should provide insights into the disease characteristics and facilitate the development of novel therapeutics. In this study, we report the autopsy findings from the lungs and lymphatic organs of 12 COVID-19 decedents-findings that evaluated histopathological changes, immune cell signature and inflammatory factor expression in the lungs, spleen and lymph nodes. Here we show that the major pulmonary alterations included diffuse alveolar damage, interstitial fibrosis and exudative inflammation featured with extensive serous and fibrin exudates, macrophage infiltration and abundant production of inflammatory factors (IL-6, IP-10, TNFα and IL-1ß). The spleen and hilar lymph nodes contained lesions with tissue structure disruption and immune cell dysregulation, including lymphopenia and macrophage accumulation. These findings provide pathological evidence that links injuries of the lungs and lymphatic organs with the fatal systematic respiratory and immune malfunction in critically ill COVID-19 patients.

13.
Am J Forensic Med Pathol ; 42(2): 164-169, 2021 Jun 01.
Article in English | MEDLINE | ID: covidwho-1035550

ABSTRACT

ABSTRACT: As of August 23, 2020, the 2019 novel coronavirus disease (COVID-19) has infected more than 23,518,340 people and caused more than 810,492 deaths worldwide including 4,717 deaths in China. We present a case of a 53-year-old woman who was admitted to the hospital because of dry coughs and high fever on January 26, 2020, in Wuhan, China. She was not tested for SARS-CoV-2 RNA until on hospital day 11 (illness day 21) because of a significant shortage of test kits at the local hospital. Then, her test was positive for COVID-19 on hospital day 20. Despite intensive medical treatments, she developed respiratory failure with secondary bacterial infection and expired on hospital day 23 (3 days after she was tested positive for SARS-CoV-2 RNA). A systemic autopsy examination, including immunohistochemistry and ultrastructural studies, demonstrates that SARS-CoV-2 can infect multiple organs with profound adverse effect on the immune system, and the lung pathology is characterized by diffuse alveolar damage. Extrapulmonary SARS-CoV-2 RNA was detected in several organs postmortem. The detailed pathological features are described. In addition, this report highlights the value of forensic autopsy in studying SARS-CoV-2 infection and the importance of clinicopathological correlation in better understanding the pathogenesis of COVID-19.


Subject(s)
COVID-19/diagnosis , Autopsy , Epiglottitis/pathology , Female , Fibroblasts/pathology , Humans , Infarction/pathology , Intracranial Thrombosis/pathology , Kidney/blood supply , Kidney/pathology , Lung/pathology , Lymph Nodes/pathology , Lymphocytes/pathology , Middle Aged , Myocytes, Cardiac/pathology , Myofibroblasts/pathology , Necrosis , RNA, Viral/analysis , Splenic Infarction/pathology , Subarachnoid Hemorrhage/pathology , Thromboembolism/pathology , Thrombosis/pathology , Thyroiditis, Autoimmune/pathology , Urinary Bladder/pathology
15.
Scand J Trauma Resusc Emerg Med ; 28(1): 106, 2020 Oct 27.
Article in English | MEDLINE | ID: covidwho-895016

ABSTRACT

BACKGROUND: Novel coronavirus disease 2019 (COVID-19) is a global public health emergency. Here, we developed and validated a practical model based on the data from a multi-center cohort in China for early identification and prediction of which patients will be admitted to the intensive care unit (ICU). METHODS: Data of 1087 patients with laboratory-confirmed COVID-19 were collected from 49 sites between January 2 and February 28, 2020, in Sichuan and Wuhan. Patients were randomly categorized into the training and validation cohorts (7:3). The least absolute shrinkage and selection operator and logistic regression analyzes were used to develop the nomogram. The performance of the nomogram was evaluated for the C-index, calibration, discrimination, and clinical usefulness. Further, the nomogram was externally validated in a different cohort. RESULTS: The individualized prediction nomogram included 6 predictors: age, respiratory rate, systolic blood pressure, smoking status, fever, and chronic kidney disease. The model demonstrated a high discriminative ability in the training cohort (C-index = 0.829), which was confirmed in the external validation cohort (C-index = 0.776). In addition, the calibration plots confirmed good concordance for predicting the risk of ICU admission. Decision curve analysis revealed that the prediction nomogram was clinically useful. CONCLUSION: We established an early prediction model incorporating clinical characteristics that could be quickly obtained on hospital admission, even in community health centers. This model can be conveniently used to predict the individual risk for ICU admission of patients with COVID-19 and optimize the use of limited resources.


Subject(s)
Betacoronavirus , Coronavirus Infections/epidemiology , Coronavirus Infections/therapy , Hospitalization , Intensive Care Units , Pneumonia, Viral/epidemiology , Pneumonia, Viral/therapy , Adult , Aged , COVID-19 , China , Coronavirus Infections/diagnosis , Female , Humans , Logistic Models , Male , Middle Aged , Nomograms , Pandemics , Pneumonia, Viral/diagnosis , Retrospective Studies , Risk Assessment , SARS-CoV-2
16.
Signal Transduct Target Ther ; 5(1): 235, 2020 10 09.
Article in English | MEDLINE | ID: covidwho-841900

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection can lead to respiratory illness and multi-organ failure in critically ill patients. Although the virus-induced lung damage and inflammatory cytokine storm are believed to be directly associated with coronavirus disease 2019 (COVID-19) clinical manifestations, the underlying mechanisms of virus-triggered inflammatory responses are currently unknown. Here we report that SARS-CoV-2 infection activates caspase-8 to trigger cell apoptosis and inflammatory cytokine processing in the lung epithelial cells. The processed inflammatory cytokines are released through the virus-induced necroptosis pathway. Virus-induced apoptosis, necroptosis, and inflammation activation were also observed in the lung sections of SARS-CoV-2-infected HFH4-hACE2 transgenic mouse model, a valid model for studying SARS-CoV-2 pathogenesis. Furthermore, analysis of the postmortem lung sections of fatal COVID-19 patients revealed not only apoptosis and necroptosis but also massive inflammatory cell infiltration, necrotic cell debris, and pulmonary interstitial fibrosis, typical of immune pathogenesis in the lung. The SARS-CoV-2 infection triggered a dual mode of cell death pathways and caspase-8-dependent inflammatory responses may lead to the lung damage in the COVID-19 patients. These discoveries might assist the development of therapeutic strategies to treat COVID-19.


Subject(s)
Apoptosis/immunology , Betacoronavirus/pathogenicity , Caspase 8/immunology , Coronavirus Infections/immunology , Cytokine Release Syndrome/immunology , Necroptosis/immunology , Pneumonia, Viral/immunology , Pulmonary Fibrosis/immunology , Animals , COVID-19 , Caspase 8/genetics , Cell Line, Tumor , Chemokine CCL5/genetics , Chemokine CCL5/immunology , Chemokine CXCL10/genetics , Chemokine CXCL10/immunology , Coronavirus Infections/genetics , Coronavirus Infections/pathology , Coronavirus Infections/virology , Cytokine Release Syndrome/genetics , Cytokine Release Syndrome/pathology , Cytokine Release Syndrome/virology , Disease Models, Animal , Epithelial Cells/immunology , Epithelial Cells/pathology , Epithelial Cells/virology , Gene Expression Regulation , Humans , Interleukin-1beta/genetics , Interleukin-1beta/immunology , Interleukin-7/genetics , Interleukin-7/immunology , Interleukin-8/genetics , Interleukin-8/immunology , Lung/immunology , Lung/pathology , Lung/virology , Mice , Mice, Transgenic , Pandemics , Pneumonia, Viral/genetics , Pneumonia, Viral/pathology , Pneumonia, Viral/virology , Pulmonary Fibrosis/genetics , Pulmonary Fibrosis/pathology , Pulmonary Fibrosis/virology , SARS-CoV-2 , Tumor Necrosis Factor-alpha/genetics , Tumor Necrosis Factor-alpha/immunology
18.
Nat Commun ; 11(1): 4207, 2020 08 21.
Article in English | MEDLINE | ID: covidwho-724410

ABSTRACT

The rapid spread of coronavirus SARS-CoV-2 greatly threatens global public health but no prophylactic vaccine is available. Here, we report the generation of a replication-incompetent recombinant serotype 5 adenovirus, Ad5-S-nb2, carrying a codon-optimized gene encoding Spike protein (S). In mice and rhesus macaques, intramuscular injection with Ad5-S-nb2 elicits systemic S-specific antibody and cell-mediated immune (CMI) responses. Intranasal inoculation elicits both systemic and pulmonary antibody responses but weaker CMI response. At 30 days after a single vaccination with Ad5-S-nb2 either intramuscularly or intranasally, macaques are protected against SARS-CoV-2 challenge. A subsequent challenge reveals that macaques vaccinated with a 10-fold lower vaccine dosage (1 × 1010 viral particles) are also protected, demonstrating the effectiveness of Ad5-S-nb2 and the possibility of offering more vaccine dosages within a shorter timeframe. Thus, Ad5-S-nb2 is a promising candidate vaccine and warrants further clinical evaluation.


Subject(s)
Betacoronavirus/immunology , Coronavirus Infections/prevention & control , Pandemics/prevention & control , Pneumonia, Viral/prevention & control , Viral Vaccines/administration & dosage , Adenoviridae/genetics , Animals , Antibodies, Neutralizing/blood , Antibodies, Viral/blood , COVID-19 , COVID-19 Vaccines , Coronavirus Infections/immunology , Dose-Response Relationship, Immunologic , Female , HEK293 Cells , Humans , Immunity, Cellular , Macaca mulatta , Male , Mice , Mice, Inbred BALB C , Pneumonia, Viral/immunology , Respiratory System/pathology , Respiratory System/virology , SARS-CoV-2 , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/immunology , Vaccines, Synthetic/administration & dosage
19.
Curr Med Sci ; 40(4): 618-624, 2020 Aug.
Article in English | MEDLINE | ID: covidwho-695581

ABSTRACT

The COVID-19 pandemic caused by SARS-CoV2 is characterized by a remarkable variation in clinical severity ranging from a mild illness to a fatal multi-organ disease. Understanding the dysregulated human immune responses in the fatal subjects is critical for management of COVID-19 patients and the pandemic. In this study, we examined the immune cell compositions in the lung tissues and hilar lymph nodes using immunohistochemistry on 6 deceased COVID-19 patients and 4 focal organizing pneumonia (FOP) patients who underwent lung surgery and served as controls. We found a dominant presence of macrophages and a general deficiency of T cells and B cells in the lung tissues from deceased COVID-19 patients. In contrast to the FOP patients, Tfh cells and germinal center formation were largely absent in the draining hilar lymph nodes in the deceased COVID-19 patients. This was correlated with reduced IgM and IgG levels compared to convalescent COVID-19 patients. In summary, our data highlight a defect of germinal center structure in deceased COVID-19 patients leading to an impaired humoral immunity. Understanding the mechanisms of this deficiency will be one of the key points for the management of this epidemic.


Subject(s)
Betacoronavirus , Coronavirus Infections/immunology , Germinal Center/immunology , Pneumonia, Viral/immunology , T-Lymphocytes, Helper-Inducer/immunology , Adaptive Immunity , Aged , Aged, 80 and over , COVID-19 , Case-Control Studies , China/epidemiology , Coronavirus Infections/mortality , Coronavirus Infections/pathology , Fatal Outcome , Female , Germinal Center/pathology , Humans , Lymphopenia/immunology , Lymphopenia/mortality , Lymphopenia/pathology , Macrophages/immunology , Macrophages/pathology , Male , Middle Aged , Pandemics , Pneumonia, Viral/mortality , Pneumonia, Viral/pathology , SARS-CoV-2 , T-Lymphocytes, Helper-Inducer/pathology
20.
Cell Res ; 30(8): 670-677, 2020 08.
Article in English | MEDLINE | ID: covidwho-637104

ABSTRACT

The 2019 novel coronavirus (SARS-CoV-2) outbreak is a major challenge for public health. SARS-CoV-2 infection in human has a broad clinical spectrum ranging from mild to severe cases, with a mortality rate of ~6.4% worldwide (based on World Health Organization daily situation report). However, the dynamics of viral infection, replication and shedding are poorly understood. Here, we show that Rhesus macaques are susceptible to the infection by SARS-CoV-2. After intratracheal inoculation, the first peak of viral RNA was observed in oropharyngeal swabs one day post infection (1 d.p.i.), mainly from the input of the inoculation, while the second peak occurred at 5 d.p.i., which reflected on-site replication in the respiratory tract. Histopathological observation shows that SARS-CoV-2 infection can cause interstitial pneumonia in animals, characterized by hyperemia and edema, and infiltration of monocytes and lymphocytes in alveoli. We also identified SARS-CoV-2 RNA in respiratory tract tissues, including trachea, bronchus and lung; and viruses were also re-isolated from oropharyngeal swabs, bronchus and lung, respectively. Furthermore, we demonstrated that neutralizing antibodies generated from the primary infection could protect the Rhesus macaques from a second-round challenge by SARS-CoV-2. The non-human primate model that we established here provides a valuable platform to study SARS-CoV-2 pathogenesis and to evaluate candidate vaccines and therapeutics.


Subject(s)
Betacoronavirus/genetics , Betacoronavirus/immunology , Coronavirus Infections/pathology , Disease Models, Animal , Macaca mulatta/virology , Pneumonia, Viral/pathology , Animals , Antibodies, Neutralizing/blood , Antibodies, Neutralizing/immunology , Antibodies, Viral/blood , Antibodies, Viral/immunology , Betacoronavirus/isolation & purification , COVID-19 , Coronavirus Infections/blood , Coronavirus Infections/diagnostic imaging , Coronavirus Infections/virology , Female , Immunohistochemistry , Male , Pandemics , Pneumonia, Viral/blood , Pneumonia, Viral/diagnostic imaging , Pneumonia, Viral/virology , RNA, Viral/genetics , Radiography, Thoracic , Real-Time Polymerase Chain Reaction , SARS-CoV-2 , Viral Load , Virus Replication
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