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1.
iScience ; : 104223, 2022.
Article in English | ScienceDirect | ID: covidwho-1783436

ABSTRACT

Summary The effect of SARS-CoV-2 infection on placental function is not well understood. Analysis of placentas from women who tested positive at delivery showed SARS-CoV-2 genomic and subgenomic RNA in 22 out of 52 placentas. Placentas from two mothers with symptomatic COVID-19 whose pregnancies resulted in adverse outcomes for the fetuses contained high levels of viral Alpha variant RNA. The RNA was localized to the trophoblasts that cover the fetal chorionic villi that are in direct contact with maternal blood. The intervillous spaces and villi were infiltrated with maternal macrophages and T cells. Transcriptome analysis showed increased expression of chemokines and pathways associated with viral infection and inflammation. Infection of placental cultures with live SARS-CoV-2 and spike protein-pseudotyped lentivirus showed infection of syncytiotrophoblast and, in rare cases, endothelial cells mediated by ACE2 and Neuropilin-1. Viruses with Alpha, Beta and Delta variant spikes infected the placental cultures at significantly greater levels.

2.
EuropePMC; 2021.
Preprint in English | EuropePMC | ID: ppcovidwho-325129

ABSTRACT

The novel coronavirus pandemic (COVID-19) outbreak has provided a distinct opportunity to explore the mechanisms by which human activities affect air quality and pollution emissions. We conduct a quasi-difference-in-differences (DID) analysis of the impacts of lockdown measures on air pollution during the first wave of COVID-19 pandemic in China. Our study covers 367 cities from the beginning of the lockdown on January 23, 2020 until April 22, two weeks after the lockdown in epicenter was lifted. Static and dynamic analysis of the average treatment effects of treated effects is conducted for the air quality index (AQI) and six criteria pollutants. The results indicate that, first, on average, the AQI decreased by about 7%. However, it was still over the threshold of the World Health Organization (WHO). Second, we detect heterogeneous changes in the level of different pollutants, which suggests heterogeneous impacts of the lockdown on human activities: carbon monoxide (CO) had the biggest drop of about 30% and nitrogen dioxide (NO 2 ) had the second-biggest drop of 20%. In contrast, ozone (O 3 ) increased by 3.74% due to the improvement of visibility. We project that it would reduce the premature deaths related to air pollution by 150 thousand nationwide during the research period, which is much larger than the death due to COVID-19 infections. Third, air pollution rebounded immediately after the number of infections dropped, which indicates a swift recovery of human activities. This study provides insights for the implementation of environmental policies in China and other developing countries.JEL codes: Q51, Q52, Q53

4.
Cell Rep ; 37(6): 109920, 2021 11 09.
Article in English | MEDLINE | ID: covidwho-1530684

ABSTRACT

It is urgent to develop disease models to dissect mechanisms regulating severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Here, we derive airway organoids from human pluripotent stem cells (hPSC-AOs). The hPSC-AOs, particularly ciliated-like cells, are permissive to SARS-CoV-2 infection. Using this platform, we perform a high content screen and identify GW6471, which blocks SARS-CoV-2 infection. GW6471 can also block infection of the B.1.351 SARS-CoV-2 variant. RNA sequencing (RNA-seq) analysis suggests that GW6471 blocks SARS-CoV-2 infection at least in part by inhibiting hypoxia inducible factor 1 subunit alpha (HIF1α), which is further validated by chemical inhibitor and genetic perturbation targeting HIF1α. Metabolic profiling identifies decreased rates of glycolysis upon GW6471 treatment, consistent with transcriptome profiling. Finally, xanthohumol, 5-(tetradecyloxy)-2-furoic acid, and ND-646, three compounds that suppress fatty acid biosynthesis, also block SARS-CoV-2 infection. Together, a high content screen coupled with transcriptome and metabolic profiling reveals a key role of the HIF1α-glycolysis axis in mediating SARS-CoV-2 infection of human airway epithelium.


Subject(s)
COVID-19/metabolism , Glycolysis/physiology , Hypoxia-Inducible Factor 1, alpha Subunit/metabolism , Lung/metabolism , Organoids/metabolism , Animals , Cell Line , Chlorocebus aethiops , Epithelial Cells/metabolism , HEK293 Cells , Humans , Pluripotent Stem Cells/metabolism , SARS-CoV-2/pathogenicity , Transcriptome/physiology , Vero Cells
5.
Stem Cell Reports ; 16(9): 2274-2288, 2021 09 14.
Article in English | MEDLINE | ID: covidwho-1360129

ABSTRACT

Heart injury has been reported in up to 20% of COVID-19 patients, yet the cause of myocardial histopathology remains unknown. Here, using an established in vivo hamster model, we demonstrate that SARS-CoV-2 can be detected in cardiomyocytes of infected animals. Furthermore, we found damaged cardiomyocytes in hamsters and COVID-19 autopsy samples. To explore the mechanism, we show that both human pluripotent stem cell-derived cardiomyocytes (hPSC-derived CMs) and adult cardiomyocytes (CMs) can be productively infected by SARS-CoV-2, leading to secretion of the monocyte chemoattractant cytokine CCL2 and subsequent monocyte recruitment. Increased CCL2 expression and monocyte infiltration was also observed in the hearts of infected hamsters. Although infected CMs suffer damage, we find that the presence of macrophages significantly reduces SARS-CoV-2-infected CMs. Overall, our study provides direct evidence that SARS-CoV-2 infects CMs in vivo and suggests a mechanism of immune cell infiltration and histopathology in heart tissues of COVID-19 patients.


Subject(s)
COVID-19/pathology , Chemokine CCL2/metabolism , Heart Injuries/virology , Monocytes/immunology , Myocytes, Cardiac/metabolism , Animals , Cell Communication/physiology , Cell Line , Chlorocebus aethiops , Cricetinae , Disease Models, Animal , Humans , Macrophages/immunology , Male , Myocytes, Cardiac/virology , Pluripotent Stem Cells/cytology , Vero Cells
6.
Crit Rev Food Sci Nutr ; : 1-16, 2021 Aug 12.
Article in English | MEDLINE | ID: covidwho-1354194

ABSTRACT

As the second most abundant trace element in the human body, zinc nutrition is constantly a hot topic. More than one-third population is suffering zinc deficiency, which results in various types of diseases or nutritional deficiencies. Traditional ways of zinc supplementation seem with low absorption rates and significant side effects. Zinc supplements with dietary components are easily accessible and improve zinc utilization rate significantly. Also, mechanisms of maintaining zinc homeostasis are of broad interest. The present review focuses on zinc nutrition in human health in inductive methods. Mainly elaborate on different diseases relating to zinc disorder, highlighting the impact on the immune system and the recent COVID-19. Then raise food-derived zinc-binding compounds, including protein, peptide, polysaccharide, and polyphenol, and also analyze their possibilities to serve as zinc complementary. Finally, illustrate the way to maintain zinc homeostasis and the corresponding mechanisms. The review provides data information for maintaining zinc homeostasis with the food-derived matrix.

7.
Cell Metab ; 33(8): 1577-1591.e7, 2021 08 03.
Article in English | MEDLINE | ID: covidwho-1240259

ABSTRACT

Recent clinical data have suggested a correlation between coronavirus disease 2019 (COVID-19) and diabetes. Here, we describe the detection of SARS-CoV-2 viral antigen in pancreatic beta cells in autopsy samples from individuals with COVID-19. Single-cell RNA sequencing and immunostaining from ex vivo infections confirmed that multiple types of pancreatic islet cells were susceptible to SARS-CoV-2, eliciting a cellular stress response and the induction of chemokines. Upon SARS-CoV-2 infection, beta cells showed a lower expression of insulin and a higher expression of alpha and acinar cell markers, including glucagon and trypsin1, respectively, suggesting cellular transdifferentiation. Trajectory analysis indicated that SARS-CoV-2 induced eIF2-pathway-mediated beta cell transdifferentiation, a phenotype that could be reversed with trans-integrated stress response inhibitor (trans-ISRIB). Altogether, this study demonstrates an example of SARS-CoV-2 infection causing cell fate change, which provides further insight into the pathomechanisms of COVID-19.


Subject(s)
COVID-19/virology , Cell Transdifferentiation , Insulin-Secreting Cells/virology , SARS-CoV-2/pathogenicity , Acetamides/pharmacology , Adolescent , Adult , Aged , Aged, 80 and over , Animals , COVID-19/mortality , Cell Transdifferentiation/drug effects , Chlorocebus aethiops , Cyclohexylamines/pharmacology , Cytokines/metabolism , Eukaryotic Initiation Factor-2/metabolism , Female , Glucagon , Host-Pathogen Interactions , Humans , Insulin/metabolism , Insulin-Secreting Cells/drug effects , Insulin-Secreting Cells/metabolism , Insulin-Secreting Cells/pathology , Male , Middle Aged , Phenotype , Signal Transduction , Tissue Culture Techniques , Trypsin/metabolism , Vero Cells , Young Adult
9.
Int J Environ Res Public Health ; 18(7)2021 03 25.
Article in English | MEDLINE | ID: covidwho-1154402

ABSTRACT

The novel coronavirus (COVID-19) pandemic has provided a distinct opportunity to explore the mechanisms by which human activities affect air quality and pollution emissions. We conduct a quasi-difference-in-differences (DID) analysis of the impacts of lockdown measures on air pollution during the first wave of the COVID-19 pandemic in China. Our study covers 367 cities from the beginning of the lockdown on 23 January 2020 until April 22, two weeks after the lockdown in the epicenter was lifted. Static and dynamic analysis of the average treatment effects on the treated is conducted for the air quality index (AQI) and six criteria pollutants. The results indicate that, first, on average, the AQI decreased by about 7%. However, it was still over the threshold set by the World Health Organization. Second, we detect heterogeneous changes in the level of different pollutants, which suggests heterogeneous impacts of the lockdown on human activities: carbon monoxide (CO) had the biggest drop, about 30%, and nitrogen dioxide (NO2) had the second-biggest drop, 20%. In contrast, ozone (O3) increased by 3.74% due to the changes in the NOx/VOCs caused by the decrease in NOx, the decrease of O3 titration, and particulate matter concentration. Third, air pollution levels rebounded immediately after the number of infections dropped, which indicates a swift recovery of human activities. This study provides insights into the implementation of environmental policies in China and other developing countries.


Subject(s)
Air Pollutants , Air Pollution , COVID-19 , Air Pollutants/analysis , Air Pollution/analysis , China/epidemiology , Cities , Communicable Disease Control , Environmental Monitoring , Humans , Pandemics , Particulate Matter/analysis , SARS-CoV-2
10.
Nature ; 589(7841): 270-275, 2021 01.
Article in English | MEDLINE | ID: covidwho-1065893

ABSTRACT

There is an urgent need to create novel models using human disease-relevant cells to study severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) biology and to facilitate drug screening. Here, as SARS-CoV-2 primarily infects the respiratory tract, we developed a lung organoid model using human pluripotent stem cells (hPSC-LOs). The hPSC-LOs (particularly alveolar type-II-like cells) are permissive to SARS-CoV-2 infection, and showed robust induction of chemokines following SARS-CoV-2 infection, similar to what is seen in patients with COVID-19. Nearly 25% of these patients also have gastrointestinal manifestations, which are associated with worse COVID-19 outcomes1. We therefore also generated complementary hPSC-derived colonic organoids (hPSC-COs) to explore the response of colonic cells to SARS-CoV-2 infection. We found that multiple colonic cell types, especially enterocytes, express ACE2 and are permissive to SARS-CoV-2 infection. Using hPSC-LOs, we performed a high-throughput screen of drugs approved by the FDA (US Food and Drug Administration) and identified entry inhibitors of SARS-CoV-2, including imatinib, mycophenolic acid and quinacrine dihydrochloride. Treatment at physiologically relevant levels of these drugs significantly inhibited SARS-CoV-2 infection of both hPSC-LOs and hPSC-COs. Together, these data demonstrate that hPSC-LOs and hPSC-COs infected by SARS-CoV-2 can serve as disease models to study SARS-CoV-2 infection and provide a valuable resource for drug screening to identify candidate COVID-19 therapeutics.


Subject(s)
Antiviral Agents/pharmacology , COVID-19/virology , Colon/cytology , Drug Evaluation, Preclinical/methods , Lung/cytology , Organoids/drug effects , Organoids/virology , SARS-CoV-2/drug effects , Animals , COVID-19/drug therapy , COVID-19/prevention & control , Colon/drug effects , Colon/virology , Drug Approval , Female , Heterografts/drug effects , Humans , In Vitro Techniques , Lung/drug effects , Lung/virology , Male , Mice , Organoids/cytology , Organoids/metabolism , SARS-CoV-2/genetics , United States , United States Food and Drug Administration , Viral Tropism , Virus Internalization/drug effects
11.
Res Sq ; 2020 Nov 17.
Article in English | MEDLINE | ID: covidwho-946476

ABSTRACT

Heart injury has been reported in up to 20% of COVID-19 patients, yet the cause of myocardial histopathology remains unknown. In order to study the cause of myocardial pathology in COVID-19 patients, we used a hamster model to determine whether following infection SARS-CoV-2, the causative agent of COVID-19, can be detected in heart tissues. Here, we clearly demonstrate that viral RNA and nucleocapsid protein is present in cardiomyocytes in the hearts of infected hamsters. Interestingly, functional cardiomyocyte associated gene expression was decreased in infected hamster hearts, corresponding to an increase in reactive oxygen species (ROS). This data using an animal model was further validated using autopsy heart samples of COVID-19 patients. Moreover, we show that both human pluripotent stem cell-derived cardiomyocytes (hPSC-derived CMs) and adult cardiomyocytes (CMs) can be infected by SARS-CoV-2 and that CCL2 is secreted upon SARS-CoV-2 infection, leading to monocyte recruitment. Increased CCL2 expression and macrophage infiltration was also observed in the hearts of infected hamsters. Using single cell RNA-seq, we also show that macrophages are able to decrease SARS-CoV-2 infection of CMs. Overall, our study provides direct evidence that SARS-CoV-2 infects CMs in vivo and proposes a mechanism of immune-cell infiltration and pathology in heart tissue of COVID-19 patients.

12.
Res Sq ; 2020 Aug 20.
Article in English | MEDLINE | ID: covidwho-729814

ABSTRACT

Dysfunctional immune responses contribute critically to the progression of Coronavirus Disease-2019 (COVID-19) from mild to severe stages including fatality, with pro-inflammatory macrophages as one of the main mediators of lung hyper-inflammation. Therefore, there is an urgent need to better understand the interactions among SARS-CoV-2 permissive cells, macrophage, and the SARS-CoV-2 virus, thereby offering important insights into new therapeutic strategies. Here, we used directed differentiation of human pluripotent stem cells (hPSCs) to establish a lung and macrophage co-culture system and model the host-pathogen interaction and immune response caused by SARS-CoV-2 infection. Among the hPSC-derived lung cells, alveolar type II and ciliated cells are the major cell populations expressing the viral receptor ACE2 and co-effector TMPRSS2, and both were highly permissive to viral infection. We found that alternatively polarized macrophages (M2) and classically polarized macrophages (M1) had similar inhibitory effects on SARS-CoV-2 infection. However, only M1 macrophages significantly up-regulated inflammatory factors including IL-6 and IL-18, inhibiting growth and enhancing apoptosis of lung cells. Inhibiting viral entry into target cells using an ACE2 blocking antibody enhanced the activity of M2 macrophages, resulting in nearly complete clearance of virus and protection of lung cells. These results suggest a potential therapeutic strategy, in that by blocking viral entrance to target cells while boosting anti-inflammatory action of macrophages at an early stage of infection, M2 macrophages can eliminate SARS-CoV-2, while sparing lung cells and suppressing the dysfunctional hyper-inflammatory response mediated by M1 macrophages.

13.
Cell Stem Cell ; 27(1): 125-136.e7, 2020 07 02.
Article in English | MEDLINE | ID: covidwho-610467

ABSTRACT

SARS-CoV-2 has caused the COVID-19 pandemic. There is an urgent need for physiological models to study SARS-CoV-2 infection using human disease-relevant cells. COVID-19 pathophysiology includes respiratory failure but involves other organ systems including gut, liver, heart, and pancreas. We present an experimental platform comprised of cell and organoid derivatives from human pluripotent stem cells (hPSCs). A Spike-enabled pseudo-entry virus infects pancreatic endocrine cells, liver organoids, cardiomyocytes, and dopaminergic neurons. Recent clinical studies show a strong association with COVID-19 and diabetes. We find that human pancreatic beta cells and liver organoids are highly permissive to SARS-CoV-2 infection, further validated using adult primary human islets and adult hepatocyte and cholangiocyte organoids. SARS-CoV-2 infection caused striking expression of chemokines, as also seen in primary human COVID-19 pulmonary autopsy samples. hPSC-derived cells/organoids provide valuable models for understanding the cellular responses of human tissues to SARS-CoV-2 infection and for disease modeling of COVID-19.


Subject(s)
Betacoronavirus/physiology , Coronavirus Infections/virology , Induced Pluripotent Stem Cells/metabolism , Models, Biological , Organoids/virology , Pneumonia, Viral/virology , Tropism , Angiotensin-Converting Enzyme 2 , Animals , Autopsy , COVID-19 , Cell Line , Coronavirus Infections/pathology , Hepatocytes/pathology , Hepatocytes/virology , Humans , Induced Pluripotent Stem Cells/virology , Liver/pathology , Mice , Pancreas/pathology , Pancreas/virology , Pandemics , Peptidyl-Dipeptidase A/metabolism , Pneumonia, Viral/pathology , SARS-CoV-2 , Virus Internalization
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