First high-dimensional examination of intestinal biopsies in patients with COVID-19

ABSTRACT

Background: SARS-CoV-2, the etiopathological agent for COVID-19, engages host ACE2 receptor for cellular entry. The brush border of the small intestines express high levels of ACE2 in physiological conditions. Gastrointestinal (GI) manifestations are common among COVID-19 patients. However, to date, there is limited information regarding intestinal response to SARS-CoV-2 infection. Methods: Intestinal biopsies were obtained from 17 COVID-19 patients (17.3-17.5 days from the last positive nasal swab) for cellular and transcriptomic analyses using mass cytometry and RNA-sequencing. Ten COVID-uninfected individuals served as controls. The epithelial compartment (EC) and lamina propria (LP) were analyzed separately. Results: The cellular profiles of intestinal tissues from COVID-19 patients showed reduced frequencies of CD206+ CDC2s and plasmacytoid dendritic cells in the LP of COVID-19 patients by mass cytometry. Effector T cell (PD1+CD38+) frequency was increased in the LP and blood of COVID-19 patients. Intraepithelial lymphocytes (IEL) were increased in the EC of COVID-19 patients, with a concomitant decrease in CD206+ CDC2s. RNA sequencing revealed an active downregulation of genes involved in inflammatory pathways including Th17 and IBD-associated pathways, while an upregulation of intestinal barrier function (mucin biosynthesis), amino acid metabolism and mineral absorption pathways was noted. Gene expression of Neuropilin-1 (NRP-1), a putative SARSCoV-2 receptor as well as key inflammatory cytokines (IL-1β, IFNγ, CCL24 and CXCL8) were significantly reduced in COVID-19 patients compared to controls. A low intensity antiviral host response signature was observed predominantly in EC reflecting the cellular localization of the virus. Conclusion: Epithelial, myeloid and lymphoid cell alterations characterize intestinal response to SARS-CoV-2 infection with an unanticipated downregulation of key inflammatory pathways that have been implicated in adverse outcomes associated with COVID-19. These data stand in contrast to reports from the pulmonary and systemic compartments and identify a potential mitigating role of the GI tract in COVID-19-associated immunopathology.