Recapitulation of SARS-CoV-2 infection and cholangiocyte damage with human liver ductal organoids.
Ontology highlight
ABSTRACT:
SUBMITTER: Zhao B
PROVIDER: S-EPMC7164704 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:COVID-19-associated acute kidney injury (COVID-AKI) is a common complication of SARS-CoV-2 infection in hospitalized patients. The susceptibility of human kidneys to direct SARS-CoV-2 infection and modulation of the renin-angiotensin II signaling (RAS) pathway by viral infection remain poorly characterized. Using induced pluripotent stem cell-derived kidney organoids, SARS-CoV-1, SARS-CoV-2, and MERS-CoV tropism, defined by the paired expression of a host receptor (ACE2, NRP1 or DPP4) and protease (TMPRSS2, TMPRSS4, FURIN, CTSB or CTSL), was identified primarily among proximal tubule cells. Losartan, an angiotensin II receptor blocker being tested in patients with COVID-19, inhibited angiotensin II-mediated internalization of ACE2, upregulated interferon-stimulated genes (IFITM1 and BST2) known to restrict viral entry, and attenuated the infection of proximal tubule cells by SARS-CoV-2. Our work highlights the susceptibility of proximal tubule cells to SARS-CoV-2 and reveals a putative protective role for RAS inhibitors during SARS-CoV-2 infection.
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Project description:COVID-19 typically manifests as a respiratory illness but several clinical reports described gastrointestinal (GI) symptoms. This is particularly true in children, whom GI symptoms are frequent and viral shedding outlasts viral clearance from the respiratory system. These observations raise the question of whether the virus can replicate within the stomach. Here we show the novel derivation of gastric organoids from fetal, pediatric and adult biopsies and prove their value as in vitro models for SARS-CoV-2 infection. To facilitate infection, we induced a reversed polarity in our organoids (RP-GOs). The pediatric RP-GOs are fully susceptible to infection with SARS-CoV-2, while the viral replication is significantly lower in organoids of fetal and adult origin. Transcriptomic analysis shows a moderate innate antiviral response and the lack of differentially expressed genes belonging to the interferon family. Collectively, we show how the virus can efficiently infect gastric epithelium, suggesting that the stomach might have an active role in fecal-oral SARS-CoV-2 transmission.
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