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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.
Elife ; 112022 03 23.
Article in English | MEDLINE | ID: covidwho-1786253

ABSTRACT

Coagulopathy is a significant aspect of morbidity in COVID-19 patients. The clotting cascade is propagated by a series of proteases, including factor Xa and thrombin. While certain host proteases, including TMPRSS2 and furin, are known to be important for cleavage activation of SARS-CoV-2 spike to promote viral entry in the respiratory tract, other proteases may also contribute. Using biochemical and cell-based assays, we demonstrate that factor Xa and thrombin can also directly cleave SARS-CoV-2 spike, enhancing infection at the stage of viral entry. Coagulation factors increased SARS-CoV-2 infection in human lung organoids. A drug-repurposing screen identified a subset of protease inhibitors that promiscuously inhibited spike cleavage by both transmembrane serine proteases and coagulation factors. The mechanism of the protease inhibitors nafamostat and camostat may extend beyond inhibition of TMPRSS2 to coagulation-induced spike cleavage. Anticoagulation is critical in the management of COVID-19, and early intervention could provide collateral benefit by suppressing SARS-CoV-2 viral entry. We propose a model of positive feedback whereby infection-induced hypercoagulation exacerbates SARS-CoV-2 infectivity.


Subject(s)
COVID-19 , SARS-CoV-2 , Blood Coagulation Factors , Humans , Spike Glycoprotein, Coronavirus , Virus Internalization
3.
JCI Insight ; 7(5)2022 03 08.
Article in English | MEDLINE | ID: covidwho-1759583

ABSTRACT

Severe acute lung injury has few treatment options and a high mortality rate. Upon injury, neutrophils infiltrate the lungs and form neutrophil extracellular traps (NETs), damaging the lungs and driving an exacerbated immune response. Unfortunately, no drug preventing NET formation has completed clinical development. Here, we report that disulfiram - an FDA-approved drug for alcohol use disorder - dramatically reduced NETs, increased survival, improved blood oxygenation, and reduced lung edema in a transfusion-related acute lung injury (TRALI) mouse model. We then tested whether disulfiram could confer protection in the context of SARS-CoV-2 infection, as NETs are elevated in patients with severe COVID-19. In SARS-CoV-2-infected golden hamsters, disulfiram reduced NETs and perivascular fibrosis in the lungs, and it downregulated innate immune and complement/coagulation pathways, suggesting that it could be beneficial for patients with COVID-19. In conclusion, an existing FDA-approved drug can block NET formation and improve disease course in 2 rodent models of lung injury for which treatment options are limited.


Subject(s)
Acute Lung Injury/drug therapy , COVID-19/complications , Disulfiram/pharmacology , Extracellular Traps/drug effects , Lung/immunology , SARS-CoV-2 , Acetaldehyde Dehydrogenase Inhibitors/pharmacology , Acute Lung Injury/etiology , Animals , COVID-19/virology , Disease Models, Animal , Extracellular Traps/immunology , Rodentia
4.
EuropePMC;
Preprint in English | EuropePMC | ID: ppcovidwho-327768

ABSTRACT

Defects in mitochondrial oxidative phosphorylation (OXPHOS) have been reported in COVID-19 patients, but the timing and organs affected vary among reports. Here, we reveal the dynamics of COVID-19 through transcription profiles in nasopharyngeal and autopsy samples from patients and infected rodent models. While mitochondrial bioenergetics is repressed in the viral nasopharyngeal portal of entry, it is up regulated in autopsy lung tissues from deceased patients. In most disease stages and organs, discrete OXPHOS functions are blocked by the virus, and this is countered by the host broadly up regulating unblocked OXPHOS functions. No such rebound is seen in autopsy heart, results in severe repression of genes across all OXPHOS modules. Hence, targeted enhancement of mitochondrial gene expression may mitigate the pathogenesis of COVID-19.

5.
EuropePMC; 2021.
Preprint in English | EuropePMC | ID: ppcovidwho-310674

ABSTRACT

SARS-CoV-2, the virus responsible for the COVID-19 pandemic, has been found capable of inducing long term effects commonly referred to as post-acute sequelae of SARS-CoV-2 (PASC) or long COVID. To define the molecular basis of this condition, we compared the short- and long-term responses to influenza A virus and SARSCoV-2 in the golden hamster model. These data demonstrated that SARS-CoV-2 resulted in sustained changes to lung, kidney, and brain. The most significant change in response to SARS-CoV-2 was observed in the olfactory bulb, where persistent inflammation was visible beyond one month post infection. This was characterized by microglial activation, pro-inflammatory cytokine production, and a Type I interferon (IFN-I) response in the absence of detectable virus. Given the connection between olfactory bulb injury and neurological disorders, we postulate that this prolonged inflammation is an underlying cause of long COVID.Funding Information: This work was funded by generous support from the Marc Haas Foundation, the National Institutes of Health (NCI (R01CA234614) and NIAID (2R01AI107301) and NIDDK (R01DK121072 and 1RO3DK117252) to Department of Medicine, Weill Cornell Medicine (R.E.S.)), and DARPA’s PREPARE Program (HR0011-20-2-0040). The work was further funded by NINDS (NS111251, NSO86444, NSO86444S1)(V.Z., R.A.S.).Ethics Approval Statement: The Tissue Procurement Facility operates under Institutional Review Board (IRB) approved protocol and follows guidelines set by Health Insurance Portability and Accountability Act (HIPAA). Experiments using samples from human subjects were conducted in accordance with local regulations and with the approval of the IRB at the Weill Cornell Medicine. The autopsy samples are considered human tissue research and were collected under IRB protocols 20-04021814 and 19-11021069. All autopsies have consent for research use from next of kin, and these studies were determined as exempt by IRB at Weill Cornell Medicine under those protocol numbers.

6.
Cell Rep Med ; 3(2): 100522, 2022 02 15.
Article in English | MEDLINE | ID: covidwho-1650891

ABSTRACT

The molecular mechanisms underlying the clinical manifestations of coronavirus disease 2019 (COVID-19), and what distinguishes them from common seasonal influenza virus and other lung injury states such as acute respiratory distress syndrome, remain poorly understood. To address these challenges, we combine transcriptional profiling of 646 clinical nasopharyngeal swabs and 39 patient autopsy tissues to define body-wide transcriptome changes in response to COVID-19. We then match these data with spatial protein and expression profiling across 357 tissue sections from 16 representative patient lung samples and identify tissue-compartment-specific damage wrought by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, evident as a function of varying viral loads during the clinical course of infection and tissue-type-specific expression states. Overall, our findings reveal a systemic disruption of canonical cellular and transcriptional pathways across all tissues, which can inform subsequent studies to combat the mortality of COVID-19 and to better understand the molecular dynamics of lethal SARS-CoV-2 and other respiratory infections.


Subject(s)
COVID-19/genetics , COVID-19/pathology , Lung/pathology , SARS-CoV-2 , Transcriptome/genetics , Adult , Aged , Aged, 80 and over , COVID-19/metabolism , COVID-19/virology , Case-Control Studies , Cohort Studies , Female , Gene Expression Regulation , Humans , Influenza, Human/genetics , Influenza, Human/pathology , Influenza, Human/virology , Lung/metabolism , Male , Middle Aged , Orthomyxoviridae , RNA-Seq/methods , Respiratory Distress Syndrome/genetics , Respiratory Distress Syndrome/microbiology , Respiratory Distress Syndrome/pathology , Viral Load
9.
J Leukoc Biol ; 110(1): 21-26, 2021 07.
Article in English | MEDLINE | ID: covidwho-1574077

ABSTRACT

The global pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a highly pathogenic RNA virus causing coronavirus disease 2019 (COVID-19) in humans. Although most patients with COVID-19 have mild illness and may be asymptomatic, some will develop severe pneumonia, acute respiratory distress syndrome, multi-organ failure, and death. RNA viruses such as SARS-CoV-2 are capable of hijacking the epigenetic landscape of host immune cells to evade antiviral defense. Yet, there remain considerable gaps in our understanding of immune cell epigenetic changes associated with severe SARS-CoV-2 infection pathology. Here, we examined genome-wide DNA methylation (DNAm) profiles of peripheral blood mononuclear cells from 9 terminally-ill, critical COVID-19 patients with confirmed SARS-CoV-2 plasma viremia compared with uninfected, hospitalized influenza, untreated primary HIV infection, and mild/moderate COVID-19 HIV coinfected individuals. Cell-type deconvolution analyses confirmed lymphopenia in severe COVID-19 and revealed a high percentage of estimated neutrophils suggesting perturbations to DNAm associated with granulopoiesis. We observed a distinct DNAm signature of severe COVID-19 characterized by hypermethylation of IFN-related genes and hypomethylation of inflammatory genes, reinforcing observations in infection models and single-cell transcriptional studies of severe COVID-19. Epigenetic clock analyses revealed severe COVID-19 was associated with an increased DNAm age and elevated mortality risk according to GrimAge, further validating the epigenetic clock as a predictor of disease and mortality risk. Our epigenetic results reveal a discovery DNAm signature of severe COVID-19 in blood potentially useful for corroborating clinical assessments, informing pathogenic mechanisms, and revealing new therapeutic targets against SARS-CoV-2.


Subject(s)
COVID-19/genetics , DNA Methylation/genetics , Epigenesis, Genetic , Genome, Human , COVID-19/virology , HIV Infections/genetics , Humans , Influenza, Human/genetics , SARS-CoV-2/physiology
12.
Cell Metab ; 33(11): 2174-2188.e5, 2021 11 02.
Article in English | MEDLINE | ID: covidwho-1446535

ABSTRACT

Individuals infected with SARS-CoV-2 who also display hyperglycemia suffer from longer hospital stays, higher risk of developing acute respiratory distress syndrome (ARDS), and increased mortality. Nevertheless, the pathophysiological mechanism of hyperglycemia in COVID-19 remains poorly characterized. Here, we show that hyperglycemia is similarly prevalent among patients with ARDS independent of COVID-19 status. Yet among patients with ARDS and COVID-19, insulin resistance is the prevalent cause of hyperglycemia, independent of glucocorticoid treatment, which is unlike patients with ARDS but without COVID-19, where pancreatic beta cell failure predominates. A screen of glucoregulatory hormones revealed lower levels of adiponectin in patients with COVID-19. Hamsters infected with SARS-CoV-2 demonstrated a strong antiviral gene expression program in the adipose tissue and diminished expression of adiponectin. Moreover, we show that SARS-CoV-2 can infect adipocytes. Together these data suggest that SARS-CoV-2 may trigger adipose tissue dysfunction to drive insulin resistance and adverse outcomes in acute COVID-19.

13.
J Virol ; 95(23): e0125721, 2021 11 09.
Article in English | MEDLINE | ID: covidwho-1410202

ABSTRACT

SARS-CoV-2, the etiological agent of COVID-19, is characterized by a delay in type I interferon (IFN-I)-mediated antiviral defenses alongside robust cytokine production. Here, we investigate the underlying molecular basis for this imbalance and implicate virus-mediated activation of NF-κB in the absence of other canonical IFN-I-related transcription factors. Epigenetic and single-cell transcriptomic analyses show a selective NF-κB signature that was most prominent in infected cells. Disruption of NF-κB signaling through the silencing of the NF-κB transcription factor p65 or p50 resulted in loss of virus replication that was rescued upon reconstitution. These findings could be further corroborated with the use of NF-κB inhibitors, which reduced SARS-CoV-2 replication in vitro. These data suggest that the robust cytokine production in response to SARS-CoV-2, despite a diminished IFN-I response, is the product of a dependency on NF-κB for viral replication. IMPORTANCE The COVID-19 pandemic has caused significant mortality and morbidity around the world. Although effective vaccines have been developed, large parts of the world remain unvaccinated while new SARS-CoV-2 variants keep emerging. Furthermore, despite extensive efforts and large-scale drug screenings, no fully effective antiviral treatment options have been discovered yet. Therefore, it is of the utmost importance to gain a better understanding of essential factors driving SARS-CoV-2 replication to be able to develop novel approaches to target SARS-CoV-2 biology.


Subject(s)
COVID-19/metabolism , Cytokines/metabolism , Interferon Type I/metabolism , SARS-CoV-2 , Transcription Factor RelA/metabolism , Transcriptome , Virus Replication , A549 Cells , Animals , COVID-19/virology , Chlorocebus aethiops , Epigenomics , Gene Expression Regulation , HEK293 Cells , HeLa Cells , Host Microbial Interactions , Humans , Signal Transduction , Single-Cell Analysis , Transcription Factor RelA/antagonists & inhibitors , Transcription Factor RelA/genetics , Transcription Factors/metabolism , Vero Cells
14.
Mol Med ; 27(1): 105, 2021 09 09.
Article in English | MEDLINE | ID: covidwho-1403209

ABSTRACT

BACKGROUND: Vaccination programs have been launched worldwide to halt the spread of COVID-19. However, the identification of existing, safe compounds with combined treatment and prophylactic properties would be beneficial to individuals who are waiting to be vaccinated, particularly in less economically developed countries, where vaccine availability may be initially limited. METHODS: We used a data-driven approach, combining results from the screening of a large transcriptomic database (L1000) and molecular docking analyses, with in vitro tests using a lung organoid model of SARS-CoV-2 entry, to identify drugs with putative multimodal properties against COVID-19. RESULTS: Out of thousands of FDA-approved drugs considered, we observed that atorvastatin was the most promising candidate, as its effects negatively correlated with the transcriptional changes associated with infection. Atorvastatin was further predicted to bind to SARS-CoV-2's main protease and RNA-dependent RNA polymerase, and was shown to inhibit viral entry in our lung organoid model. CONCLUSIONS: Small clinical studies reported that general statin use, and specifically, atorvastatin use, are associated with protective effects against COVID-19. Our study corroborrates these findings and supports the investigation of atorvastatin in larger clinical studies. Ultimately, our framework demonstrates one promising way to fast-track the identification of compounds for COVID-19, which could similarly be applied when tackling future pandemics.


Subject(s)
Antiviral Agents/pharmacology , Atorvastatin/pharmacology , COVID-19/drug therapy , Lung/drug effects , Organoids/drug effects , SARS-CoV-2/drug effects , Antiviral Agents/chemistry , Atorvastatin/chemistry , COVID-19/prevention & control , Cell Line , Coronavirus 3C Proteases/chemistry , Coronavirus RNA-Dependent RNA Polymerase/chemistry , Doxycycline/pharmacology , Drug Approval , Drug Repositioning , Gene Expression Regulation/drug effects , Humans , Lung/virology , Models, Biological , Molecular Docking Simulation , Organoids/virology , Raloxifene Hydrochloride/chemistry , Raloxifene Hydrochloride/pharmacology , SARS-CoV-2/physiology , Spike Glycoprotein, Coronavirus/genetics , Trifluoperazine/chemistry , Trifluoperazine/pharmacology , United States , United States Food and Drug Administration , Vesiculovirus/genetics , Virus Internalization/drug effects
15.
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
16.
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
17.
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
19.
Nature ; 593(7860): 564-569, 2021 05.
Article in English | MEDLINE | ID: covidwho-1155701

ABSTRACT

Recent studies have provided insights into the pathology of and immune response to COVID-191-8. However, a thorough investigation of the interplay between infected cells and the immune system at sites of infection has been lacking. Here we use high-parameter imaging mass cytometry9 that targets the expression of 36 proteins to investigate the cellular composition and spatial architecture of acute lung injury in humans (including injuries derived from SARS-CoV-2 infection) at single-cell resolution. These spatially resolved single-cell data unravel the disordered structure of the infected and injured lung, alongside the distribution of extensive immune infiltration. Neutrophil and macrophage infiltration are hallmarks of bacterial pneumonia and COVID-19, respectively. We provide evidence that SARS-CoV-2 infects predominantly alveolar epithelial cells and induces a localized hyperinflammatory cell state that is associated with lung damage. We leverage the temporal range of fatal outcomes of COVID-19 in relation to the onset of symptoms, which reveals increased macrophage extravasation and increased numbers of mesenchymal cells and fibroblasts concomitant with increased proximity between these cell types as the disease progresses-possibly as a result of attempts to repair the damaged lung tissue. Our data enable us to develop a biologically interpretable landscape of lung pathology from a structural, immunological and clinical standpoint. We use this landscape to characterize the pathophysiology of the human lung from its macroscopic presentation to the single-cell level, which provides an important basis for understanding COVID-19 and lung pathology in general.


Subject(s)
COVID-19/pathology , COVID-19/virology , Disease Progression , Lung/pathology , Lung/virology , SARS-CoV-2/pathogenicity , Single-Cell Analysis , Alveolar Epithelial Cells/pathology , Alveolar Epithelial Cells/virology , COVID-19/mortality , COVID-19/physiopathology , Humans , Inflammation/pathology , Inflammation/physiopathology , Inflammation/virology , Lung/physiopathology , Macrophages/immunology , Neutrophils/immunology , Time Factors , Viral Tropism
20.
Gastroenterology ; 160(7): 2435-2450.e34, 2021 06.
Article in English | MEDLINE | ID: covidwho-1116737

ABSTRACT

BACKGROUND & AIMS: Given that gastrointestinal (GI) symptoms are a prominent extrapulmonary manifestation of COVID-19, we investigated intestinal infection with SARS-CoV-2, its effect on pathogenesis, and clinical significance. METHODS: Human intestinal biopsy tissues were obtained from patients with COVID-19 (n = 19) and uninfected control individuals (n = 10) for microscopic examination, cytometry by time of flight analyses, and RNA sequencing. Additionally, disease severity and mortality were examined in patients with and without GI symptoms in 2 large, independent cohorts of hospitalized patients in the United States (N = 634) and Europe (N = 287) using multivariate logistic regressions. RESULTS: COVID-19 case patients and control individuals in the biopsy cohort were comparable for age, sex, rates of hospitalization, and relevant comorbid conditions. SARS-CoV-2 was detected in small intestinal epithelial cells by immunofluorescence staining or electron microscopy in 15 of 17 patients studied. High-dimensional analyses of GI tissues showed low levels of inflammation, including down-regulation of key inflammatory genes including IFNG, CXCL8, CXCL2, and IL1B and reduced frequencies of proinflammatory dendritic cells compared with control individuals. Consistent with these findings, we found a significant reduction in disease severity and mortality in patients presenting with GI symptoms that was independent of sex, age, and comorbid illnesses and despite similar nasopharyngeal SARS-CoV-2 viral loads. Furthermore, there was reduced levels of key inflammatory proteins in circulation in patients with GI symptoms. CONCLUSIONS: These data highlight the absence of a proinflammatory response in the GI tract despite detection of SARS-CoV-2. In parallel, reduced mortality in patients with COVID-19 presenting with GI symptoms was observed. A potential role of the GI tract in attenuating SARS-CoV-2-associated inflammation needs to be further examined.


Subject(s)
COVID-19/virology , Gastrointestinal Diseases/virology , Immunity, Mucosal , Intestinal Mucosa/virology , SARS-CoV-2/pathogenicity , Aged , Aged, 80 and over , COVID-19/diagnosis , COVID-19/immunology , COVID-19/mortality , Case-Control Studies , Cells, Cultured , Cytokines/blood , Female , Gastrointestinal Diseases/diagnosis , Gastrointestinal Diseases/immunology , Gastrointestinal Diseases/mortality , Host-Pathogen Interactions , Humans , Inflammation Mediators/blood , Intestinal Mucosa/immunology , Italy , Male , Middle Aged , New York City , Prognosis , Risk Assessment , Risk Factors , SARS-CoV-2/immunology , Viral Load
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