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1.
Mol Med Rep ; 25(4)2022 04.
Article in English | MEDLINE | ID: covidwho-1715860

ABSTRACT

In addition to the angiotensin­converting enzyme 2 (ACE2), a number of host cell entry mediators have been identified for severe acute respiratory syndrome coronavirus­2 (SARS­CoV­2), including transmembrane protease serine 4 (TMPRSS4). The authors have recently demonstrated the upregulation of TMPRSS4 in 11 different cancers, as well as its specific expression within the central nervous system using in silico tools. The present study aimed to expand the initial observations and, using immunohistochemistry, TMPRSS4 protein expression in the gastrointestinal (GI) tract and lungs was further mapped. Immunohistochemistry was performed on tissue arrays and lung tissues of patients with non­small cell lung cancer with concurrent coronavirus disease 2019 (COVID­19) infection using TMPRSS4 antibody. The results revealed that TMPRSS4 was abundantly expressed in the oesophagus, stomach, small intestine, jejunum, ileum, colon, liver and pancreas. Moreover, the extensive TMPRSS4 protein expression in the lungs of a deceased patient with COVID­19 with chronic obstructive pulmonary disease and bronchial carcinoma, as well in the adjacent normal tissue, was demonstrated for the first time, at least to the best of our knowledge. On the whole, the immunohistochemistry data of the present study suggest that TMPRSS4 may be implicated in the broader (pulmonary and extra­pulmonary) COVID­19 symptomatology; thus, it may be responsible for the tropism of this coronavirus both in the GI tract and lungs.


Subject(s)
COVID-19/pathology , Gastrointestinal Tract/pathology , Lung Neoplasms/pathology , Lung/pathology , Membrane Proteins/metabolism , Serine Endopeptidases/metabolism , Aged , Angiotensin-Converting Enzyme 2/metabolism , COVID-19/complications , COVID-19/virology , Gastrointestinal Tract/virology , Humans , Immunohistochemistry , Lung/virology , Lung Neoplasms/complications , Male , Membrane Proteins/analysis , SARS-CoV-2/metabolism , SARS-CoV-2/pathogenicity , Serine Endopeptidases/analysis , Virus Internalization
2.
J Med Virol ; 94(1): 246-252, 2022 01.
Article in English | MEDLINE | ID: covidwho-1544341

ABSTRACT

Recently, the coronavirus disease 2019 (COVID-19) has caused a global pandemic. Several studies indicate that the digestive system can also be affected by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Therefore, patients with digestive symptoms should have a capsule endoscopy (CE). COVID-19 patients with gastrointestinal (GI) symptoms who underwent CE were recruited from March 2020 to April 2020. We collected patients' data and performed a prospective follow-up study for 6 months. All 11 COVID-19 cases with GI symptoms who underwent CE presented gastritis. Eight cases (72.7%) had intestinal mucosa inflammation. Among them, two cases showed intestinal ulcers or erosions. Moreover, two cases displayed colonic mucositis. One case was lost during follow-up. At 3-6 months after hospital discharge, five patients underwent CE again, presenting gastrointestinal lesions. Five of the 10 cases had GI symptoms, such as abdominal pain, diarrhea, constipation, and others. Among these five cases, the GI symptoms of three patients disappeared at the last follow-up and two patients still presented diarrhea symptoms. Overall, we observed damaged digestive tract mucosa that could be caused by SARS-CoV-2. Moreover, after discharge, some patients still presented intestinal lesions and GI symptoms.


Subject(s)
COVID-19/complications , COVID-19/pathology , Capsule Endoscopy , Gastrointestinal Diseases/diagnosis , Gastrointestinal Tract/pathology , Adult , Aged , Female , Follow-Up Studies , Gastritis/complications , Gastritis/diagnosis , Gastritis/pathology , Gastrointestinal Diseases/complications , Gastrointestinal Diseases/pathology , Humans , Male , Middle Aged , Prospective Studies
3.
Cells ; 10(12)2021 11 25.
Article in English | MEDLINE | ID: covidwho-1542428

ABSTRACT

Acute respiratory distress syndrome (ARDS) is a serious lung condition characterized by severe hypoxemia leading to limitations of oxygen needed for lung function. In this study, we investigated the effect of anandamide (AEA), an endogenous cannabinoid, on Staphylococcal enterotoxin B (SEB)-mediated ARDS in female mice. Single-cell RNA sequencing data showed that the lung epithelial cells from AEA-treated mice showed increased levels of antimicrobial peptides (AMPs) and tight junction proteins. MiSeq sequencing data on 16S RNA and LEfSe analysis demonstrated that SEB caused significant alterations in the microbiota, with increases in pathogenic bacteria in both the lungs and the gut, while treatment with AEA reversed this effect and induced beneficial bacteria. AEA treatment suppressed inflammation both in the lungs as well as gut-associated mesenteric lymph nodes (MLNs). AEA triggered several bacterial species that produced increased levels of short-chain fatty acids (SCFAs), including butyrate. Furthermore, administration of butyrate alone could attenuate SEB-mediated ARDS. Taken together, our data indicate that AEA treatment attenuates SEB-mediated ARDS by suppressing inflammation and preventing dysbiosis, both in the lungs and the gut, through the induction of AMPs, tight junction proteins, and SCFAs that stabilize the gut-lung microbial axis driving immune homeostasis.


Subject(s)
Arachidonic Acids/therapeutic use , Endocannabinoids/therapeutic use , Gastrointestinal Microbiome , Gastrointestinal Tract/pathology , Lung/pathology , Polyunsaturated Alkamides/therapeutic use , Respiratory Distress Syndrome/drug therapy , Respiratory Distress Syndrome/microbiology , Animals , Arachidonic Acids/pharmacology , Butyrates/metabolism , Cecum/pathology , Cell Separation , Colon/drug effects , Colon/pathology , Discriminant Analysis , Dysbiosis/complications , Dysbiosis/microbiology , Endocannabinoids/pharmacology , Enterotoxins , Female , Gastrointestinal Tract/drug effects , Lymph Nodes/drug effects , Lymph Nodes/pathology , Lymphocyte Activation/drug effects , Mice, Inbred C57BL , Pneumonia/drug therapy , Pneumonia/microbiology , Polyunsaturated Alkamides/pharmacology , Respiratory Distress Syndrome/complications , T-Lymphocytes/drug effects
4.
Tissue Cell ; 74: 101679, 2022 Feb.
Article in English | MEDLINE | ID: covidwho-1521561

ABSTRACT

BACKGROUND: It is known that SARS-CoV-2 mostly infects the respiratory system causing pneumonia; although it can also affect the gastrointestinal tract (GIT), which covered with a bi-layer of mucus rich in glycosylated proteins that terminated by sialic acid. Therefore; this study aimed to evaluate serum total sialic acid (TSA) in moderate COVID-19 patients with and without GIT manifestations. METHODS: A total of 161 moderate COVID-19 patients without and with GIT manifestations and 50 controls were enrolled into our study. Serum electrolytes levels were measured by using colorimetric or turbidmetric commercial assay kits, while the level of serum TSA was measured by using a commercial ELISA kit. RESULTS: Our results showed that serum TSA level was highly significantly increased in moderate COVID-19 patients with GIT manifestations (81.43 ± 8.91) when compared with controls (61.24 ± 6.41) or even moderate COVID-19 patients without GIT manifestations (69.46 ± 7.03). ROC curve analysis showed that AUC for TSA is 0.84 with 76.2 % sensitivity and 73.7 % specificity in discrimination between moderate COVID-19 patients with and without GIT manifestations. Serum potassium and sodium levels were highly significantly decreased in moderate COVID-19 patients with GIT manifestations when compared with controls or even moderate COVID-19 patients without GIT manifestations; while serum calcium level was found to be significantly decreased in moderate COVID-19 patients with GIT manifestations when compared with controls. CONCLUSION: Finally, we can conclude that SA plays a crucial role in the pathogenesis of GIT complications associated with COVID-19 and could be a potential biomarker for the COVID-19 gastrointestinal complications.


Subject(s)
COVID-19/pathology , Gastrointestinal Tract/pathology , N-Acetylneuraminic Acid/blood , Adult , Biomarkers/blood , Enzyme-Linked Immunosorbent Assay , Female , Gastrointestinal Tract/virology , Humans , Male , Middle Aged , Mucus/metabolism , Mucus/virology , SARS-CoV-2
5.
Pediatr Ann ; 50(8): e315-e319, 2021 Aug.
Article in English | MEDLINE | ID: covidwho-1456367

ABSTRACT

Since its initial onset in 2019, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spread quickly across the globe, resulting in the potentially life-threatening respiratory coronavirus disease 2019 (COVID-19). Although less commonly reported, COVID-19 has also been associated with gastrointestinal and hepatic manifestations, which may occur more frequently in children. This has also led to concern about the susceptibility of children to the SARS-CoV-2 virus who have underlying chronic digestive disease and may be treated with immune suppression. As such, recommendations and expert consensus regarding the management of chronic gastrointestinal and hepatobiliary disease have been of great interest during the pandemic and international database reporting has informed our understanding. The impact of COVID-19 on the gastrointestinal tract and its influence on the management of pediatric digestive disease is reviewed in this article. [Pediatr Ann. 2021;50(8):e315-e319.].


Subject(s)
COVID-19 , Digestive System Diseases , Gastrointestinal Diseases , Child , Gastrointestinal Diseases/diagnosis , Gastrointestinal Diseases/therapy , Gastrointestinal Tract/pathology , Humans , Pandemics , SARS-CoV-2
6.
Curr Opin Infect Dis ; 34(5): 471-476, 2021 10 01.
Article in English | MEDLINE | ID: covidwho-1408783

ABSTRACT

PURPOSE OF REVIEW: The ubiquitous expression of angiotensin-converting enzyme-2 receptors and its significance as the origin of viral entry have assisted in comprehending the pathophysiology of extrapulmonary manifestations of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. In this review, we focus on the clinical significance of gastrointestinal manifestations. RECENT FINDINGS: The global pandemic, a result of the widespread implications of SARS-CoV-2, remains a significant burden to current healthcare systems. Fever, dyspnea, and tussive symptoms have primarily been recognized as the most common presenting signs/symptoms. During the past one year our scope of practice has transcended beyond the management of the respiratory system to incorporate other varying systemic manifestations such as anorexia, nausea, vomiting, diarrhea, and abdominal pain. The outcomes reported by recent studies suggest an association between the presence of gastrointestinal symptoms and important clinical factors such as delay in presentation, disease severity, and mortality. SUMMARY: We provide a summarization of the most recent in-depth investigations of coronavirus disease 2019 with gastrointestinal manifestations and their conclusions. Although the pathophysiology remains an area of evolving interest, a better understanding of this disease process may allow for early recognition, efficient triage, and improved prognostication for those presenting with gastrointestinal manifestations of SARS-CoV-2.


Subject(s)
COVID-19/complications , COVID-19/pathology , Gastrointestinal Diseases/etiology , Gastrointestinal Diseases/pathology , Gastrointestinal Tract/pathology , Gastrointestinal Diseases/virology , Gastrointestinal Tract/virology , Humans , Pandemics/prevention & control , SARS-CoV-2/pathogenicity
7.
J Pediatric Infect Dis Soc ; 9(6): 781-784, 2020 Dec 31.
Article in English | MEDLINE | ID: covidwho-1387931

ABSTRACT

We describe an 8-week-old infant with severe gastrointestinal symptoms, significant hypoalbuminemia, and mild carditis following asymptomatic infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The infant's symptoms, including their temporal appearance, were consistent with multisystem inflammatory syndrome in children (MIS-C). A unique finding on colonic histology which may shed light on the pathogenesis of MIS-C was identified. The patient improved significantly following several anti-inflammatory treatments. The lag between the presentation of MIS-C and initial SARS-CoV-2 exposure, which may often be asymptomatic, together with the young age of our patient, makes this a challenging diagnosis. Clinicians should be aware of this entity, even in the neonatal and infantile age groups, to facilitate timely identification and treatment.


Subject(s)
COVID-19/diagnosis , Systemic Inflammatory Response Syndrome/diagnosis , COVID-19/pathology , COVID-19/therapy , Colon/pathology , Female , Gastrointestinal Tract/pathology , Humans , Infant , SARS-CoV-2 , Systemic Inflammatory Response Syndrome/pathology , Systemic Inflammatory Response Syndrome/therapy
8.
Mol Biol Rep ; 48(7): 5745-5758, 2021 Jul.
Article in English | MEDLINE | ID: covidwho-1321814

ABSTRACT

To date, the latest research results suggest that the novel severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) can enter host cells directly via the gastrointestinal tract by binding to the enterocyte-expressed ACE2 receptor, or indirectly as a result of infection of type II alveolar epithelial cells. At the same time, entry of SARS-CoV-2 through the gastrointestinal tract initiates the activation of innate and adaptive immune responses, the formation of an excessive inflammatory reaction and critical increase in the expression of proinflammatory cytokines, which, subsequently, can presumably increase inflammation and induce intestinal damage in patients suffering from inflammatory bowel disease (IBD). The aims of the present review were to reveal and analyze possible molecular pathways and consequences of the induction of an innate and adaptive immune response during infection with SARS-CoV-2 in patients with IBD. A thorough literature search was carried out by using the keywords: IBD, SARS-CoV-2, COVID-19. Based on the screening, a number of intracellular and extracellular pathways were considered and discussed, which can impact the immune response during SARS-CoV-2 infection in IBD patients. Additionally, the possible consequences of the infection for such patients were estimated. We further hypothesize that any virus, including the new SARS-CoV-2, infecting intestinal tissues and/or entering the host's body through receptors located on intestinal enterocytes may be a trigger for the onset of IBD in individuals with a genetic predisposition and/or the risk of developing IBD associated with other factors.


Subject(s)
Adaptive Immunity , COVID-19/epidemiology , Gastrointestinal Tract , Immunity, Innate , Inflammatory Bowel Diseases , COVID-19/immunology , COVID-19/virology , Gastrointestinal Tract/immunology , Gastrointestinal Tract/pathology , Gastrointestinal Tract/virology , Humans , Inflammatory Bowel Diseases/epidemiology , Inflammatory Bowel Diseases/immunology , Receptors, Virus/immunology , SARS-CoV-2/immunology , SARS-CoV-2/physiology , Virus Internalization
9.
Front Immunol ; 12: 676828, 2021.
Article in English | MEDLINE | ID: covidwho-1320577

ABSTRACT

In coronavirus disease 2019 (COVID-19), ulcerative lesions have been episodically reported in various segments of the gastrointestinal (GI) tract, including the oral cavity, oropharynx, esophagus, stomach and bowel. In this report, we describe an autopsy case of a COVID-19 patient who showed two undiagnosed ulcers at the level of the anterior and posterior walls of the hypopharynx. Molecular testing of viruses involved in pharyngeal ulcers demonstrated the presence of severe acute respiratory syndrome - coronavirus type 2 (SARS-CoV-2) RNA, together with herpes simplex virus 1 DNA. Histopathologic analysis demonstrated full-thickness lympho-monocytic infiltration (mainly composed of CD68-positive cells), with hemorrhagic foci and necrosis of both the mucosal layer and deep skeletal muscle fibers. Fibrin and platelet microthrombi were also found. Cytological signs of HSV-1 induced damage were not found. Cells expressing SARS-CoV-2 spike subunit 1 were immunohistochemically identified in the inflammatory infiltrations. Immunohistochemistry for HSV1 showed general negativity for inflammatory infiltration, although in the presence of some positive cells. Thus, histopathological, immunohistochemical and molecular findings supported a direct role by SARS-CoV-2 in producing local ulcerative damage, although a possible contributory role by HSV-1 reactivation cannot be excluded. From a clinical perspective, this autopsy report of two undiagnosed lesions put the question if ulcers along the GI tract could be more common (but frequently neglected) in COVID-19 patients.


Subject(s)
COVID-19/complications , Hypopharynx/pathology , SARS-CoV-2/isolation & purification , Ulcer/pathology , Aged , Antigens, CD/metabolism , Antigens, Differentiation, Myelomonocytic/metabolism , Autopsy , Blood Platelets/metabolism , Blood Platelets/pathology , COVID-19/mortality , COVID-19/pathology , COVID-19/physiopathology , Gastrointestinal Tract/pathology , Herpesvirus 1, Human/genetics , Herpesvirus 1, Human/isolation & purification , Humans , Hypopharynx/virology , Immunohistochemistry , Inflammation/immunology , Inflammation/metabolism , Inflammation/virology , Lymphocytes/metabolism , Monocytes/metabolism , Mucous Membrane/pathology , Muscle, Skeletal/pathology , Necrosis/pathology , SARS-CoV-2/genetics , Spike Glycoprotein, Coronavirus/metabolism , Thrombosis/pathology , Ulcer/virology
10.
Viruses ; 13(7)2021 06 29.
Article in English | MEDLINE | ID: covidwho-1289029

ABSTRACT

In stark contrast to the rapid development of vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), an effective human immunodeficiency virus (HIV) vaccine is still lacking. Furthermore, despite virologic suppression and CD4 T-cell count normalization with antiretroviral therapy (ART), people living with HIV (PLWH) still exhibit increased morbidity and mortality compared to the general population. Such differences in health outcomes are related to higher risk behaviors, but also to HIV-related immune activation and viral coinfections. Among these coinfections, cytomegalovirus (CMV) latent infection is a well-known inducer of long-term immune dysregulation. Cytomegalovirus contributes to the persistent immune activation in PLWH receiving ART by directly skewing immune response toward itself, and by increasing immune activation through modification of the gut microbiota and microbial translocation. In addition, through induction of immunosenescence, CMV has been associated with a decreased response to infections and vaccines. This review provides a comprehensive overview of the influence of CMV on the immune system, the mechanisms underlying a reduced response to vaccines, and discuss new therapeutic advances targeting CMV that could be used to improve vaccine response in PLWH.


Subject(s)
Coinfection/virology , Cytomegalovirus Infections/virology , Cytomegalovirus/immunology , HIV Infections/virology , Vaccines/immunology , Animals , Anti-HIV Agents/therapeutic use , Clinical Trials as Topic , Cytomegalovirus/pathogenicity , Cytomegalovirus Infections/drug therapy , Cytomegalovirus Infections/immunology , Gastrointestinal Tract/immunology , Gastrointestinal Tract/pathology , Gastrointestinal Tract/virology , HIV Infections/complications , HIV Infections/drug therapy , HIV Infections/immunology , Humans , Immunosenescence , Inflammation , Latent Infection/immunology , Latent Infection/virology , Mice , Vaccines/administration & dosage
11.
Drug Dev Res ; 82(7): 873-879, 2021 11.
Article in English | MEDLINE | ID: covidwho-1263077

ABSTRACT

COVID-19 manifests as a mild disease in most people but can progress to severe disease in nearly 20% of individuals. Disease progression is likely driven by a cytokine storm, either directly stimulated by SARS-CoV-2 or by increased systemic inflammation in which the gut might play an integral role. SARS-CoV-2 replication in the gut may cause increased intestinal permeability, alterations to the fecal microbiome, and increased inflammatory cytokines. Each effect may lead to increased systemic inflammation and the transport of cytokines and inflammatory antigens from the gut to the lung. Few interventions are being studied to treat people with mild disease and prevent the cytokine storm. Serumderived bovine immunoglobulin/protein isolate (SBI) may prevent progression by (1) binding and neutralizing inflammatory antigens, (2) decreasing gut permeability, (3) interfering with ACE2 binding by viral proteins, and (4) improving the fecal microbiome. SBI is therefore a promising intervention to prevent disease progression in COVID-19 patients.


Subject(s)
COVID-19/drug therapy , Immunization, Passive/methods , Angiotensin-Converting Enzyme 2/metabolism , Animals , COVID-19/complications , Cattle , Cytokine Release Syndrome/etiology , Cytokine Release Syndrome/prevention & control , Gastrointestinal Microbiome , Gastrointestinal Tract/pathology , Humans , Permeability
12.
Brief Bioinform ; 22(6)2021 11 05.
Article in English | MEDLINE | ID: covidwho-1228438

ABSTRACT

Coronavirus Disease 2019 (COVID-19), although most commonly demonstrates respiratory symptoms, but there is a growing set of evidence reporting its correlation with the digestive tract and faeces. Interestingly, recent studies have shown the association of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection with gastrointestinal symptoms in infected patients but any sign of respiratory issues. Moreover, some studies have also shown that the presence of live SARS-CoV-2 virus in the faeces of patients with COVID-19. Therefore, the pathophysiology of digestive symptoms associated with COVID-19 has raised a critical need for comprehensive investigative efforts. To address this issue we have developed a bioinformatics pipeline involving a system biological framework to identify the effects of SARS-CoV-2 messenger RNA expression on deciphering its association with digestive symptoms in COVID-19 positive patients. Using two RNA-seq datasets derived from COVID-19 positive patients with celiac (CEL), Crohn's (CRO) and ulcerative colitis (ULC) as digestive disorders, we have found a significant overlap between the sets of differentially expressed genes from SARS-CoV-2 exposed tissue and digestive tract disordered tissues, reporting 7, 22 and 13 such overlapping genes, respectively. Moreover, gene set enrichment analysis, comprehensive analyses of protein-protein interaction network, gene regulatory network, protein-chemical agent interaction network revealed some critical association between SARS-CoV-2 infection and the presence of digestive disorders. The infectome, diseasome and comorbidity analyses also discover the influences of the identified signature genes in other risk factors of SARS-CoV-2 infection to human health. We hope the findings from this pathogenetic analysis may reveal important insights in deciphering the complex interplay between COVID-19 and digestive disorders and underpins its significance in therapeutic development strategy to combat against COVID-19 pandemic.


Subject(s)
COVID-19/drug therapy , Gastrointestinal Tract/virology , SARS-CoV-2/drug effects , COVID-19/virology , Comorbidity , Computational Biology , Gastrointestinal Tract/pathology , Gene Regulatory Networks/genetics , Humans , Pandemics , Protein Interaction Maps/genetics , SARS-CoV-2/pathogenicity , Systems Biology
13.
Arch Pathol Lab Med ; 145(9): 1062-1068, 2021 09 01.
Article in English | MEDLINE | ID: covidwho-1220191

ABSTRACT

CONTEXT.­: Although primarily considered a respiratory illness, coronavirus disease 2019 (COVID-19) can cause gastrointestinal manifestations. OBJECTIVE.­: To evaluate histopathology and in situ hybridization for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in gastrointestinal samples from patients with recent and remote COVID-19. DESIGN.­: Patients with positive SARS-CoV-2 nasopharyngeal tests and a gastrointestinal tissue specimen were included. SARS-CoV-2 in situ hybridization (ISH) was performed on each sample. A subset had SARS-CoV-2 next-generation sequencing (NGS) performed. RESULTS.­: Twenty-five patients met inclusion criteria. Five had positive SARS-CoV-2 nasopharyngeal tests within 7 days of their gastrointestinal procedure. Two were ulcerative colitis patients on steroid therapy who lacked typical COVID-19 symptoms. Their colectomies showed severe ulcerative colitis; one demonstrated SARS-CoV-2 by NGS but a negative ISH. Another had an ischemic colon resected as a complication of the COVID-19 course; however, both ISH and NGS were negative. A fourth had a normal-appearing terminal ileum but positive ISH and NGS. The fifth patient had ileal ulcers with SARS-CoV-2 negativity by both modalities. The remaining 20 patients had positive nasopharyngeal tests an average of 53 days prior to procedure. None of their samples demonstrated SARS-CoV-2 ISH positivity, but one was positive on NGS despite a negative nasopharyngeal test. CONCLUSIONS.­: Gastrointestinal findings from SARS-CoV-2-infected patients ranged from normal with virus detected by ISH and NGS to bowel ischemia secondary to systemic viral effects without evidence of virus in the tissue. No distinct histologic finding was identified in those with gastrointestinal tissue specimens demonstrating SARS-CoV-2 positivity in this cohort.


Subject(s)
COVID-19/pathology , COVID-19/virology , Gastrointestinal Tract/pathology , Gastrointestinal Tract/virology , SARS-CoV-2 , Adult , Aged , Aged, 80 and over , COVID-19/complications , COVID-19 Nucleic Acid Testing , Cohort Studies , Colitis, Ischemic/etiology , Colitis, Ischemic/pathology , Colitis, Ischemic/virology , Colitis, Ulcerative/etiology , Colitis, Ulcerative/pathology , Colitis, Ulcerative/virology , Female , High-Throughput Nucleotide Sequencing , Humans , In Situ Hybridization , Male , Middle Aged , Nasopharynx/virology , Pandemics , SARS-CoV-2/genetics , SARS-CoV-2/isolation & purification , Young Adult
14.
Int J Mol Sci ; 22(5)2021 Feb 26.
Article in English | MEDLINE | ID: covidwho-1115421

ABSTRACT

In this Review, we briefly describe the basic virology and pathogenesis of SARS-CoV-2, highlighting how stem cell technology and organoids can contribute to the understanding of SARS-CoV-2 cell tropisms and the mechanism of disease in the human host, supporting and clarifying findings from clinical studies in infected individuals. We summarize here the results of studies, which used these technologies to investigate SARS-CoV-2 pathogenesis in different organs. Studies with in vitro models of lung epithelia showed that alveolar epithelial type II cells, but not differentiated lung alveolar epithelial type I cells, are key targets of SARS-CoV-2, which triggers cell apoptosis and inflammation, while impairing surfactant production. Experiments with human small intestinal organoids and colonic organoids showed that the gastrointestinal tract is another relevant target for SARS-CoV-2. The virus can infect and replicate in enterocytes and cholangiocytes, inducing cell damage and inflammation. Direct viral damage was also demonstrated in in vitro models of human cardiomyocytes and choroid plexus epithelial cells. At variance, endothelial cells and neurons are poorly susceptible to viral infection, thus supporting the hypothesis that neurological symptoms and vascular damage result from the indirect effects of systemic inflammatory and immunological hyper-responses to SARS-CoV-2 infection.


Subject(s)
COVID-19/pathology , Organoids/virology , SARS-CoV-2/physiology , Stem Cells/virology , Animals , Apoptosis , COVID-19/virology , Cardiovascular System/cytology , Cardiovascular System/pathology , Cardiovascular System/virology , Central Nervous System/cytology , Central Nervous System/pathology , Central Nervous System/virology , Gastrointestinal Tract/cytology , Gastrointestinal Tract/pathology , Gastrointestinal Tract/virology , Humans , Inflammation/pathology , Inflammation/virology , Lung/cytology , Lung/pathology , Lung/virology , Organoids/pathology , Stem Cells/pathology , Viral Tropism , Virus Internalization
15.
Gastroenterology ; 160(5): 1647-1661, 2021 04.
Article in English | MEDLINE | ID: covidwho-1065985

ABSTRACT

BACKGROUND & AIMS: Gastrointestinal (GI) manifestations have been increasingly reported in patients with coronavirus disease 2019 (COVID-19). However, the roles of the GI tract in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection are not fully understood. We investigated how the GI tract is involved in SARS-CoV-2 infection to elucidate the pathogenesis of COVID-19. METHODS: Our previously established nonhuman primate (NHP) model of COVID-19 was modified in this study to test our hypothesis. Rhesus monkeys were infected with an intragastric or intranasal challenge with SARS-CoV-2. Clinical signs were recorded after infection. Viral genomic RNA was quantified by quantitative reverse transcription polymerase chain reaction. Host responses to SARS-CoV-2 infection were evaluated by examining inflammatory cytokines, macrophages, histopathology, and mucin barrier integrity. RESULTS: Intranasal inoculation with SARS-CoV-2 led to infections and pathologic changes not only in respiratory tissues but also in digestive tissues. Expectedly, intragastric inoculation with SARS-CoV-2 resulted in the productive infection of digestive tissues and inflammation in both the lung and digestive tissues. Inflammatory cytokines were induced by both types of inoculation with SARS-CoV-2, consistent with the increased expression of CD68. Immunohistochemistry and Alcian blue/periodic acid-Schiff staining showed decreased Ki67, increased cleaved caspase 3, and decreased numbers of mucin-containing goblet cells, suggesting that the inflammation induced by these 2 types of inoculation with SARS-CoV-2 impaired the GI barrier and caused severe infections. CONCLUSIONS: Both intranasal and intragastric inoculation with SARS-CoV-2 caused pneumonia and GI dysfunction in our rhesus monkey model. Inflammatory cytokines are possible connections for the pathogenesis of SARS-CoV-2 between the respiratory and digestive systems.


Subject(s)
COVID-19/transmission , Gastroenteritis/pathology , Gastrointestinal Tract/pathology , Lung/pathology , Animals , Bronchi/metabolism , Bronchi/pathology , COVID-19/immunology , COVID-19/metabolism , COVID-19/pathology , COVID-19 Nucleic Acid Testing , Caspase 3/metabolism , Cytokines/immunology , Disease Models, Animal , Gastric Mucosa , Gastroenteritis/metabolism , Gastroenteritis/virology , Gastrointestinal Tract/immunology , Gastrointestinal Tract/metabolism , Goblet Cells/pathology , Intestine, Small/metabolism , Intestine, Small/pathology , Ki-67 Antigen/metabolism , Lung/diagnostic imaging , Lung/immunology , Lung/metabolism , Macaca mulatta , Nasal Mucosa , RNA, Viral/isolation & purification , Random Allocation , Rectum/metabolism , Rectum/pathology , SARS-CoV-2 , Trachea/metabolism , Trachea/pathology
16.
Biomed Pharmacother ; 133: 111064, 2021 Jan.
Article in English | MEDLINE | ID: covidwho-1059802

ABSTRACT

COVID-19 is a pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Early reported symptoms include fever, cough, and respiratory symptoms. There were few reports of digestive symptoms. However, with COVID-19 spreading worldwide, symptoms such as vomiting, diarrhoea, and abdominal pain have gained increasing attention. Research has found that angiotensin-converting enzyme 2 (ACE2), the SARS-CoV-2 receptor, is strongly expressed in the gastrointestinal tract and liver. Whether theoretically or clinically, many studies have suggested a close connection between COVID-19 and the digestive system. In this review, we summarize the digestive symptoms reported in existing research, discuss the impact of SARS-CoV-2 on the gastrointestinal tract and liver, and determine the possible mechanisms and aetiology, such as cytokine storm. In-depth exploration of the relationship between COVID-19 and the digestive system is urgently needed.


Subject(s)
COVID-19/complications , Gastrointestinal Diseases/etiology , Liver Diseases/etiology , Pandemics , SARS-CoV-2/pathogenicity , Angiotensin-Converting Enzyme 2/metabolism , Anorexia/etiology , Antiviral Agents/adverse effects , Bile Ducts/metabolism , Bile Ducts/virology , COVID-19/epidemiology , COVID-19/immunology , COVID-19/pathology , Chemical and Drug Induced Liver Injury/etiology , Comorbidity , Cytokine Release Syndrome/etiology , Cytopathogenic Effect, Viral , Gastrointestinal Diseases/epidemiology , Gastrointestinal Microbiome , Gastrointestinal Tract/metabolism , Gastrointestinal Tract/pathology , Gastrointestinal Tract/virology , Humans , Immunosuppressive Agents/adverse effects , Liver/metabolism , Liver/pathology , Liver/virology , Liver Diseases/epidemiology , Liver Transplantation , Non-alcoholic Fatty Liver Disease/etiology , Non-alcoholic Fatty Liver Disease/pathology , Non-alcoholic Fatty Liver Disease/virology , Postoperative Complications , Receptors, Virus/metabolism
17.
Clin Transl Gastroenterol ; 12(1): e00293, 2021 01 12.
Article in English | MEDLINE | ID: covidwho-1028690

ABSTRACT

INTRODUCTION: Coronavirus disease (COVID-19) has spread from Wuhan, China, and become a worldwide pandemic. Most patients display respiratory symptoms but up to 50% report gastrointestinal symptoms. Neopterin is a surrogate marker for viral inflammation, and its production by macrophages is driven by interferon-γ. METHODS: We measured fecal neopterin in 37 hospitalized COVID-19 patients not requiring intensive care measures and 22 healthy controls. RESULTS: Fecal neopterin was elevated in stool samples from COVID-19 patients compared with that in samples from healthy controls. Especially, patients reporting gastrointestinal symptoms exhibited increased fecal neopterin values. DISCUSSION: COVID-19 is associated with an inflammatory immune response in the gastrointestinal tract.


Subject(s)
COVID-19/complications , Feces/chemistry , Gastrointestinal Diseases/metabolism , Gastrointestinal Diseases/virology , Neopterin/analysis , Adult , Aged , Austria/epidemiology , COVID-19/diagnosis , COVID-19/epidemiology , COVID-19/virology , Case-Control Studies , Female , Gastrointestinal Diseases/diagnosis , Gastrointestinal Tract/immunology , Gastrointestinal Tract/pathology , Gastrointestinal Tract/virology , Humans , Inflammation/immunology , Inflammation/virology , Inpatients , Interferon-gamma/metabolism , Macrophages/metabolism , Male , Middle Aged , SARS-CoV-2/genetics
18.
Lancet ; 396(10247): 320-332, 2020 08 01.
Article in English | MEDLINE | ID: covidwho-981695

ABSTRACT

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the cause of an ongoing pandemic, with increasing deaths worldwide. To date, documentation of the histopathological features in fatal cases of the disease caused by SARS-CoV-2 (COVID-19) has been scarce due to sparse autopsy performance and incomplete organ sampling. We aimed to provide a clinicopathological report of severe COVID-19 cases by documenting histopathological changes and evidence of SARS-CoV-2 tissue tropism. METHODS: In this case series, patients with a positive antemortem or post-mortem SARS-CoV-2 result were considered eligible for enrolment. Post-mortem examinations were done on 14 people who died with COVID-19 at the King County Medical Examiner's Office (Seattle, WA, USA) and Snohomish County Medical Examiner's Office (Everett, WA, USA) in negative-pressure isolation suites during February and March, 2020. Clinical and laboratory data were reviewed. Tissue examination was done by light microscopy, immunohistochemistry, electron microscopy, and quantitative RT-PCR. FINDINGS: The median age of our cohort was 73·5 years (range 42-84; IQR 67·5-77·25). All patients had clinically significant comorbidities, the most common being hypertension, chronic kidney disease, obstructive sleep apnoea, and metabolic disease including diabetes and obesity. The major pulmonary finding was diffuse alveolar damage in the acute or organising phases, with five patients showing focal pulmonary microthrombi. Coronavirus-like particles were detected in the respiratory system, kidney, and gastrointestinal tract. Lymphocytic myocarditis was observed in one patient with viral RNA detected in the tissue. INTERPRETATION: The primary pathology observed in our cohort was diffuse alveolar damage, with virus located in the pneumocytes and tracheal epithelium. Microthrombi, where observed, were scarce and endotheliitis was not identified. Although other non-pulmonary organs showed susceptibility to infection, their contribution to the pathogenesis of SARS-CoV-2 infection requires further examination. FUNDING: None.


Subject(s)
Coronavirus Infections/pathology , Pneumonia, Viral/pathology , Adult , Aged , Aged, 80 and over , Alveolar Epithelial Cells/pathology , Alveolar Epithelial Cells/ultrastructure , Alveolar Epithelial Cells/virology , Autopsy , Betacoronavirus , COVID-19 , Coronavirus Infections/epidemiology , Female , Gastrointestinal Tract/pathology , Gastrointestinal Tract/ultrastructure , Gastrointestinal Tract/virology , Heart/virology , Humans , Kidney/pathology , Kidney/ultrastructure , Kidney/virology , Liver/pathology , Liver/ultrastructure , Liver/virology , Male , Middle Aged , Myocardium/pathology , Myocardium/ultrastructure , Pandemics , Pneumonia, Viral/epidemiology , Pulmonary Alveoli/pathology , Pulmonary Alveoli/ultrastructure , Respiratory Mucosa/pathology , Respiratory Mucosa/ultrastructure , Respiratory Mucosa/virology , SARS-CoV-2 , Spleen/pathology , Spleen/ultrastructure , Spleen/virology , Thrombosis/pathology , Trachea/pathology , Trachea/ultrastructure , Trachea/virology , Washington/epidemiology
20.
Indian J Med Microbiol ; 38(3 & 4): 261-264, 2020.
Article in English | MEDLINE | ID: covidwho-914619

ABSTRACT

Although children with novel coronavirus infection (COVID-19) typically present with fever and respiratory symptoms, some children have reported gastrointestinal (GI) symptoms including vomiting and diarrhoea during the course of the disease. The continuous positive detection of the viral RNA from faeces in children even after nasopharyngeal swabs turned negative suggests that the GI tract may shed virus and a tentative faecal-oral transmission. The presence of angiotensin-converting enzyme 2 receptor and transmembrane serine protease 2, which are the key proteins of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) cell entry process, in the GI tract can explain the digestive symptoms in COVID-19. COVID-19 has implications for the management of children with chronic luminal diseases. There is increasing concern regarding the risk that children with inflammatory bowel disease being infected with SARS-CoV-2.


Subject(s)
Coronavirus Infections/pathology , Gastrointestinal Diseases/diagnosis , Gastrointestinal Diseases/pathology , Gastrointestinal Tract/pathology , Pneumonia, Viral/pathology , Betacoronavirus , COVID-19 , Child , Coronavirus Infections/diagnosis , Feces/virology , Gastrointestinal Microbiome/physiology , Gastrointestinal Tract/microbiology , Humans , Inflammatory Bowel Diseases/pathology , Pandemics , Pneumonia, Viral/diagnosis , RNA, Viral/isolation & purification , SARS-CoV-2
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