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Intestinal immune response to SARS-CoV-2, which is very different from the lungs

Intestinal immune response to SARS-CoV-2, which is very different from the lungs

 


Common symptoms of 2019 coronavirus disease (COVID-19) are cough, fever, malaise, and loss of odor. Many COVID-19 patients also have gastrointestinal symptoms. This correlates with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection of the intestinal epithelium in COVID-19 patients. The SARS-CoV-2 virus has killed more than 1.16 million people worldwide since the first case was discovered in Wuhan, China in late December 2019.

However, little is known about the importance of the intestinal phase of SARS-CoV-2-for both the viral life cycle and the development of COVID-19-related pathologies. It is not clear whether the symptoms seen in the patient are associated with direct replication of SARS-CoV-2 in the gastrointestinal (GI) tract or as a result of a strong pro-inflammatory response.

Megan L. Stanifer et al. We will study the immune response of the human intestine during SARS-CoV-2 infection.Published as a study bioRxiv* Preprints reveal a potent pro-inflammatory response: cell-type or tissue-specific regulation of interferon-mediated signaling during SARS-CoV-2 infection.

In this study, researchers investigate whether the innate immune response that occurs in the human gut to combat viral infections is similar or different from that caused in other organs. It also compares the response of infected cells to bystander cells. They use organoids from the human ileum and colon as a non-transformed culture model. The intestinal “mini-intestinal” organoid is an excellent model for studying SARS-CoV-2 infection in the gastrointestinal tract.

SARS-CoV-2 is understood to replicate in human intestinal epithelial cells. However, the specific cell type to infect is not well defined. Using the single-cell transcriptomics approach (scRNAseq) and targeted scRNAseq, the authors use a subpopulation of enterocytes most susceptible to SARS-CoV-2 infection (ie, immature enterocytes 2). Is identified.

An important observation in this study is that there is no correlation between ACE2 expression levels and intracellular SARS-CoV-2 genome copy number. This means that ACE2 expression cannot be used to infer infectivity.

Single cell sequencing of human organoids from the colon and ileum infected with SARS-CoV-2.  A. Schematic diagram of the  workflow.  625 B. Uniform manifold approximation and projection of single-cell RNA-Seq data from simulated and SARS-CoV-2 infected colon-derived (left panel) and ileum-derived (right panel) organoids colored according to cells (UMAP) ) Embedded type. The small inset shows the UMAP of simulated and infectious organoids at 12 and 24 hpi.  C. Dot plot of top marker genes for each cell type of (left) colon and (right) ileum-derived organoids. The dot size represents the percentage of cells expressing the gene. The color represents the average expression of all cell types.  D. Bar graphs showing the proportion of each cell type of simulated and infected organoids (12 and 24 hpi).

Single cell sequencing of human organoids from the colon and ileum infected with SARS-CoV-2. A. Schematic diagram of the workflow. 625 B. Uniform manifold approximation and projection of single-cell RNA-Seq data from simulated and SARS-CoV-2 infected colon-derived (left panel) and ileum-derived (right panel) organoids colored according to cells (UMAP) ) Embedded type. The small inset shows the UMAP of simulated and infectious organoids at 12 and 24 hpi. C. Dot plot of top marker genes for each cell type of (left) colon and (right) ileum-derived organoids. The dot size represents the percentage of cells expressing the gene. The color represents the average expression of all cell types. D. Bar graphs showing the proportion of each cell type of simulated and infected organoids (12 and 24 hpi).

Therefore, the authors should conduct SARS-CoV-2 tropism studies based on biological validation of infection and should not be based solely on analysis of transcriptional profiles of individual cells or tissues. I emphasize that.

They found that the expression level of TMPRSS2 (type II transmembrane serine protease 2) was associated with the number of SARS-CoV-2 genomic copies in human intestinal epithelial cells, so TMPRSS2 is suitable for SARS-CoV-2 cells. I speculate that it will play an important role in sex. It’s more so than the role of ACE2.

They also found that when infected, ACE2 levels were reduced in both infected hIEC and bystander hIEC (human intestinal epithelial cells). These indicate that the regulation of ACE2 observed during infection may be tissue-specific and time-dependent.

When researchers treated cells with UV-inactivated SARS-CoV-2-interferon (IFN), no interferon-stimulating gene (ISG) production occurred. This means that active viral replication is required to elicit a response via IFN.

The pro-inflammatory response is caused by up-regulation of the NFκB and TNF pathways. This is clearly observed in infected enterocytes. Bystander cells do not activate pro-inflammatory responses, as observed in other similar studies. The inflammatory response of human intestinal epithelial cells infected with SARS-CoV-2 has been discussed in detail by researchers. In the current model, moderate up-regulation of IFN expression is observed in infected cells, whereas strong ISG up-regulation is observed in bystander cells.

Researchers also compare the immune responses produced by organoids from different gastrointestinal sections: 1) ileal organoids were more immunoresponsive than colonic organoids, 2) homogeneous of pro-inflammatory genes Upregulation, and 3) ileal organoids, especially bystander cells, produced a relatively large number of ISGs.

Schematic of SARS-CoV-2 infection of human intestinal epithelial cells.  SARS CoV-2 infects a subpopulation of enterocytes. Upon infection, enterocytes initiate an pro-inflammatory response characterized by up-regulation of NFκB and TNF. Bystander cells respond to secreted IFN and upregulate ISG expression.  SARS-CoV-2 infection induces down-regulation of ACE2 expression and interferes with IFN-mediated signaling in infected cells.

Schematic of SARS-CoV-2 infection of human intestinal epithelial cells. SARS CoV-2 infects a subpopulation of enterocytes. Upon infection, enterocytes initiate an pro-inflammatory response characterized by up-regulation of NFκB and TNF. Bystander cells respond to secreted IFN and upregulate ISG expression. SARS-CoV-2 infection induces down-regulation of ACE2 expression and interferes with IFN-mediated signaling in infected cells.

This is consistent with the previously known fact that different sections of the gastrointestinal tract respond differently to microbial challenges.

The results of this study reveal that IFN production is predominantly detected in infected cells, whereas ISG production is predominantly restricted to bystanders. The latter also fails to produce ISG and becomes resistant to IFN stimulation. This means that SARS-CoV-2 has developed a proviral mechanism that arrests IFN-mediated signaling and subsequent production of ISG in infected cells.

This reveals the following replication benefits: again Virus production by suppressing signal transduction of antiviral pathways.

This is an important study identifying cell and molecular players in SARS-CoV-2 infection in the human gut model. This study advances us in understanding the complete etiology of SARS-CoV-2 interference in the intestines of patients with COVID-19.

*Important Notices

bioRxiv Publish preliminary scientific reports that should not be considered definitive as they are not peer-reviewed, guide clinical practice / health-related behaviors, and should not be treated as established information

Journal reference:

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