Journal Article

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

Kee, Carmon, Herrmann, Carl, Steinmetz, Lars M, Triana, Sergio, Shahraz, Mohammed, Sharma, Ashwini K, Alexandrov, Theodore, Ramirez, Carlos, Boulant, Steeve, Doldan, Patricio, Metz‐Zumaran, Camila, Gschwind, Andreas R, Schraivogel, Daniel, Stanifer, Megan L

2021

Overview

Exacerbated pro‐inflammatory immune response contributes to COVID‐19 pathology. However, despite the mounting evidence about SARS‐CoV‐2 infecting the human gut, little is known about the antiviral programs triggered in this organ. To address this gap, we performed single‐cell transcriptomics of SARS‐CoV‐2‐infected intestinal organoids. We identified a subpopulation of enterocytes as the prime target of SARS‐CoV‐2 and, interestingly, found the lack of positive correlation between susceptibility to infection and the expression of ACE2 . Infected cells activated strong pro‐inflammatory programs and produced interferon, while expression of interferon‐stimulated genes was limited to bystander cells due to SARS‐CoV‐2 suppressing the autocrine action of interferon. These findings reveal that SARS‐CoV‐2 curtails the immune response and highlights the gut as a pro‐inflammatory reservoir that should be considered to fully understand SARS‐CoV‐2 pathogenesis. Synopsis Single cell sequencing and multiplex single‐molecule RNA FISH analyses on SARS‐CoV‐2 infected human intestinal organoids characterize the tropism of SARS‐CoV‐2 and identify strategies developed by the virus to interfere with the host intrinsic innate immune response. SARS‐CoV‐2 primarily infects the enterocyte lineage. High expression levels of ACE2 does not correlate with higher infectability of cells by SARS‐CoV‐2. ACE2 expression is downregulated upon SARS‐CoV‐2 infection of human intestinal epithelial cells. Infected cells show a high pro‐inflammatory response and little to no interferon‐mediated response as the result of a SARS‐CoV‐2‐mediated inhibition of interferon signaling. Graphical Abstract Single cell sequencing and multiplex single‐molecule RNA FISH analyses on SARS‐CoV‐2 infected human intestinal organoids characterize the tropism of SARS‐CoV‐2 and identify strategies developed by the virus to interfere with the host intrinsic innate immune response.

• Publisher: Nature Publishing Group UK,EMBO Press,John Wiley and Sons Inc,Springer Nature
• Subject: ACE2 / Angiotensin-converting enzyme 2 / Antiviral drugs / Autocrine signalling / Colon / Coronaviruses / COVID-19 / COVID-19 - virology / Digestive system / Disease transmission / EMBO09 / EMBO19 / EMBO23 / Enterocytes / Gastrointestinal Microbiome / Gastrointestinal tract / Gene expression / Genomes / human intestinal epithelial cells / Humans / Immune response / Immune system / In Situ Hybridization, Fluorescence / Infections / Inflammation / Interferon / Intestine / Intestines - immunology / intrinsic immune response / Organoids / Organoids - metabolism / Pathogenesis / Pathogens / SARS-CoV-2 - physiology / SARS‐CoV‐2 / Sequence Analysis, RNA / Severe acute respiratory syndrome / Severe acute respiratory syndrome coronavirus 2 / Single-Cell Analysis / single‐cell RNA sequencing / Small intestine / Stem cells / Viral infections