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1.
Brief Bioinform ; 23(1)2022 01 17.
Article in English | MEDLINE | ID: covidwho-1545905

ABSTRACT

Spatial transcriptomics has been emerging as a powerful technique for resolving gene expression profiles while retaining tissue spatial information. These spatially resolved transcriptomics make it feasible to examine the complex multicellular systems of different microenvironments. To answer scientific questions with spatial transcriptomics and expand our understanding of how cell types and states are regulated by microenvironment, the first step is to identify cell clusters by integrating the available spatial information. Here, we introduce SC-MEB, an empirical Bayes approach for spatial clustering analysis using a hidden Markov random field. We have also derived an efficient expectation-maximization algorithm based on an iterative conditional mode for SC-MEB. In contrast to BayesSpace, a recently developed method, SC-MEB is not only computationally efficient and scalable to large sample sizes but is also capable of choosing the smoothness parameter and the number of clusters. We performed comprehensive simulation studies to demonstrate the superiority of SC-MEB over some existing methods. We applied SC-MEB to analyze the spatial transcriptome of human dorsolateral prefrontal cortex tissues and mouse hypothalamic preoptic region. Our analysis results showed that SC-MEB can achieve a similar or better clustering performance to BayesSpace, which uses the true number of clusters and a fixed smoothness parameter. Moreover, SC-MEB is scalable to large 'sample sizes'. We then employed SC-MEB to analyze a colon dataset from a patient with colorectal cancer (CRC) and COVID-19, and further performed differential expression analysis to identify signature genes related to the clustering results. The heatmap of identified signature genes showed that the clusters identified using SC-MEB were more separable than those obtained with BayesSpace. Using pathway analysis, we identified three immune-related clusters, and in a further comparison, found the mean expression of COVID-19 signature genes was greater in immune than non-immune regions of colon tissue. SC-MEB provides a valuable computational tool for investigating the structural organizations of tissues from spatial transcriptomic data.


Subject(s)
Algorithms , COVID-19/metabolism , Computer Simulation , Gene Expression Profiling , SARS-CoV-2/metabolism , Animals , Colon/metabolism , Colorectal Neoplasms/metabolism , Humans , Hypothalamus/metabolism , Markov Chains , Mice
2.
Gut Microbes ; 13(1): 1984105, 2021.
Article in English | MEDLINE | ID: covidwho-1462225

ABSTRACT

Infection with severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) is responsible for the COVID-19 pandemic. Angiotensin-converting enzyme 2 (Ace2) is expressed in the gastrointestinal (GI) tract and a receptor for SARS-CoV-2, making the GI tract a potential infection site. This study investigated the effects of commensal intestinal microbiota on colonic Ace2 expression using a humanized mouse model. We found that colonic Ace2 expression decreased significantly upon microbial colonization. Humanization with healthy volunteer or dysbiotic microbiota from irritable bowel syndrome (IBS) patients resulted in similar Ace2 expression. Despite the differences in microbiota, no associations between α-diversity, ß-diversity or individual taxa, and Ace2 were noted post-humanization. These results highlight that commensal microbiota play a key role in regulating intestinal Ace2 expression and the need to further examine the underlying mechanisms of this regulation.


Subject(s)
Angiotensin-Converting Enzyme 2/metabolism , Colon/metabolism , Gastrointestinal Microbiome , Animals , Colon/microbiology , Dysbiosis , Gene Expression Regulation , Germ-Free Life , Humans , Inflammatory Bowel Diseases/microbiology , Mice , Receptors, Virus/metabolism , SARS-CoV-2
4.
Elife ; 102021 07 06.
Article in English | MEDLINE | ID: covidwho-1298242

ABSTRACT

Background: To understand a causal role of modifiable lifestyle factors in angiotensin-converting enzyme 2 (ACE2) expression (a putative severe acute respiratory syndrome coronavirus 2 [SARS-CoV-2] receptor) across 44 human tissues/organs, and in coronavirus disease 2019 (COVID-19) susceptibility and severity, we conducted a phenome-wide two-sample Mendelian randomization (MR) study. Methods: More than 500 genetic variants were used as instrumental variables to predict smoking and alcohol consumption. Inverse-variance weighted approach was adopted as the primary method to estimate a causal association, while MR-Egger regression, weighted median, and MR pleiotropy residual sum and outlier (MR-PRESSO) were performed to identify potential horizontal pleiotropy. Results: We found that genetically predicted smoking intensity significantly increased ACE2 expression in thyroid (ß=1.468, p=1.8×10-8), and increased ACE2 expression in adipose, brain, colon, and liver with nominal significance. Additionally, genetically predicted smoking initiation significantly increased the risk of COVID-19 onset (odds ratio=1.14, p=8.7×10-5). No statistically significant result was observed for alcohol consumption. Conclusions: Our work demonstrates an important role of smoking, measured by both status and intensity, in the susceptibility to COVID-19. Funding: XJ is supported by research grants from the Swedish Research Council (VR-2018-02247) and Swedish Research Council for Health, Working Life and Welfare (FORTE-2020-00884).


Subject(s)
Angiotensin-Converting Enzyme 2/metabolism , COVID-19/pathology , Mendelian Randomization Analysis , SARS-CoV-2/physiology , Tobacco Smoking/adverse effects , Adipose Tissue/metabolism , Alcohol Drinking/genetics , Angiotensin-Converting Enzyme 2/genetics , Brain/metabolism , COVID-19/virology , Causality , Colon/metabolism , Gene Expression Regulation , Humans , Liver/metabolism , Polymorphism, Single Nucleotide , Thyroid Gland/metabolism
5.
Pharmacol Res ; 167: 105548, 2021 05.
Article in English | MEDLINE | ID: covidwho-1135540

ABSTRACT

Acute Respiratory Distress Syndrome (ARDS) is triggered by a variety of agents, including Staphylococcal Enterotoxin B (SEB). Interestingly, a significant proportion of patients with COVID-19, also develop ARDS. In the absence of effective treatments, ARDS results in almost 40% mortality. Previous studies from our laboratory demonstrated that resveratrol (RES), a stilbenoid, with potent anti-inflammatory properties can attenuate SEB-induced ARDS. In the current study, we investigated the role of RES-induced alterations in the gut and lung microbiota in the regulation of ARDS. Our studies revealed that SEB administration induced inflammatory cytokines, ARDS, and 100% mortality in C3H/HeJ mice. Additionally, SEB caused a significant increase in pathogenic Proteobacteria phylum and Propionibacterium acnes species in the lungs. In contrast, RES treatment attenuated SEB-mediated ARDS and mortality in mice, and significantly increased probiotic Actinobacteria phylum, Tenericutes phylum, and Lactobacillus reuteri species in both the colon and lungs. Colonic Microbiota Transplantation (CMT) from SEB-injected mice that were treated with RES as well as the transfer of L. reuteri into recipient mice inhibited the production of SEB-mediated induction of pro-inflammatory cytokines such as IFN-γ and IL-17 but increased that of anti-inflammatory IL-10. Additionally, such CMT and L. reuteri recipient mice exposed to SEB, showed a decrease in lung-infiltrating mononuclear cells, cytotoxic CD8+ T cells, NKT cells, Th1 cells, and Th17 cells, but an increase in the population of regulatory T cells (Tregs) and Th3 cells, and increase in the survival of mice from SEB-mediated ARDS. Together, the current study demonstrates that ARDS induced by SEB triggers dysbiosis in the lungs and gut and that attenuation of ARDS by RES may be mediated, at least in part, by alterations in microbiota in the lungs and the gut, especially through the induction of beneficial bacteria such as L. reuteri.


Subject(s)
Anti-Inflammatory Agents/pharmacology , Colon/drug effects , Enterotoxins , Fecal Microbiota Transplantation , Gastrointestinal Microbiome/drug effects , Lung/drug effects , Respiratory Distress Syndrome/prevention & control , Resveratrol/pharmacology , Superantigens , Animals , Cell Line , Colon/immunology , Colon/metabolism , Colon/microbiology , Cytokines/metabolism , Disease Models, Animal , Dysbiosis , Female , Inflammation Mediators/metabolism , Lactobacillus reuteri/drug effects , Lactobacillus reuteri/growth & development , Lung/immunology , Lung/metabolism , Lung/microbiology , Mice, Inbred C3H , Respiratory Distress Syndrome/immunology , Respiratory Distress Syndrome/metabolism , Respiratory Distress Syndrome/microbiology
6.
Nat Rev Gastroenterol Hepatol ; 18(4): 269-283, 2021 04.
Article in English | MEDLINE | ID: covidwho-1085424

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread to more than 200 countries and regions globally. SARS-CoV-2 is thought to spread mainly through respiratory droplets and close contact. However, reports have shown that a notable proportion of patients with coronavirus disease 2019 (COVID-19) develop gastrointestinal symptoms and nearly half of patients confirmed to have COVID-19 have shown detectable SARS-CoV-2 RNA in their faecal samples. Moreover, SARS-CoV-2 infection reportedly alters intestinal microbiota, which correlated with the expression of inflammatory factors. Furthermore, multiple in vitro and in vivo animal studies have provided direct evidence of intestinal infection by SARS-CoV-2. These lines of evidence highlight the nature of SARS-CoV-2 gastrointestinal infection and its potential faecal-oral transmission. Here, we summarize the current findings on the gastrointestinal manifestations of COVID-19 and its possible mechanisms. We also discuss how SARS-CoV-2 gastrointestinal infection might occur and the current evidence and future studies needed to establish the occurrence of faecal-oral transmission.


Subject(s)
COVID-19/physiopathology , Diarrhea/physiopathology , Dysbiosis/physiopathology , Gastroenteritis/physiopathology , Gastrointestinal Microbiome , Nausea/physiopathology , Vomiting/physiopathology , Abdominal Pain/physiopathology , Angiotensin-Converting Enzyme 2/metabolism , Animals , Anorexia/physiopathology , COVID-19/transmission , Cell Line , Colon/metabolism , Cytokines/metabolism , Disease Models, Animal , Feces/chemistry , Gastroenteritis/virology , Humans , Intestinal Mucosa/metabolism , Intestine, Small/metabolism , Leukocyte L1 Antigen Complex/metabolism , Organoids , RNA, Viral , Receptors, Coronavirus/metabolism , SARS-CoV-2/metabolism , Serine Endopeptidases/metabolism , Viral Load , Virus Shedding
7.
Life Sci ; 264: 118450, 2021 Jan 01.
Article in English | MEDLINE | ID: covidwho-885374

ABSTRACT

AIMS: Hydroxychloroquine (HCQ), a widely used antimalarial drug, is proposed to treat coronavirus disease 2019 (COVID-19). However, no report is currently available regarding the direct effects of HCQ on gut microbiota, which is associated with the outcomes of elderly patients with COVID-19. Here, we first investigated the effects of HCQ on intestinal microecology in mice. MAIN METHODS: Fifteen female C57BL/6J mice were randomly divided into two groups: HCQ group (n = 10) and control group (n = 5). Mice in the HCQ group were administered with HCQ at dose of 100 mg/kg by gavage daily for 14 days. The feces of mice were collected before and on the 7th and 14th days after HCQ challenge, and then analyzed by 16S rRNA amplicon sequencing. At the end of the experiment, the hematology, serum biochemistry and cytokines were determined, respectively. The mRNA expression of tight junction proteins in colonic tissues were also studied by RT-PCR. KEY FINDINGS: HCQ challenge had no effects on the counts of white blood cells, the levels of serum cytokines, and the gene expression of tight junction proteins in colon. HCQ also did not increase the content of serum d-lactate in mice. Notably, HCQ significantly decreased the diversity of gut microbiota, increased the relative abundance of phylum Bacteroidetes whereas decreased that of Firmicutes. SIGNIFICANCE: Short-term high dose HCQ challenge changes gut microbiota but not the intestinal integrity and immunological responses in mice. Special attention should be paid to the effects of HCQ on intestinal microecology in future clinical use.


Subject(s)
Colon/drug effects , Colon/immunology , Gastrointestinal Microbiome/drug effects , Gastrointestinal Microbiome/immunology , Hydroxychloroquine/administration & dosage , Hydroxychloroquine/adverse effects , Administration, Oral , Animals , Colon/metabolism , Cytokines/blood , Cytokines/immunology , Feces/microbiology , Female , Lactic Acid/blood , Mice , RNA, Ribosomal, 16S/genetics , Tight Junction Proteins/biosynthesis
8.
Proc Natl Acad Sci U S A ; 117(45): 28336-28343, 2020 11 10.
Article in English | MEDLINE | ID: covidwho-882991

ABSTRACT

Coronavirus disease 2019 (COVID-19), the global pandemic caused by SARS-CoV-2, has resulted thus far in greater than 933,000 deaths worldwide; yet disease pathogenesis remains unclear. Clinical and immunological features of patients with COVID-19 have highlighted a potential role for changes in immune activity in regulating disease severity. However, little is known about the responses in human lung tissue, the primary site of infection. Here we show that pathways related to neutrophil activation and pulmonary fibrosis are among the major up-regulated transcriptional signatures in lung tissue obtained from patients who died of COVID-19 in Wuhan, China. Strikingly, the viral burden was low in all samples, which suggests that the patient deaths may be related to the host response rather than an active fulminant infection. Examination of the colonic transcriptome of these patients suggested that SARS-CoV-2 impacted host responses even at a site with no obvious pathogenesis. Further proteomics analysis validated our transcriptome findings and identified several key proteins, such as the SARS-CoV-2 entry-associated protease cathepsins B and L and the inflammatory response modulator S100A8/A9, that are highly expressed in fatal cases, revealing potential drug targets for COVID-19.


Subject(s)
COVID-19/metabolism , Proteome/metabolism , Transcriptome , Aged , Aged, 80 and over , COVID-19/genetics , COVID-19/immunology , COVID-19/pathology , Colon/metabolism , Fatal Outcome , Female , Humans , Lung/metabolism , Lung/pathology , Lung/virology , Male , Middle Aged , Neutrophil Activation , Proteome/genetics , SARS-CoV-2/pathogenicity , Viral Load
9.
Signal Transduct Target Ther ; 5(1): 121, 2020 07 08.
Article in English | MEDLINE | ID: covidwho-640304
10.
J Mol Cell Biol ; 12(12): 946-957, 2020 06 11.
Article in English | MEDLINE | ID: covidwho-637628

ABSTRACT

For patients with COVID-19 caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the damages to multiple organs have been clinically observed. Since most of current investigations for virus-host interaction are based on cell level, there is an urgent demand to probe tissue-specific features associated with SARS-CoV-2 infection. Based on collected proteomic datasets from human lung, colon, kidney, liver, and heart, we constructed a virus-receptor network, a virus-interaction network, and a virus-perturbation network. In the tissue-specific networks associated with virus-host crosstalk, both common and different key hubs are revealed in diverse tissues. Ubiquitous hubs in multiple tissues such as BRD4 and RIPK1 would be promising drug targets to rescue multi-organ injury and deal with inflammation. Certain tissue-unique hubs such as REEP5 might mediate specific olfactory dysfunction. The present analysis implies that SARS-CoV-2 could affect multi-targets in diverse host tissues, and the treatment of COVID-19 would be a complex task.


Subject(s)
COVID-19/metabolism , COVID-19/virology , Host Microbial Interactions/physiology , Proteome/metabolism , SARS-CoV-2 , Cell Cycle Proteins/metabolism , Colon/metabolism , Colon/virology , Heart/virology , Humans , Kidney/metabolism , Kidney/virology , Liver/metabolism , Liver/virology , Lung/metabolism , Lung/virology , Membrane Proteins/metabolism , Metabolic Networks and Pathways , Myocardium/metabolism , Pandemics , Protein Interaction Maps , Proteomics , Receptor-Interacting Protein Serine-Threonine Kinases/metabolism , Receptors, Virus/metabolism , SARS-CoV-2/pathogenicity , SARS-CoV-2/physiology , Tissue Distribution , Transcription Factors/metabolism
13.
Inflamm Bowel Dis ; 26(6): 797-808, 2020 05 12.
Article in English | MEDLINE | ID: covidwho-116826

ABSTRACT

BACKGROUND: Patients with inflammatory bowel disease (IBD) have intestinal inflammation and are treated with immune-modulating medications. In the face of the coronavirus disease-19 pandemic, we do not know whether patients with IBD will be more susceptible to infection or disease. We hypothesized that the viral entry molecules angiotensin I converting enzyme 2 (ACE2) and transmembrane serine protease 2 (TMPRSS2) are expressed in the intestine. We further hypothesized that their expression could be affected by inflammation or medication usage. METHODS: We examined the expression of Ace2 and Tmprss2 by quantitative polymerase chain reacion in animal models of IBD. Publicly available data from organoids and mucosal biopsies from patients with IBD were examined for expression of ACE2 and TMPRSS2. We conducted RNA sequencing for CD11b-enriched cells and peripheral and lamina propria T-cells from well-annotated patient samples. RESULTS: ACE2 and TMPRSS2 were abundantly expressed in the ileum and colon and had high expression in intestinal epithelial cells. In animal models, inflammation led to downregulation of epithelial Ace2. Expression of ACE2 and TMPRSS2 was not increased in samples from patients with compared with those of control patients. In CD11b-enriched cells but not T-cells, the level of expression of ACE2 and TMPRSS2 in the mucosa was comparable to other functional mucosal genes and was not affected by inflammation. Anti-tumor necrosis factor drugs, vedolizumab, ustekinumab, and steroids were linked to significantly lower expression of ACE2 in CD11b-enriched cells. CONCLUSIONS: The viral entry molecules ACE2 and TMPRSS2 are expressed in the ileum and colon. Patients with IBD do not have higher expression during inflammation; medical therapy is associated with lower levels of ACE2. These data provide reassurance for patients with IBD.


Subject(s)
Gene Expression Regulation , Immunosuppressive Agents/pharmacology , Irritable Bowel Syndrome/physiopathology , Peptidyl-Dipeptidase A/genetics , Serine Endopeptidases/genetics , Adolescent , Adult , Aged , Angiotensin-Converting Enzyme 2 , Animals , Betacoronavirus/metabolism , Biopsy , COVID-19 , Colon/drug effects , Colon/metabolism , Computational Biology , Coronavirus Infections/physiopathology , Disease Models, Animal , Female , Gene Expression Regulation/drug effects , Humans , Ileum/drug effects , Ileum/metabolism , Immunosuppressive Agents/therapeutic use , Inflammation/physiopathology , Intestinal Mucosa/metabolism , Irritable Bowel Syndrome/drug therapy , Male , Mice , Mice, Inbred C57BL , Middle Aged , Pandemics , Pneumonia, Viral/physiopathology , Real-Time Polymerase Chain Reaction , SARS-CoV-2 , Transcriptome , Young Adult
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