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

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

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.