Immune response landscapes in lung and intestinal tissue of SARS-CoV-2-infected rhesus macaques

The pathological and immune response dynamics in the lungs of individuals with COVID-19 have been broadly studied and characterized. Notably, SARS-CoV-2 also causes complex gastrointestinal symptoms and has a long period of rectal shedding. SARS-CoV-2 initially infects the upper airways, and the differential tissue response between the intestines and lungs remains unclear. To better understand how nasal infection leads to subsequent modulation of the intestinal mucosal immune system, we depicted the single-cell transcriptional atlas of longitudinally collected lung and intestinal tissue samples from SARS-CoV-2-infected rhesus macaques at 3 to 10 days post-infection. We found a decrease in alveolar macrophage (AM) numbers caused by viral infection, with the involvement of neutrophil and monocyte infiltration and an increase in alveolar epithelial cell (AT) and endothelial cell (EC) numbers related to pathological changes. In addition, we demonstrated that intestinal enterocytes (IECs) were degraded at 3 days post-infection (dpi) but recovered rapidly at 7 and 10 dpi, revealing that viral infection had mild effects on the intestine. Crucially, we observed suppression of the inflammatory response and tissue damage related to B-cell and Paneth cell accumulation in the intestines, although T cells were activated in the early and middle stages of SARS-CoV-2 infection. Compared with that in the lung, the expression of genes related to the interferon response was inhibited and inflammatory actor secretion was reduced in the intestines.Further analysis of SARS-CoV-2 receptors revealed the widespread distribution of ACE2+/TMPRSS2+ cells in intestinal tissues, and the expression of IFN-γ response markers was detected in ACE2-expressing cells at 3-7 dpi. The above findings show that intestinal mucosal-immunology is in a state of dynamic imbalance during SARS-CoV-2 infection, which may underlie ongoing rectal viral shedding and mild tissue damage.