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1.
Cell Death Differ ; 29(6): 1240-1254, 2022 Jun.
Article in English | MEDLINE | ID: covidwho-1612182

ABSTRACT

A recent mutation analysis suggested that Non-Structural Protein 6 (NSP6) of the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is a key determinant of the viral pathogenicity. Here, by transcriptome analysis, we demonstrated that the inflammasome-related NOD-like receptor signaling was activated in SARS-CoV-2-infected lung epithelial cells and Coronavirus Disease 2019 (COVID-19) patients' lung tissues. The induction of inflammasomes/pyroptosis in patients with severe COVID-19 was confirmed by serological markers. Overexpression of NSP6 triggered NLRP3/ASC-dependent caspase-1 activation, interleukin-1ß/18 maturation, and pyroptosis of lung epithelial cells. Upstream, NSP6 impaired lysosome acidification to inhibit autophagic flux, whose restoration by 1α,25-dihydroxyvitamin D3, metformin or polydatin abrogated NSP6-induced pyroptosis. NSP6 directly interacted with ATP6AP1, a vacuolar ATPase proton pump component, and inhibited its cleavage-mediated activation. L37F NSP6 variant, which was associated with asymptomatic COVID-19, exhibited reduced binding to ATP6AP1 and weakened ability to impair lysosome acidification to induce pyroptosis. Consistently, infection of cultured lung epithelial cells with live SARS-CoV-2 resulted in autophagic flux stagnation, inflammasome activation, and pyroptosis. Overall, this work supports that NSP6 of SARS-CoV-2 could induce inflammatory cell death in lung epithelial cells, through which pharmacological rectification of autophagic flux might be therapeutically exploited.


Subject(s)
COVID-19 , Coronavirus Nucleocapsid Proteins , NLR Family, Pyrin Domain-Containing 3 Protein , SARS-CoV-2 , Vacuolar Proton-Translocating ATPases , COVID-19/metabolism , COVID-19/virology , Coronavirus Nucleocapsid Proteins/genetics , Coronavirus Nucleocapsid Proteins/metabolism , Humans , Inflammasomes/metabolism , Interleukin-1beta/metabolism , NLR Family, Pyrin Domain-Containing 3 Protein/genetics , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , Pyroptosis , SARS-CoV-2/genetics , SARS-CoV-2/metabolism , SARS-CoV-2/pathogenicity , Vacuolar Proton-Translocating ATPases/metabolism
2.
United European Gastroenterol J ; 9(9): 1027-1038, 2021 11.
Article in English | MEDLINE | ID: covidwho-1460274

ABSTRACT

BACKGROUND: With increasing number of clinical trials relating to fecal microbiota transplantation (FMT), it is crucial to identify and recruit long-term, healthy, and regular fecal donors. OBJECTIVE: We aimed to report the outcomes of screening and recruitment of fecal donors for FMT. METHODS: Potential donors were recruited via advertisement through internal mass emails at a university. They were required to undergo a pre-screening telephone interview, a detailed questionnaire, followed by blood and stool investigations. RESULTS: From January 2017 to December 2020, 119 potential donors were assessed with 75 failed pre-screening. Reasons for failure included: inability to come back for regular and long-term donation (n = 19), high body mass index (n = 17), underlying chronic illness or on long-term medications (n = 11), being healthcare professionals (n = 10), use of antibiotics within 3 months (n = 5) and others (n = 13). Forty-four donors completed questionnaires and 11 did not fulfill the clinical criteria. Of the remaining 33 potential donors who had stool and blood tests, 21 failed stool investigations (19 extended-spectrum beta-lactamase [ESBL] organisms, one Clostridioides difficile, one C. difficile plus Methicillin Resistant Staphylococcus aureus), one failed blood tests (high serum alkaline phosphatase level), one required long-term medication and nine withdrew consent and/or lost to follow-up. In total, only one out of 119 (0.8%) potential donors was successfully recruited as a regular donor. CONCLUSION: There was a high failure rate in donor screening for FMT. Main reasons for screening failure included high prevalence of positive ESBL organisms in stool and failed commitment to regular stool donation.


Subject(s)
Donor Selection , Fecal Microbiota Transplantation , Adolescent , Adult , COVID-19 , Feces/microbiology , Female , Hong Kong , Humans , Male , Middle Aged , Pandemics , Prevalence , Young Adult , beta-Lactamases
3.
Brief Bioinform ; 22(2): 1466-1475, 2021 03 22.
Article in English | MEDLINE | ID: covidwho-1343667

ABSTRACT

Coronavirus disease 2019 (COVID-19) has spread rapidly worldwide, causing significant mortality. There is a mechanistic relationship between intracellular coronavirus replication and deregulated autophagosome-lysosome system. We performed transcriptome analysis of peripheral blood mononuclear cells (PBMCs) from COVID-19 patients and identified the aberrant upregulation of genes in the lysosome pathway. We further determined the capability of two circulating markers, namely microtubule-associated proteins 1A/1B light chain 3B (LC3B) and (p62/SQSTM1) p62, both of which depend on lysosome for degradation, in predicting the emergence of moderate-to-severe disease in COVID-19 patients requiring hospitalization for supplemental oxygen therapy. Logistic regression analyses showed that LC3B was associated with moderate-to-severe COVID-19, independent of age, sex and clinical risk score. A decrease in LC3B concentration <5.5 ng/ml increased the risk of oxygen and ventilatory requirement (adjusted odds ratio: 4.6; 95% CI: 1.1-22.0; P = 0.04). Serum concentrations of p62 in the moderate-to-severe group were significantly lower in patients aged 50 or below. In conclusion, lysosome function is deregulated in PBMCs isolated from COVID-19 patients, and the related biomarker LC3B may serve as a novel tool for stratifying patients with moderate-to-severe COVID-19 from those with asymptomatic or mild disease. COVID-19 patients with a decrease in LC3B concentration <5.5 ng/ml will require early hospital admission for supplemental oxygen therapy and other respiratory support.


Subject(s)
COVID-19/virology , Leukocytes, Mononuclear/metabolism , Lysosomes/metabolism , Microtubule-Associated Proteins/blood , SARS-CoV-2/metabolism , Adult , Autophagy , Biomarkers/blood , COVID-19/blood , Cell Cycle , Cholesterol/metabolism , Female , Humans , Male , Middle Aged , RNA-Binding Proteins/blood , Real-Time Polymerase Chain Reaction , Retrospective Studies , Reverse Transcriptase Polymerase Chain Reaction
4.
Brief Bioinform ; 22(2): 1466-1475, 2021 03 22.
Article in English | MEDLINE | ID: covidwho-1096499

ABSTRACT

Coronavirus disease 2019 (COVID-19) has spread rapidly worldwide, causing significant mortality. There is a mechanistic relationship between intracellular coronavirus replication and deregulated autophagosome-lysosome system. We performed transcriptome analysis of peripheral blood mononuclear cells (PBMCs) from COVID-19 patients and identified the aberrant upregulation of genes in the lysosome pathway. We further determined the capability of two circulating markers, namely microtubule-associated proteins 1A/1B light chain 3B (LC3B) and (p62/SQSTM1) p62, both of which depend on lysosome for degradation, in predicting the emergence of moderate-to-severe disease in COVID-19 patients requiring hospitalization for supplemental oxygen therapy. Logistic regression analyses showed that LC3B was associated with moderate-to-severe COVID-19, independent of age, sex and clinical risk score. A decrease in LC3B concentration <5.5 ng/ml increased the risk of oxygen and ventilatory requirement (adjusted odds ratio: 4.6; 95% CI: 1.1-22.0; P = 0.04). Serum concentrations of p62 in the moderate-to-severe group were significantly lower in patients aged 50 or below. In conclusion, lysosome function is deregulated in PBMCs isolated from COVID-19 patients, and the related biomarker LC3B may serve as a novel tool for stratifying patients with moderate-to-severe COVID-19 from those with asymptomatic or mild disease. COVID-19 patients with a decrease in LC3B concentration <5.5 ng/ml will require early hospital admission for supplemental oxygen therapy and other respiratory support.


Subject(s)
COVID-19/virology , Leukocytes, Mononuclear/metabolism , Lysosomes/metabolism , Microtubule-Associated Proteins/blood , SARS-CoV-2/metabolism , Adult , Autophagy , Biomarkers/blood , COVID-19/blood , Cell Cycle , Cholesterol/metabolism , Female , Humans , Male , Middle Aged , RNA-Binding Proteins/blood , Real-Time Polymerase Chain Reaction , Retrospective Studies , Reverse Transcriptase Polymerase Chain Reaction
5.
J Gastroenterol Hepatol ; 36(1): 171-173, 2021 Jan.
Article in English | MEDLINE | ID: covidwho-1032414

ABSTRACT

BACKGROUND AND AIM: It is unsure whether inflammatory bowel disease (IBD) is a risk factor for novel coronavirus infection (COVID-19). METHODS: IBD patients were identified from population-based databases in Hong Kong and Taiwan from January 21, 2020, until April 15, 2020. RESULTS: Total 2954 and 2554 IBD patients were identified in Hong Kong and Taiwan, respectively. None had COVID-19. Pooled analysis showed that 65.3%, 39.1%, 4.3%, and 12.8% IBD patients in Hong Kong and 75.8 %, 51.4 %, 26.1%, and 52.3 % in Taiwan were on 5-aminosalicylates, immunomodulators, corticosteroids, and biologics, respectively. CONCLUSION: There were no reported cases of COVID-19 infection amongst IBD patients in Hong Kong and Taiwan. IBD patients should continue their usual medications during the COVID-19 pandemic.


Subject(s)
COVID-19/epidemiology , Inflammatory Bowel Diseases/complications , Adult , Aged , COVID-19/diagnosis , Female , Hong Kong/epidemiology , Humans , Inflammatory Bowel Diseases/diagnosis , Inflammatory Bowel Diseases/drug therapy , Male , Middle Aged , Registries , Taiwan/epidemiology
6.
JGH Open ; 4(3): 320-323, 2020 Jun.
Article in English | MEDLINE | ID: covidwho-592734

ABSTRACT

The COVID-19 pandemic, secondary to SARS-CoV-2, has resulted in high mortality and morbidity worldwide. As inflammatory bowel disease (IBD) is a chronic disease, and most patients are on long-term immunosuppressive agents, there is understandable concern, particularly in terms of therapy. In view of this, experts in IBD across the Asia Pacific region were invited to put together recommendations based on their experience and the currently available data. In general, most IBD therapies (with a few exceptions) can be continued safely, and the general consensus is that maintaining disease control should remain the main principle of management. In addition, social distancing measures and the appropriate use of personal protective equipment should be strictly adhered to. During the current pandemic, face-to-face clinic follow ups and non-urgent procedures should be kept to a minimum.

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