Reduced SARS-CoV-2 infection and altered antiviral transcriptional response in IBD intestinal organoids.

IBD is characterized by altered immune reactions and infections are thought to trigger the chronic inflammatory response in IBD. The gut represents a productive reservoir for SARS-CoV-2 and the aforementioned factors together with immunosuppression used to treat IBD are likely influencing the outcomes of IBD patients in COVID-19. We used large and small intestinal organoids from IBD patients and controls to comparatively assess the transcriptional response of the gut epithelium during SARS-CoV-2 infection. Our analysis showed that IBD epithelia exhibit reduced viral loads compared to controls associated with a reduced expression of SARS-CoV-2 entry factors including the host receptor ACE2. Moreover, several genes implicated in the epithelial response to viral infection are intrinsically altered in IBD likely counteracting viral propagation. Notably, differences between IBD phenotypes exist wherein ulcerative colitis represents with induced cell death pathways and an induction of IL-1β despite overall lower viral loads suggestive of increased epithelial stress in this IBD phenotype. Altogether our analysis shows that IBD epithelia are not more prone to SARS-CoV-2 infection but epithelia from ulcerative colitis and Crohn's disease exhibit specific differences which might explain the differing COVID-19 outcomes between IBD phenotypes. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement G.G. received funding from the Austrian Science fund (FWF, DK-MOLIN W1241). A.M. is supported by the Christian Doppler research foundation. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Generation and use of organoids were approved by the ethics committee of Medical University Innsbruck, Austria (ethics vote no.: AN4994 323/4.4). All patients gave their informed written consent for participation in this study. SARS\_CoV\_2 isolation was done during an autopsy study approved by the ethics committee of the Medical University of Graz (EK-number: 32_362 ex 19/20). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes The RNAseq data have been deposited in NCBI-GEO under the accession number GSE208684. There are restrictions to the availability of human intestinal organoids generated in this study due to difficulties in their long-term preservation. Further information and requests for resources and reagents should be directed to and will be fulfilled by the lead contact Gregor Gorkiewicz (gregor.gorkiewicz@medunigraz.at).