Insights into how COVID outsmarts the gut's immune response could point to new treatments

European Molecular Biology Laboratory researchers monitored areas of SARS-CoV-2 infection, shown in pink and red, in human lung organoids. (Mohammed Shahraz, Sergio Triana/EMBL; Camila Metz-Zumaran/Heidelberg University)

Scientists studying SARS-CoV-2, the virus behind COVID-19, have known since the early days of the pandemic that it can infect the stomach. But how the gut mounts an immune response to the virus is still largely a mystery.

A team from the European Molecular Biology Laboratory (EMBL) used live models of the human gut to study how intestinal cells respond to COVID-19—and what they learned could inform efforts to develop new therapies, they said.

The researchers discovered that SARS-CoV-2 disrupts interferon signaling in certain gut cells to cause an inflammatory immune response to the virus. They described their findings in the journal Molecular Systems Biology.

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The EMBL team started by creating 3D tissue models, or organoids, of the human gut. The models allowed them to determine that a particular subpopulation of cells called enterocytes are most affected by SARS-CoV-2.

They used single-cell RNA sequencing to track cell activity as the disease progressed, observing how the enterocytes triggered a response from the immune system by scrutinizing the activity of 12 genes.

The researchers were surprised to discover that the enterocytes most affected by the virus did not display high levels of ACE2, a cell-surface receptor that has previously been fingered as a culprit in causing COVID-19 infection. Furthermore, they found that infected gut cells mounted a pro-inflammatory response to the virus by pumping up levels of the transcription factor NFkB and the cytokine TNF.

Interferon-stimulated genes were only dialed up in bystander cells, suggesting COVID-infected cells were actively blocking interferon signaling, the EMBL researchers concluded.

The gut’s role in respiratory diseases has piqued the interest of other research teams, including one at Monash University in Australia. Researchers there suggested earlier this year that L-tyrosine metabolized by gut microbes might shield the lungs from inflammation. They demonstrated that over-the-counter L-tyrosine supplements were effective in mouse models of acute respiratory distress syndrome, which can occur in severe cases of COVID-19.

The variety of immune responses that the EMBL researchers found among different cells of the gut suggest “that there are cell type-specific or tissue-specific regulations of interferon-mediated signaling during SARS-CoV-2 infection,” they wrote in the study. “This needs to be considered when studying replication and pathogenesis of SARS-CoV-2 in different organs as well as when developing therapies against COVID-19.”