ABSTRACT
The coronavirus SARS-CoV-2 caused the COVID-19 global pandemic leading to 3.5 million deaths worldwide as of June 2021. The human intestine was found to be a major viral target which could have a strong impact on virus spread and pathogenesis since it is one of the largest organs. While type I interferons (IFNs) are key cytokines acting against systemic virus spread, in the human intestine type III IFNs play a major role by restricting virus infection and dissemination without disturbing homeostasis. Recent studies showed that both type I and III IFNs can inhibit SARS-CoV-2 infection, but it is not clear if one IFN controls SARS-CoV-2 infection of the human intestine better or with a faster kinetics. In this study, we could show that both type I and III IFNs possess antiviral activity against SARS-CoV-2 in human intestinal epithelial cells (hIECs), however type III IFN is more potent. Shorter type III IFN pretreatment times and lower concentrations were required to efficiently reduce virus load when compared to type I IFNs. Moreover, type III IFNs significantly inhibited SARS-CoV-2 even 4 hours post-infection and induced a long-lasting antiviral effect in hIECs. Importantly, the sensitivity of SARS-CoV-2 to type III IFNs was virus-specific since type III IFN did not control VSV infection as efficiently. Together these results suggest that type III IFNs have a higher potential for IFN-based treatment of SARS-CoV-2 intestinal infection as compared to type I IFNs.
ABSTRACT
ObjectiveExacerbated pro-inflammatory immune response contributes to COVID-19 pathology. Despite the evidence about SARS-CoV-2 infecting the human gut, little is known about the importance of the enteric phase of SARS-CoV-2 for the viral lifecycle and for the development of COVID-19-associated pathologies. Similarly, it remains unknown whether the innate immune response triggered in this organ to combat viral infection is similar or distinct compared to the one triggered in other organs. DesignWe exploited human ileum- and colon-derived organoids as a non-transformed culture model supporting SARS-CoV-2 infection. We characterized the replication kinetics of SARS-CoV-2 in intestinal epithelial cells and correlated the expression of the viral receptor ACE2 with infection. We performed conventional and targeted single-cell transcriptomics and multiplex single-molecule RNA fluorescence in situ hybridization and used IFN-reporter bioassays to characterize the response of primary human intestinal epithelial cells to SARS-CoV-2 infection. ResultsWe identified a subpopulation of enterocytes as the prime target of SARS-CoV-2. We found the lack of positive correlation between susceptibility to infection and the expression of ACE2 and revealed that SARS-CoV-2 downregulates ACE2 expression upon infection. Infected cells activated strong proinflammatory 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 in infected cells. ConclusionOur findings reveal that SARS-CoV-2 curtails the immune response in primary human intestinal epithelial cells to promote its replication and spread and this highlights the gut as a proinflammatory reservoir that should be considered to fully understand SARS-CoV-2 pathogenesis. Significance of the studyWhat is already known about this subject? O_LICOVID-19 patients have gastrointestinal symptoms which likely correlates with SARS-CoV-2 infection of the intestinal epithelium C_LIO_LISARS-CoV-2 replicates in human intestinal epithelial cells. C_LIO_LIIntestinal organoids are a good model to study SARS-CoV-2 infection of the gastrointestinal tract C_LIO_LIThere is a limited interferon response in human lung epithelial cells upon SARS-CoV-2 infection. C_LI What are the new findings? O_LIA specific subpopulation of enterocytes are the prime targets of SARS-CoV-2 infection of the human gut. C_LIO_LIThere is a lack of correlation between ACE2 expression and susceptibility to SARS-CoV-2 infection. SARS-CoV-2 downregulates ACE2 expression upon infection. C_LIO_LIHuman intestinal epithelium cells produce interferon upon SARS-CoV-2 infection. C_LIO_LIInterferon acts in a paracrine manner to induce interferon stimulated genes that control viral infection only in bystander cells. C_LIO_LISARS-CoV-2 actively blocks interferon signaling in infected cells. C_LI How might it impact on clinical practice in the foreseeable future? O_LIThe absence of correlation between ACE2 levels and susceptibility suggest that medications influencing ACE2 levels (e.g. high blood pressure drugs) will not make patients more susceptible to SARS-CoV-2 infection. C_LIO_LIThe restricted cell tropism and the distinct immune response mounted by the GI tract, suggests that specific cellular restriction/replication factors and organ specific intrinsic innate immune pathways can represent unique therapeutic targets to treat COVD-19 patients by considering which organ is most infected/impacted by SARS-CoV-2. C_LIO_LIThe strong pro-inflammatory signal mounted by the intestinal epithelium can fuel the systemic inflammation observed in COVID-19 patients and is likely participating in the lung specific pathology. C_LI
