Single-cell analyses reveal SARS-CoV-2 interference with intrinsic immune response in the human gut

Triana, Sergio; Zumaran, Camila Metz; Ramı́rez, C.; Kee, Carmon; Doldan, Patricio; Shahraz, Mohammed; Schraivogel, Daniel; Gschwind, Andreas R.; Steinmetz, Lars M.; Herrmann, Carl; Alexandrov, Theodore; Boulant, Steeve; Stanifer, Megan L.

doi:10.1101/2020.10.21.348854

Cited by 26 publications

(66 citation statements)

References 48 publications

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“…Since SPINT2 is also able to regulate ST14 activity in small and large intestines 16 we decided to use enterocytes as a model to test this hypothesis. In order to find common TFs regulators of SPINT2 / TMPRSS2 we performed two independent analysis: i ) A footprinting analysis of chromatin open regions using ATAC-seq data from Human Intestinal Organoids 17 identifying potential TF binding sites and ii ) Using scRNA-seq data from ileum derived organoids 18 we calculated the activity of transcription factors based on the gene expression of their targets using the SCENIC algorithm 19 . TF activities were then correlated to SPINT2 and TMPRSS2 gene expression.…”

Section: Resultsmentioning

confidence: 99%

“…We found Transcription Factor Binding Sites (TFBS) for ten regulators including IRF1, IRF3, JUNB, JUND and ELF3 whose TF activities were found to be correlated to both SPINT2 and TMPRSS2 gene expression which suggests their possible role as common regulators of both genes. Interestingly, ELF3 and IRF7 TF activity has been found to be modulated in SARS-CoV-2 infected vs bystander enterocytes from ileum 18 , which could point to viral load modulation mediated by TMPRSS2 and SPINT2 through these TFs. We show that SPINT2 and TMPRSS2 gene expression levels are correlated across cell types and tissues.…”

Section: Discussionmentioning

confidence: 96%

“…For this work we used the following datasets available in public repositories: scRNA-seq profiles of Calu-3 and H1299 cell lines 22 ; scRNA-seq from ileum derived organoids 18 ; translatome and proteome quantifications of Caco-2 cell line 13 ; bulk RNA-seq profiles of lung samples of COVID-19 deceased patient autopsies 44 ; Peripheral Blood Mononuclear Cells 40 ; Nasopharynx samples from COVID-19 patients 38 ; Human Cell Landscape 25 ; The Cancer Genome Atlas. Tumor scRNA-seq datasets: Human Hepatocellular Carcinoma 51 , renal Clear Cell Carcinoma 50 , Lung Adenocarcinoma 53 , Colon Adenocarcinoma 52 , pancreatic cells from Diabetes Type 2 patients 54 ; ATAC-seq data from Human intestinal organoids 17 .…”

Section: Data and Script Availabilitymentioning

confidence: 99%

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SPINT2 controls SARS-CoV-2 viral infection and is associated to disease severity

Alvarez

Sharma

Kee

et al. 2020

Preprint

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COVID-19 outbreak is the biggest threat to human health in recent history. Currently, there are over 1.5 million related deaths and 75 million people infected around the world (as of 22/12/2020). The identification of virulence factors which determine disease susceptibility and severity in different cell types remains an essential challenge. The serine protease TMPRSS2 has been shown to be important for S protein priming and viral entry, however, little is known about its regulation. SPINT2 is a member of the family of Kunitz type serine protease inhibitors and has been shown to inhibit TMPRSS2. Here, we explored the existence of a co-regulation between SPINT2/TMPRSS2 and found a tightly regulated protease/inhibitor expression balance across tissues. We found that SPINT2 negatively correlates with SARS-CoV-2 expression in Calu-3 and Caco-2 cell lines and was down-regulated in secretory cells from COVID-19 patients. We validated our findings using Calu-3 cell lines and observed a strong increase in viral load after SPINT2 knockdown. Additionally, we evaluated the expression of SPINT2 in datasets from comorbid diseases using bulk and scRNA-seq data. We observed its down-regulation in colon, kidney and liver tumors as well as in alpha pancreatic islets cells from diabetes Type 2 patients, which could have implications for the observed comorbidities in COVID-19 patients suffering from chronic diseases.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 96%

Section: Data and Script Availabilitymentioning

confidence: 99%

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SPINT2 controls SARS-CoV-2 viral infection and is associated to disease severity

Alvarez

Sharma

Kee

et al. 2020

Preprint

Self Cite

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“…Multiple additional (co-)receptors have been proposed for SARS-CoV-2, including CD209/DC-SIGN, and NRP1 13,14,36 . Recent findings in human IOs have found no correlation between infectability of cells and their levels of ACE2 expression, suggesting the potential existence of alternative entry receptors 37 . In line with these findings, we observed both ACE2-positive and ACE2-negative SARS-CoV-2 infected cells in IOs (Fig.…”

Section: Ace2 Is the Obligate Entry Receptor Of Sars-cov And Sars-cov-2mentioning

confidence: 96%

A CRISPR/Cas9 genetically engineered organoid biobank reveals essential host factors for coronaviruses

Beumer

Geurts

Lamers³

et al. 2021

Preprint

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Rapid identification of host genes essential for virus replication may expedite the generation of therapeutic interventions. Genetic screens are often performed in transformed cell lines that poorly represent viral target cells in vivo, leading to discoveries that may not be translated to the clinic. Intestinal organoids (IOs) are increasingly used to model human disease and are amenable to genetic engineering. To discern which host factors are reliable anti-coronavirus therapeutic targets, we generate mutant clonal IOs for 19 host genes previously implicated in coronavirus biology. We verify ACE2 and DPP4 as entry receptors for SARS-CoV/SARS-CoV-2 and MERS-CoV respectively. SARS-CoV-2 replication in IOs does not require the endosomal Cathepsin B/L proteases, but specifically depends on the cell surface protease TMPRSS2. Other TMPRSS family members were not essential. The newly emerging coronavirus variant B.1.1.7, as well as SARS-CoV and MERS-CoV similarly depended on TMPRSS2. These findings underscore the relevance of non-transformed human models for coronavirus research, identify TMPRSS2 as an attractive pan-coronavirus therapeutic target, and demonstrate that an organoid knockout biobank is a valuable tool to investigate the biology of current and future emerging coronaviruses.

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“…The differential expression of ACE2 receptors in children and smokers accounts in part for the differences in infection rates [ 26 ]. Intriguingly, SARS-CoV-2 also appears to intervene with the intrinsic immune response in the gut [ 27 ], curtailing the autocrine action of interferon, as was previously described by Blanco-Melo [ 5 ]. In this way, the virus curtails the immune responses in the gut and creates a reservoir for itself.…”

Section: Viral Infection Of the Lungmentioning

confidence: 99%

Fucoidan and Lung Function: Value in Viral Infection

Fitton¹,

Park²,

Karpiniec³

et al. 2020

Marine Drugs

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Compromised lung function is a feature of both infection driven and non-infective pathologies. Viral infections—including the current pandemic strain SARS-CoV-2—that affect lung function can cause both acute and long-term chronic damage. SARS-CoV-2 infection suppresses innate immunity and promotes an inflammatory response. Targeting these aspects of SARS-CoV-2 is important as the pandemic affects greater proportions of the population. In clinical and animal studies, fucoidans have been shown to increase innate immunity and decrease inflammation. In addition, dietary fucoidan has been shown to attenuate pulmonary damage in a model of acute viral infection. Direct inhibition of SARS-CoV-2 in vitro has been described, but is not universal. This short review summarizes the current research on fucoidan with regard to viral lung infections and lung damage.

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Single-cell analyses reveal SARS-CoV-2 interference with intrinsic immune response in the human gut

Cited by 26 publications

References 48 publications

SPINT2 controls SARS-CoV-2 viral infection and is associated to disease severity

SPINT2 controls SARS-CoV-2 viral infection and is associated to disease severity

A CRISPR/Cas9 genetically engineered organoid biobank reveals essential host factors for coronaviruses

Fucoidan and Lung Function: Value in Viral Infection

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