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1.
Int J Mol Sci ; 23(6)2022 Mar 10.
Article in English | MEDLINE | ID: covidwho-1742487

ABSTRACT

The published literature makes a very strong case that a wide range of disease morbidity associates with and may in part be due to epithelial barrier leak. An equally large body of published literature substantiates that a diverse group of micronutrients can reduce barrier leak across a wide array of epithelial tissue types, stemming from both cell culture as well as animal and human tissue models. Conversely, micronutrient deficiencies can exacerbate both barrier leak and morbidity. Focusing on zinc, Vitamin A and Vitamin D, this review shows that at concentrations above RDA levels but well below toxicity limits, these micronutrients can induce cell- and tissue-specific molecular-level changes in tight junctional complexes (and by other mechanisms) that reduce barrier leak. An opportunity now exists in critical care-but also medical prophylactic and therapeutic care in general-to consider implementation of select micronutrients at elevated dosages as adjuvant therapeutics in a variety of disease management. This consideration is particularly pointed amidst the COVID-19 pandemic.


Subject(s)
Inflammatory Bowel Diseases/metabolism , Intestinal Mucosa/metabolism , Micronutrients/metabolism , Vitamin A/metabolism , Vitamin D/metabolism , Zinc/metabolism , Animals , COVID-19/epidemiology , COVID-19/metabolism , COVID-19/virology , Humans , Micronutrients/pharmacology , Pandemics/prevention & control , SARS-CoV-2/physiology , Tight Junctions/drug effects , Tight Junctions/metabolism , Vitamin A/pharmacology , Vitamin D/pharmacology , Vitamins/metabolism , Vitamins/pharmacology , Zinc/pharmacology
2.
Cytokine ; 152: 155826, 2022 04.
Article in English | MEDLINE | ID: covidwho-1693705

ABSTRACT

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is the causative agent of the newly emerging lung disease pandemic COVID-19. This viral infection causes a series of respiratory disorders, and although this virus mainly infects respiratory cells, the small intestine can also be an important site of entry or interaction, as enterocytes highly express in angiotensin-2 converting enzyme (ACE) receptors. There are countless reports pointing to the importance of interferons (IFNs) with regard to the mediation of the immune system in viral infection by SARS-CoV-2. Thus, this review will focus on the main cells that make up the large intestine, their specific immunology, as well as the function of IFNs in the intestinal mucosa after the invasion of coronavirus-2.


Subject(s)
Angiotensin-Converting Enzyme 2/metabolism , COVID-19/metabolism , Intestinal Mucosa/metabolism , Intestine, Large/metabolism , SARS-CoV-2/metabolism , COVID-19/pathology , Humans , Intestinal Mucosa/injuries , Intestinal Mucosa/pathology , Intestinal Mucosa/virology , Intestine, Large/injuries , Intestine, Large/pathology , Intestine, Large/virology
3.
Int J Mol Sci ; 22(21)2021 Oct 21.
Article in English | MEDLINE | ID: covidwho-1480797

ABSTRACT

The intestinal barrier plays an extremely important role in maintaining the immune homeostasis of the gut and the entire body. It is made up of an intricate system of cells, mucus and intestinal microbiota. A complex system of proteins allows the selective permeability of elements that are safe and necessary for the proper nutrition of the body. Disturbances in the tightness of this barrier result in the penetration of toxins and other harmful antigens into the system. Such events lead to various digestive tract dysfunctions, systemic infections, food intolerances and autoimmune diseases. Pathogenic and probiotic bacteria, and the compounds they secrete, undoubtedly affect the properties of the intestinal barrier. The discovery of zonulin, a protein with tight junction regulatory activity in the epithelia, sheds new light on the understanding of the role of the gut barrier in promoting health, as well as the formation of diseases. Coincidentally, there is an increasing number of reports on treatment methods that target gut microbiota, which suggests that the prevention of gut-barrier defects may be a viable approach for improving the condition of COVID-19 patients. Various bacteria-intestinal barrier interactions are the subject of this review, aiming to show the current state of knowledge on this topic and its potential therapeutic applications.


Subject(s)
Bacterial Infections/therapy , Haptoglobins/metabolism , Intestinal Mucosa/metabolism , Probiotics/therapeutic use , Protein Precursors/metabolism , Anti-Bacterial Agents/therapeutic use , Bacterial Infections/drug therapy , Bacterial Infections/pathology , Bacterial Physiological Phenomena , Gastrointestinal Microbiome , Humans , Intestinal Mucosa/microbiology , Mucus/metabolism , Tight Junctions/metabolism
4.
Front Immunol ; 12: 636966, 2021.
Article in English | MEDLINE | ID: covidwho-1438414

ABSTRACT

Since 2003, the world has been confronted with three new betacoronaviruses that cause human respiratory infections: SARS-CoV, which causes severe acute respiratory syndrome (SARS), MERS-CoV, which causes Middle East respiratory syndrome (MERS), and SARS-CoV-2, which causes Coronavirus Disease 2019 (COVID-19). The mechanisms of coronavirus transmission and dissemination in the human body determine the diagnostic and therapeutic strategies. An important problem is the possibility that viral particles overcome tissue barriers such as the intestine, respiratory tract, blood-brain barrier, and placenta. In this work, we will 1) consider the issue of endocytosis and the possibility of transcytosis and paracellular trafficking of coronaviruses across tissue barriers with an emphasis on the intestinal epithelium; 2) discuss the possibility of antibody-mediated transcytosis of opsonized viruses due to complexes of immunoglobulins with their receptors; 3) assess the possibility of the virus transfer into extracellular vesicles during intracellular transport; and 4) describe the clinical significance of these processes. Models of the intestinal epithelium and other barrier tissues for in vitro transcytosis studies will also be briefly characterized.


Subject(s)
Endocytosis , Intestinal Mucosa/virology , SARS-CoV-2/metabolism , Antibodies, Viral/metabolism , Antiviral Agents/pharmacology , Antiviral Agents/therapeutic use , COVID-19/drug therapy , COVID-19/transmission , COVID-19/virology , Clinical Trials as Topic , Endocytosis/drug effects , Humans , Intestinal Mucosa/metabolism , Models, Biological , SARS-CoV-2/drug effects , SARS-CoV-2/immunology , Tight Junctions/metabolism , Tight Junctions/virology , Transcytosis/drug effects , Virus Attachment
6.
Nat Commun ; 12(1): 134, 2021 01 08.
Article in English | MEDLINE | ID: covidwho-1387323

ABSTRACT

Understanding the factors that contribute to efficient SARS-CoV-2 infection of human cells may provide insights on SARS-CoV-2 transmissibility and pathogenesis, and reveal targets of intervention. Here, we analyze host and viral determinants essential for efficient SARS-CoV-2 infection in both human lung epithelial cells and ex vivo human lung tissues. We identify heparan sulfate as an important attachment factor for SARS-CoV-2 infection. Next, we show that sialic acids present on ACE2 prevent efficient spike/ACE2-interaction. While SARS-CoV infection is substantially limited by the sialic acid-mediated restriction in both human lung epithelial cells and ex vivo human lung tissues, infection by SARS-CoV-2 is limited to a lesser extent. We further demonstrate that the furin-like cleavage site in SARS-CoV-2 spike is required for efficient virus replication in human lung but not intestinal tissues. These findings provide insights on the efficient SARS-CoV-2 infection of human lungs.


Subject(s)
Angiotensin-Converting Enzyme 2/metabolism , COVID-19/pathology , COVID-19/transmission , Sialic Acids/metabolism , Spike Glycoprotein, Coronavirus/metabolism , Virus Attachment , Animals , Caco-2 Cells , Cell Line, Tumor , Chlorocebus aethiops , Cricetinae , Furin/metabolism , HEK293 Cells , Heparitin Sulfate/metabolism , Humans , Intestinal Mucosa/metabolism , Intestines/virology , Lung/pathology , Lung/virology , SARS-CoV-2/physiology , Severe Acute Respiratory Syndrome/pathology , Vero Cells , Virus Internalization , Virus Replication/physiology
8.
Front Immunol ; 12: 708149, 2021.
Article in English | MEDLINE | ID: covidwho-1337643

ABSTRACT

Microbial translocation (MT) and intestinal damage (ID) are poorly explored in COVID-19. Aims were to assess whether alteration of gut permeability and cell integrity characterize COVID-19 patients, whether it is more pronounced in severe infections and whether it influences the development of subsequent bloodstream infection (BSI). Furthermore, we looked at the potential predictive role of TM and ID markers on Intensive Care Unit (ICU) admission and in-hospital mortality. Over March-July 2020, 45 COVID-19 patients were enrolled. Markers of MT [LPB (Lipopolysacharide Binding Protein) and EndoCab IgM] and ID [I-FABP (Intestinal Fatty Acid Binding Protein)] were evaluated at COVID-19 diagnosis and after 7 days. As a control group, age- and gender-matched healthy donors (HDs) enrolled during the same study period were included. Median age was 66 (56-71) years. Twenty-one (46.6%) were admitted to ICU and mortality was 22% (10/45). Compared to HD, a high degree of MT and ID was observed. ICU patients had higher levels of MT, but not of ID, than non-ICU ones. Likewise, patients with BSI had lower EndoCab IgM than non-BSI. Interestingly, patients with high degree of MT and low ID were likely to be admitted to ICU (AUC 0.822). Patients with COVID-19 exhibited high level of MT, especially subjects admitted to ICU. COVID-19 is associated with gut permeability.


Subject(s)
COVID-19/metabolism , Intestinal Mucosa/metabolism , SARS-CoV-2/physiology , Acute-Phase Proteins/metabolism , Aged , Biomarkers/metabolism , COVID-19/diagnosis , COVID-19/mortality , COVID-19/pathology , Carrier Proteins/metabolism , Disease Progression , Fatty Acid-Binding Proteins/metabolism , Female , Humans , Intensive Care Units , Intestinal Mucosa/pathology , Male , Membrane Glycoproteins/metabolism , Middle Aged , Predictive Value of Tests , Prognosis , Survival Analysis , Tight Junctions/metabolism
9.
J Virol ; 95(18): e0085321, 2021 08 25.
Article in English | MEDLINE | ID: covidwho-1299218

ABSTRACT

Porcine epidemic diarrhea virus (PEDV) is an enteric coronavirus causing acute intestinal infection in pigs, with high mortality often seen in neonatal pigs. The newborns rely on innate immune responses against invading pathogens because of lacking adaptive immunity. However, how PEDV disables the innate immunity of newborns toward severe infection remains unknown. We found that PEDV infection led to reduced expression of histone deacetylases (HDACs), especially HDAC1, in porcine IPEC-J2 cells. HDACs are considered important regulators of innate immunity. We hypothesized that PEDV interacts with certain host factors to regulate HDAC1 expression in favor of its replication. We show that HDAC1 acted as a negative regulator of PEDV replication in IPEC-J2 cells, as shown by chemical inhibition, gene knockout, and overexpression. A GC-box (GCCCCACCCCC) within the HDAC1 promoter region was identified for Sp1 binding in IPEC-J2 cells. Treatment of the cells with Sp1 inhibitor mithramycin A inhibited HDAC1 expression, indicating direct regulation of HDAC1 expression by Sp1. Of the viral proteins that were overexpressed in IPEC-J2 cells, the N protein was found to be present in the nuclei and more inhibitory to HDAC1 transcription. The putative nuclear localization sequence 261PKKNKSR267 contributed to its nuclear localization. The N protein interacted with Sp1 and interfered with its binding to the promoter region, thereby inhibiting its transcriptional activity for HDAC1 expression. Our findings reveal a novel mechanism of PEDV evasion of the host responses, offering implications for studying the infection processes of other coronaviruses. IMPORTANCE The enteric coronavirus porcine epidemic diarrhea virus (PEDV) causes fatal acute intestinal infection in neonatal pigs that rely on innate immune responses. Histone deacetylases (HDACs) play important roles in innate immune regulation. Our study found PEDV suppresses HDAC1 expression via the interaction of its N protein and porcine Sp1, which identified a novel mechanism of PEDV evasion of the host responses to benefit its replication. This study suggests that other coronaviruses, including SARS-CoV and SARS-CoV-2, also make use of their N proteins to intercept the host immune responses in favor of their infection.


Subject(s)
Coronavirus Infections/veterinary , Epithelial Cells/virology , Histone Deacetylase 1/antagonists & inhibitors , Intestinal Mucosa/virology , Sp1 Transcription Factor/metabolism , Swine Diseases/virology , Viral Nonstructural Proteins/metabolism , Virus Replication , Animals , Cells, Cultured , Coronavirus Infections/metabolism , Coronavirus Infections/virology , Epithelial Cells/metabolism , Epithelial Cells/pathology , Intestinal Mucosa/metabolism , Intestinal Mucosa/pathology , Porcine epidemic diarrhea virus/pathogenicity , Sp1 Transcription Factor/genetics , Swine , Swine Diseases/metabolism , Swine Diseases/pathology , Viral Nonstructural Proteins/genetics
10.
Commun Biol ; 4(1): 631, 2021 05 27.
Article in English | MEDLINE | ID: covidwho-1283664

ABSTRACT

IL22 is an important cytokine involved in the intestinal defense mechanisms against microbiome. By using ileum-derived organoids, we show that the expression of anti-microbial peptides (AMPs) and anti-viral peptides (AVPs) can be induced by IL22. In addition, we identified a bacterial and a viral route, both leading to IL22 production by T cells, but via different pathways. Bacterial products, such as LPS, induce enterocyte-secreted SAA1, which triggers the secretion of IL6 in fibroblasts, and subsequently IL22 in T cells. This IL22 induction can then be enhanced by macrophage-derived TNFα in two ways: by enhancing the responsiveness of T cells to IL6 and by increasing the expression of IL6 by fibroblasts. Viral infections of intestinal cells induce IFNß1 and subsequently IL7. IFNß1 can induce the expression of IL6 in fibroblasts and the combined activity of IL6 and IL7 can then induce IL22 expression in T cells. We also show that IL22 reduces the expression of viral entry receptors (e.g. ACE2, TMPRSS2, DPP4, CD46 and TNFRSF14), increases the expression of anti-viral proteins (e.g. RSAD2, AOS, ISG20 and Mx1) and, consequently, reduces the viral infection of neighboring cells. Overall, our data indicates that IL22 contributes to the innate responses against both bacteria and viruses.


Subject(s)
Interleukins/biosynthesis , Interleukins/metabolism , Animals , Anti-Bacterial Agents/metabolism , Antiviral Agents/metabolism , Cell Culture Techniques , Cytokines/immunology , Cytokines/metabolism , Disease Models, Animal , Enterocytes/immunology , Enterocytes/metabolism , Female , Fibroblasts/immunology , Fibroblasts/metabolism , Interleukins/immunology , Intestinal Mucosa/metabolism , Intestines/physiology , Mice , Mice, Inbred C57BL , Myeloid Cells/immunology , Myeloid Cells/metabolism , Organoids/metabolism , Pore Forming Cytotoxic Proteins/genetics , Pore Forming Cytotoxic Proteins/metabolism
11.
Front Immunol ; 12: 660179, 2021.
Article in English | MEDLINE | ID: covidwho-1264332

ABSTRACT

The complex interplay between the gut microbiota, the intestinal barrier, the immune system and the liver is strongly influenced by environmental and genetic factors that can disrupt the homeostasis leading to disease. Among the modulable factors, diet has been identified as a key regulator of microbiota composition in patients with metabolic syndrome and related diseases, including the metabolic dysfunction-associated fatty liver disease (MAFLD). The altered microbiota disrupts the intestinal barrier at different levels inducing functional and structural changes at the mucus lining, the intercellular junctions on the epithelial layer, or at the recently characterized vascular barrier. Barrier disruption leads to an increased gut permeability to bacteria and derived products which challenge the immune system and promote inflammation. All these alterations contribute to the pathogenesis of MAFLD, and thus, therapeutic approaches targeting the gut-liver-axis are increasingly being explored. In addition, the specific changes induced in the intestinal flora may allow to characterize distinctive microbial signatures for non-invasive diagnosis, severity stratification and disease monitoring.


Subject(s)
Gastrointestinal Microbiome/immunology , Intestinal Mucosa/immunology , Liver/immunology , Metabolic Syndrome/immunology , Non-alcoholic Fatty Liver Disease/immunology , Animals , CCR5 Receptor Antagonists/therapeutic use , Dysbiosis/immunology , Dysbiosis/microbiology , Humans , Imidazoles/therapeutic use , Intestinal Mucosa/metabolism , Intestinal Mucosa/microbiology , Liver/metabolism , Liver/pathology , Metabolic Syndrome/drug therapy , Metabolic Syndrome/metabolism , Non-alcoholic Fatty Liver Disease/drug therapy , Non-alcoholic Fatty Liver Disease/metabolism , Sulfoxides/therapeutic use
12.
Clin Transl Gastroenterol ; 12(6): e00348, 2021 06 04.
Article in English | MEDLINE | ID: covidwho-1259760

ABSTRACT

INTRODUCTION: Patients with community-acquired pneumonia display enhanced levels of lipopolysaccharides (LPS) compared with controls, suggesting that low-grade endotoxemia may be implicated in vascular disturbances. It is unknown whether this occurs in patients with coronavirus 2019 (COVID-19) and its impact on thrombotic complications. METHODS: We measured serum levels of zonulin, a marker of gut permeability, LPS, and D-dimer in 81 patients with COVID-19 and 81 healthy subjects; the occurrence of thrombotic events in COVID-19 during the intrahospital stay was registered. RESULTS: Serum LPS and zonulin were higher in patients with COVID-19 than in control subjects and, in COVID-19, significantly correlated (R = 0.513; P < 0.001). Among the 81 patients with COVID-19, 11 (14%) experienced thrombotic events in the arterial (n = 5) and venous circulation (n = 6) during a median follow-up of 18 days (interquartile range 11-27 days). A logistic regression analysis showed that LPS (P = 0.024) and D-dimer (P = 0.041) independently predicted thrombotic events. DISCUSSION: The study reports that low-grade endotoxemia is detectable in patients with COVID-19 and is associated with thrombotic events. The coexistence of low-grade endotoxemia with enhanced levels of zonulin may suggest enhanced gut permeability as an underlying mechanism.


Subject(s)
COVID-19 , Endotoxemia , Haptoglobins/metabolism , Intestinal Mucosa , Protein Precursors/metabolism , SARS-CoV-2 , Thrombosis , Biomarkers/blood , COVID-19/blood , COVID-19/complications , COVID-19/physiopathology , Correlation of Data , Endotoxemia/diagnosis , Endotoxemia/metabolism , Endotoxemia/virology , Female , Fibrin Fibrinogen Degradation Products/analysis , Humans , Intestinal Mucosa/metabolism , Intestinal Mucosa/virology , Lipopolysaccharides/analysis , Male , Middle Aged , Permeability , Pneumonia, Viral/diagnosis , Pneumonia, Viral/etiology , SARS-CoV-2/pathogenicity , SARS-CoV-2/physiology , Thrombosis/blood , Thrombosis/diagnosis , Thrombosis/etiology
13.
Diagn Pathol ; 16(1): 40, 2021 May 05.
Article in English | MEDLINE | ID: covidwho-1216913

ABSTRACT

AIMS: Patients with COVID-19 can also have enteric symptoms. Here we analyzed the histopathology of intestinal detachment tissue from a patient with COVID-19. METHODS: The enteric tissue was examined by hematoxylin & eosin stain, PAS (Periodic acid-Schiff) staining, Gram staining, Ziehl-Neelsen stain and Grocott's Methenamine Silver (GMS) Stain. The distribution of CD3, CD4, CK20 and CD68, cytomegalovirus (CMV) and Herpes Simplex Virus (HSV) antigen were determined by immunohistochemistry. In situ hybridization (ISH) of SARS-CoV-2 and Epstein-Barr virus-encoded small RNA (EBER) were also performed. RESULTS: We observed mucosal epithelium shedding, intestinal mucosal erosion, focal inflammatory necrosis with hemorrhage, massive neutrophil infiltration, macrophage proliferation accompanied by minor lymphocyte infiltration. Fungal spores and gram positive cocci but not mycobacteria tuberculosis were identified. Immunohistochemistry staining showed abundant CD68+ macrophages but few lymphocytes infiltration. HSV, CMV and EBV were negative. ISH of SARS-CoV-2 RNA showed positive signal which mostly overlapped with CD68 positivity. CONCLUSIONS: The in situ detection of SARS-CoV-2 RNA in intestinal macrophages implicates a possible route for gastrointestinal infection. Further study is needed to further characterize the susceptibility of enteric cells to SARS-CoV-2 infection.


Subject(s)
COVID-19/pathology , Gastrointestinal Diseases/pathology , Intestinal Mucosa/pathology , Macrophages/virology , RNA, Viral/isolation & purification , SARS-CoV-2/isolation & purification , Aged , Biomarkers/metabolism , COVID-19/diagnosis , COVID-19/immunology , COVID-19/microbiology , COVID-19 Testing , Gastrointestinal Diseases/diagnosis , Gastrointestinal Diseases/immunology , Gastrointestinal Diseases/microbiology , Humans , Immunohistochemistry , In Situ Hybridization , Intestinal Mucosa/immunology , Intestinal Mucosa/metabolism , Intestinal Mucosa/microbiology , Macrophages/metabolism , Male
14.
Mucosal Immunol ; 14(3): 566-573, 2021 05.
Article in English | MEDLINE | ID: covidwho-1091501

ABSTRACT

Viral infections with SARS-CoV-2 can cause a multi-facetted disease, which is not only characterized by pneumonia and overwhelming systemic inflammatory immune responses, but which can also directly affect the digestive system and infect intestinal epithelial cells. Here, we review the current understanding of intestinal tropism of SARS-CoV-2 infection, its impact on mucosal function and immunology and summarize the effect of immune-suppression in patients with inflammatory bowel disease (IBD) on disease outcome of COVID-19 and discuss IBD-relevant implications for the clinical management of SARS-CoV-2 infected individuals.


Subject(s)
COVID-19/complications , COVID-19/immunology , Host-Pathogen Interactions/immunology , Immunity, Mucosal , Inflammatory Bowel Diseases/complications , Inflammatory Bowel Diseases/immunology , SARS-CoV-2/physiology , Biomarkers , COVID-19/diagnosis , COVID-19/virology , Humans , Immunity, Innate , Inflammatory Bowel Diseases/diagnosis , Intestinal Mucosa/immunology , Intestinal Mucosa/metabolism , Intestinal Mucosa/pathology , Severity of Illness Index , Symptom Assessment , Viral Tropism , Virus Internalization
15.
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
16.
Dig Dis Sci ; 66(12): 4557-4564, 2021 12.
Article in English | MEDLINE | ID: covidwho-1064547

ABSTRACT

Collagenous colitis (CC) is associated with non-bloody, watery diarrhea, which is pathophysiologically reasonable because normal colonic absorption (or excretion) of water and electrolytes can be blocked by the abnormally thick collagen layer in CC. However, CC has also been associated with six previous cases of protein-losing enteropathy (PLE), with no pathophysiologic explanation. The colon does not normally absorb (or excrete) amino acids/proteins, which is primarily the function of the small bowel. Collagenous duodenitis (CD) has not been associated with PLE. This work reports a novel case of CD (and CC) associated with PLE; a pathophysiologically reasonable mechanism for CD causing PLE (by the thick collagen layer of CD blocking normal intestinal amino acid absorption); and a novel association of PLE with severe COVID-19 infection (attributed to relative immunosuppression from hypoproteinemia, hypoalbuminemia, hypogammaglobulinemia, and malnutrition from PLE).


Subject(s)
Amino Acids/metabolism , COVID-19/etiology , Colitis, Collagenous/complications , Duodenitis/complications , Duodenum/physiopathology , Intestinal Absorption , Intestinal Mucosa/physiopathology , Protein-Losing Enteropathies/etiology , Aged , COVID-19/diagnosis , COVID-19/drug therapy , COVID-19/physiopathology , Colitis, Collagenous/diagnosis , Colitis, Collagenous/physiopathology , Colitis, Collagenous/therapy , Duodenitis/diagnosis , Duodenitis/physiopathology , Duodenitis/therapy , Duodenum/metabolism , Female , Fluid Therapy , Glucocorticoids/therapeutic use , Humans , Intestinal Mucosa/metabolism , Nutritional Status , Parenteral Nutrition, Total , Protein-Losing Enteropathies/diagnosis , Protein-Losing Enteropathies/physiopathology , Protein-Losing Enteropathies/therapy , Risk Factors , Treatment Outcome
17.
Virology ; 556: 1-8, 2021 04.
Article in English | MEDLINE | ID: covidwho-1045103

ABSTRACT

Porcine deltacoronavirus (PDCoV) is one of the emerged coronaviruses posing a significant threat to the swine industry. Previous work showed the presence of a viral accessory protein NS6 in PDCoV-infected cells. In this study, we detected the expression of the NS6 protein in small intestinal tissues of PDCoV-infected piglets. In addition, SDS-PAGE and Western blot analysis of sucrose gradient-purified virions showed the presence of a 13-kDa NS6 protein. Further evidences of the presence of NS6 in the PDCoV virions were obtained by immunogold staining of purified virions with anti-NS6 antiserum, and by immunoprecipitation of NS6 from purified virions. Finally, the anti-NS6 antibody was not able to neutralize PDCoV in cultured cells. These data establish for the first time that the accessory protein NS6 is expressed during infection in vivo and incorporated into PDCoV virions.


Subject(s)
Coronavirus Infections/veterinary , Deltacoronavirus/metabolism , Swine Diseases/virology , Viral Nonstructural Proteins/metabolism , Virion/metabolism , Animals , Antibodies, Viral/immunology , Cell Line , Coronavirus Infections/metabolism , Coronavirus Infections/virology , Intestinal Mucosa/metabolism , Intestinal Mucosa/virology , Mice , Rabbits , Swine , Swine Diseases/metabolism , Viral Nonstructural Proteins/immunology
18.
Medicina (Kaunas) ; 57(1)2021 Jan 09.
Article in English | MEDLINE | ID: covidwho-1016197

ABSTRACT

Nowadays, humanity faces one of the most serious health crises, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic. The severity of coronavirus disease 2019 (COVID-19) pandemic is related to the high rate of interhuman transmission of the virus, variability of clinical presentation, and the absence of specific therapeutic methods. COVID-19 can manifest with non-specific symptoms and signs, especially among the elderly. In some cases, the clinical manifestations of hyponatremia may be the first to appear. The pathophysiological mechanisms of hyponatremia among patients with COVID-19 are diverse, including syndrome of inappropriate antidiuretic hormone secretion (SIADH), digestive loss of sodium ions, reduced sodium ion intake or use of diuretic therapy. Hyponatremia may also be considered a negative prognostic factor in patients diagnosed with COVID-19. We need further studies to evaluate the etiology and therapeutic management of hyponatremia in patients with COVID-19.


Subject(s)
COVID-19/metabolism , Hyponatremia/metabolism , Inappropriate ADH Syndrome/metabolism , COVID-19/complications , Diuretics/adverse effects , Fluid Therapy/methods , Humans , Hyponatremia/epidemiology , Hyponatremia/etiology , Hyponatremia/therapy , Inappropriate ADH Syndrome/etiology , Incidence , Interleukin-6/metabolism , Intestinal Mucosa/metabolism , Prognosis , SARS-CoV-2 , Saline Solution, Hypertonic/therapeutic use , Sodium, Dietary
19.
Aging (Albany NY) ; 12(22): 22425-22444, 2020 11 22.
Article in English | MEDLINE | ID: covidwho-969889

ABSTRACT

With the current COVID-19 pandemic, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), there is an urgent need for new therapies and prevention strategies that can help curtail disease spread and reduce mortality. The inhibition of viral entry and thus spread is a plausible therapeutic avenue. SARS-CoV-2 uses receptor-mediated entry into a human host via the angiotensin-converting enzyme 2 (ACE2), which is expressed in lung tissue as well as the oral and nasal mucosa, kidney, testes and gastrointestinal tract. The modulation of ACE2 levels in these gateway tissues may be an effective strategy for decreasing disease susceptibility. Cannabis sativa, especially those high in the anti-inflammatory cannabinoid cannabidiol (CBD), has been found to alter gene expression and inflammation and harbour anti-cancer and anti-inflammatory properties. However, its effects on ACE2 expression remain unknown. Working under a Health Canada research license, we developed over 800 new C. sativa cultivars and hypothesized that high-CBD C. sativa extracts may be used to down-regulate ACE2 expression in target COVID-19 tissues. Using artificial 3D human models of oral, airway and intestinal tissues, we identified 13 high-CBD C. sativa extracts that decrease ACE2 protein levels. Some C. sativa extracts down-regulate serine protease TMPRSS2, another critical protein required for SARS-CoV-2 entry into host cells. While our most effective extracts require further large-scale validation, our study is important for future analyses of the effects of medical cannabis on COVID-19. The extracts of our most successful novel high-CBD C. sativa lines, pending further investigation, may become a useful and safe addition to the prevention/treatment of COVID-19 as an adjunct therapy.


Subject(s)
Angiotensin-Converting Enzyme 2/antagonists & inhibitors , COVID-19/prevention & control , Cannabis/chemistry , Plant Extracts/pharmacology , SARS-CoV-2/drug effects , Angiotensin-Converting Enzyme 2/metabolism , COVID-19/drug therapy , COVID-19/epidemiology , COVID-19/virology , Cannabidiol/pharmacology , Cannabidiol/therapeutic use , Computer Simulation , Gene Expression Regulation/drug effects , Humans , Intestinal Mucosa/drug effects , Intestinal Mucosa/metabolism , Intestinal Mucosa/virology , Models, Anatomic , Mouth Mucosa/drug effects , Mouth Mucosa/metabolism , Mouth Mucosa/virology , Pandemics/prevention & control , Plant Extracts/chemistry , Plant Extracts/therapeutic use , Respiratory Mucosa/drug effects , Respiratory Mucosa/metabolism , Respiratory Mucosa/virology , SARS-CoV-2/metabolism , SARS-CoV-2/pathogenicity , Virus Internalization/drug effects
20.
J Virol ; 94(14)2020 07 01.
Article in English | MEDLINE | ID: covidwho-922525

ABSTRACT

Porcine deltacoronavirus (PDCoV) is an economically important enteropathogen of swine with worldwide distribution. PDCoV primarily infects the small intestine instead of the large intestine in vivo However, the underlying mechanism of PDCoV tropism to different intestinal segments remains poorly understood as a result of the lack of a suitable in vitro intestinal model that recapitulates the cellular diversity and complex functions of the gastrointestinal tract. Here, we established the PDCoV infection model of crypt-derived enteroids from different intestinal segments. Enteroids were susceptible to PDCoV, and multiple types of different functional intestinal epithelia were infected by PDCoV in vitro and in vivo We further found that PDCoV favorably infected the jejunum and ileum and restrictedly replicated in the duodenum and colon. Mechanistically, enteroids from different intestinal regions displayed a distinct gene expression profile, and the differential expression of primary viral receptor host aminopeptidase N (APN) instead of the interferon (IFN) responses determined the susceptibility of different intestinal segments to PDCoV, although PDCoV substantially elicited antiviral genes production in enteroids after infection. Additional studies showed that PDCoV infection significantly induced the expression of type I and III IFNs at the late stage of infection, and exogenous IFN inhibited PDCoV replication in enteroids. Hence, our results provide critical inputs to further dissect the molecular mechanisms of PDCoV-host interactions and pathogenesis.IMPORTANCE The zoonotic potential of the PDCoV, a coronavirus efficiently infecting cells from a broad range species, including porcine, chicken, and human, emphasizes the urgent need to further study the cell and tissue tropism of PDCoV in its natural host. Herein, we generated crypt stem cell-derived enteroids from porcine different intestinal regions, which well recapitulated the events in vivo of PDCoV infection that PDCoV targeted multiple types of intestinal epithelia and preferably infected the jejunum and ileum over the duodenum and colon. Mechanistically, we demonstrated that the expression of APN receptor rather than the IFN responses determined the susceptibility of different regions of the intestines to PDCoV infection, though PDCoV infection markedly elicited the IFN responses. Our findings provide important insights into how the distinct gene expression profiles of the intestinal segments determine the cell and tissue tropism of PDCoV.


Subject(s)
CD13 Antigens/genetics , Coronavirus Infections/veterinary , Coronavirus/physiology , Gene Expression Regulation, Viral , Host-Pathogen Interactions , Swine Diseases/metabolism , Swine Diseases/virology , Viral Tropism , Animals , Enterocolitis/metabolism , Enterocolitis/pathology , Enterocolitis/virology , Interferons/metabolism , Intestinal Mucosa/metabolism , Intestinal Mucosa/pathology , Intestinal Mucosa/virology , Swine , Swine Diseases/pathology , Virus Replication
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