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Gut microbiota-derived metabolites confer protection against SARS-CoV-2 infection [16S rRNA]

ABSTRACT: The gut microbiome is intricately coupled with immune regulation and metabolism, but its role in Coronavirus Disease 2019 (COVID-19) is not fully understood. Severe and fatal COVID-19 is characterized by poor anti-viral immunity and hypercoagulation, particularly in males. Via 16S sequencing of antibiotic-treated mice, we found that Clostridia species protect mammalian hosts from SARS-CoV-2 intranasal infection, both locally and systemically, via production of short-chain fatty acids (SCFAs). SCFAs reduced viral burdens in the airways and intestines by downregulating the SARS-CoV-2 entry receptor, angiotensin-converting enzyme 2 (ACE2), and enhancing adaptive immunity in male animals. In order to identify other mechanisms by which SCFAs influence the outcome of SARS-CoV-2 infection, we performed RNA-seq on lungs from male GF mice given control or SCFA water for two weeks. We identified a novel role for the gut microbiome in regulating systemic coagulation response by limiting megakaryocyte proliferation and platelet turnover via the Sh2b3-Mpl axis. Taken together, our findings have unraveled novel functions of SCFAs and fiber-fermenting gut bacteria that might be leveraged as pan-coronavirus therapeutics to dampen viral entry and hypercoagulation and promote adaptive anti-viral immunity.

ORGANISM(S): Mus musculus

PROVIDER: GSE189791 | GEO | 2022/08/02

REPOSITORIES: GEO

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Gut microbiota-derived metabolites confer protection against SARS-CoV-2 infection [RNA-Seq]

Project description:The gut microbiome is intricately coupled with immune regulation and metabolism, but its role in Coronavirus Disease 2019 (COVID-19) is not fully understood. Severe and fatal COVID-19 is characterized by poor anti-viral immunity and hypercoagulation, particularly in males. Here we define multiple pathways by which the gut microbiome protects mammalian hosts from SARS-CoV-2 intranasal infection, both locally and systemically, via production of short-chain fatty acids (SCFAs). SCFAs reduced viral burdens in the airways and intestines by downregulating the SARS-CoV-2 entry receptor, angiotensin-converting enzyme 2 (ACE2), and enhancing adaptive immunity in male animals. In order to identify other mechanisms by which SCFAs influence the outcome of SARS-CoV-2 infection, we performed RNA-seq on lungs from male GF mice given control or SCFA water for two weeks. We identified a novel role for the gut microbiome in regulating systemic coagulation response by limiting megakaryocyte proliferation and platelet turnover via the Sh2b3-Mpl axis. Taken together, our findings have unraveled novel functions of SCFAs and fiber-fermenting gut bacteria that might be leveraged as pan-coronavirus therapeutics to dampen viral entry and hypercoagulation and promote adaptive anti-viral immunity.

2022-08-02 | GSE189792 | GEO

RNA-Seq of Human iPSC-cardiomyocytes infected with SARS-CoV-2

Project description:Coronavirus disease 2019 (COVID-19) is a viral pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). COVID-19 is predominantly defined by respiratory symptoms, but cardiac complications including arrhythmias, heart failure, and viral myocarditis are also prevalent. Although the systemic ischemic and inflammatory responses caused by COVID-19 can detrimentally affect cardiac function, the direct impact of SARS-CoV-2 infection on human cardiomyocytes is not well understood.

2020-06-19 | GSE150392 | GEO

Identification of A Drug Blocking SARS-CoV-2 Infection using Human Pluripotent Stem Cell-derived Colon Organoids

Project description:The current COVID-19 pandemic is caused by the novel coronavirus SARS-coronavirus 2 (SARS-CoV-2). There are currently no therapeutic options for mitigating this disease due to lack of a vaccine and limited knowledge of SARS-CoV-2 virus biology. As a result, there is an urgent need to create new disease models to study SARS-CoV-2 biology and to screen for therapeutics using human disease-relevant tissues. COVID-19 patients often present with respiratory symptoms including cough, dyspnea, and respiratory distress but upwards of 25% of respiratory dysfunction, many COVID-19 patients have digestive system indications, including anorexia, diarrhea, vomiting, and abdominal pain. Moreover, these symptoms are associated with more severe COVID-19 outcomes1. Here, we report using human pluripotent stem cell-derived colonic organoids (hPSC-COs) to explore the permissiveness of different colonic cell types to SARS-CoV-2 infection. Single cell RNA-seq and immunostaining showed that the putative viral entry receptor ACE2 is expressed in multiple types of hESC-derived colon cells, but are highly enriched in hPSC-derivedKRT20+ enterocytes. Distinct cell types in the COs can be infected by a SARS-CoV-2 pseudo-entry virus, which is further validated in vivo using a humanized mouse model. Finally, we adapted hPSC-derived COs to a high throughput platform to screen 1280 FDA-approved drugs. Mycophenolic acid was found to block the entry of SARS-Cov-2 pseudo-entry virus in COs, and confirmed to block infection of SARS-CoV-2 virus. In summary, this study established both in vitro and in vivo organoid models to investigate infection of SARS-CoV-2 disease-relevant human colonic cell types and identified a drug suitable for rapid clinical testing that blocks SARS-CoV-2 infection.

2020-08-11 | GSE147975 | GEO

SUMOylation restrains the degradation of ACE2 through TOLLIP-mediated selective autophagy to facilitate the host susceptibility to SARS-CoV-2 infection

Project description:Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of the ongoing coronavirus disease 2019 (COVID-19) pandemic. Alongside investigations into the virology of SARS-CoV-2, understanding the host–virus dependencies are vital for the identification and rational design of effective antiviral therapy. Here, we report the dominant SARS-CoV-2 entry receptor, ACE2, conjugates with small ubiquitin-like modifier 3 (SUMO3) through a proteome-wide protein interaction analysis. We further demonstrate that E3 SUMO ligase PIAS4 prompts the SUMOylation and stabilization of ACE2, whereas deSUMOylation enzyme SENP3 reverses this process. Conjugation of SUMO3 with ACE2 at lysine (K) 187 hampers the K48-linked ubiquitination of ACE2, thus suppressing its subsequent cargo receptor TOLLIP-dependent autophagic degradation. Pharmacological intervention of ACE2 SUMOylation blocks the entry of SARS-CoV-2 and viral infection-triggered immune responses. Collectively, our findings suggest selective autophagic degradation of ACE2 orchestrated by SUMOylation and ubiquitination can be targeted to future antiviral therapy of SARS-CoV-2.

2022-07-18 | GSE171130 | GEO

Differential Whole Genome CRISPR Screening Strategy for SARS-CoV-2 Spike and VSV-G Mediated Pseudoviral Entry

Project description:The coronavirus disease 2019 (COVID-19) has caused over 6 million deaths worldwide and disrupted the global economy. The causative agent for this disease, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes mild to lethal respiratory infections. Understanding the cellular host factors that promote and inhibit for SARS-CoV-2 infection is important for identifying virial countermeasures. Moreover, new methods are needed to be to identify host genes influencing specific steps of viral infections. Here, we developed a CRISPR whole genome screen against SARS-CoV-2 spike enveloped retro-pseudoviruses with a GFP reporter to specifically identify host genes that facilitate viral entry. By including two counter screen strategies, this approach can be used to distinguish host genes affecting the pseudoviral reporter from those unique to envelope-mediated entry. First, an alternate envelope, VSV-G allowed identification of shared genes associated with retro-transcription, integration and reporter expression. Second, a recently developed Cre-Gag fusion pseudovirus bypassed retro transcription and integration by directly activating a floxed GFP reporter. Our approach correctly identified SARS-CoV-2 and VSV-G receptors ACE2 and LDLR, respectively and distinguished genes associated with retroviral reporter expression from envelope mediated entry. Overall, this work provides a new strategy for screening genes influencing envelope mediated entry without the complexity of live-viral screens which are complicated with large numbers of genes associated with all aspects of viral pathogenesis and replication. This approach should be of use for identifying genes contributing to and inhibiting SARS-CoV-2 entry and provide a platform for the analysis of newly emerging viruses.

2022-06-27 | GSE206996 | GEO

SARS-CoV-2 infection of primary human lung epithelium for COVID-19 modeling and drug discovery

Project description:Coronavirus disease 2019 (COVID-19) is the latest respiratory pandemic resulting from zoonotic transmission of severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2). Severe symptoms include viral pneumonia secondary to infection and inflammation of the lower respiratory tract, in some cases causing death. We developed primary human lung epithelial infection models to understand responses of proximal and distal lung epithelium to SARS-CoV-2 infection. Differentiated air-liquid interface cultures of proximal airway epithelium and 3D organoid cultures of alveolar epithelium were readily infected by SARS-CoV-2 leading to an epithelial cell-autonomous proinflammatory response. We validated the efficacy of selected candidate COVID-19 drugs confirming that Remdesivir strongly suppressed viral infection/replication. We provide a relevant platform for studying COVID-19 pathobiology and for rapid drug screening against SARS-CoV-2 and future emergent respiratory pathogens.

2020-11-06 | GSE155518 | GEO

bulk RNAseq of SARS-COV2 infected human lung organoid

Project description:Coronavirus disease 2019 (COVID-19) is the latest respiratory pandemic resulting from zoonotic transmission of severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2). Severe symptoms include viral pneumonia secondary to infection and inflammation of the lower respiratory tract, in some cases causing death. We developed primary human lung epithelial 5 infection models to understand responses of proximal and distal lung epithelium to SARS-CoV-2 infection. Differentiated air-liquid interface cultures of proximal airway epithelium and 3D organoid cultures of alveolar epithelium were readily infected by SARS-CoV-2 leading to an epithelial cell-autonomous proinflammatory response. We validated the efficacy of selected candidate COVID-19 drugs confirming that Remdesivir strongly suppressed viral 10 infection/replication. We provide a relevant platform for studying COVID-19 pathobiology and for rapid drug screening against SARS-CoV-2 and future emergent respiratory pathogens.

2020-11-06 | GSE160435 | GEO

Decoding SARS-CoV-2 coding capacity

Project description:SARS-CoV-2 is a coronavirus responsible for the COVID-19 pandemic. Although the SARS-CoV-2 trascriptome was reported recently, its coding capacity and the relative production of different viral proteins remained unclear. Utilizing a suit of ribosome profiling techniques, we present a high resolution map of the SARS-CoV-2 coding regions.

2020-05-08 | GSE149973 | GEO

m6A modification in SARS-CoV-2 virus regulates host cell innate immune response

Project description:It is urgent and important to understand the relationship of the widespread severe acute respiratory syndrome coronavirus clade 2 (SARS-CoV-2) with host immune response and study the underlying molecular mechanism. RNA modification landscape of SARS-CoV-2 and its functional relevance to host cell innate immune response remain unknown. N6-methylation of adenosine (m6A) in RNA regulates many physiological and disease processes. Here, we investigated m6A modification of SARS-CoV-2 gene in regulating host cell innate immune response. Our data showed that SARS-CoV-2 virus has m6A modification enriched in 3' region of the viral genome. We also found that host cell m6A methyltransferase METTL3 depletion reduced viral load in infected cells, decreased m6A levels in SARS-CoV-2 and host genes, and m6A reduction in viral RNA increased RIG-1 binding and subsequently enhanced downstream innate immune signaling pathway and inflammatory gene expression. METTL3 expression is reduced and inflammatory genes are induced in severe COVID-19 patients. These findings will aid to understand the COVID-19 pathogenesis and help in designing future studies of regulating innate immunity for COVID-19 treatment.

2021-04-27 | GSE167075 | GEO

Longitudinal host transcriptional responses to SARS-CoV-2 infection in adults with extremely high viral load

Project description:Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is the etiologic agent of the coronavirus disease 2019 (COVID-19) pandemic. We conducted a longitudinal study to investigate gene expression patterns during the acute SARS-CoV-2 illness. The cases included SARS-CoV-2 infected individuals with an extremely high viral load early in their illness matched to individuals who either had a low SARS-CoV-2 viral load early in their infection or were otherwise stable patients who tested negative for SARS-CoV-2 prior to their outpatient surgical or aerosol generating procedure. We detected hundreds of up-regulated genes that were highly correlated to the SARS-CoV-2 viral load. Many of these up-regulated genes were enriched in cellular pathways involved in the innate immune response, antiviral interferon and cytokine signaling, and cell death.

2023-09-28 | GSE234486 | GEO

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