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Nat Med ; 26(7): 1077-1083, 2020 07.
Article in English | MEDLINE | ID: covidwho-260261


A novel coronavirus-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-emerged in humans in Wuhan, China, in December 2019 and has since disseminated globally1,2. As of April 16, 2020, the confirmed case count of coronavirus disease 2019 (COVID-19) had surpassed 2 million. Based on full-genome sequence analysis, SARS-CoV-2 shows high homology to SARS-related coronaviruses identified in horseshoe bats1,2. Here we show the establishment and characterization of expandable intestinal organoids derived from horseshoe bats of the Rhinolophus sinicus species that can recapitulate bat intestinal epithelium. These bat enteroids are fully susceptible to SARS-CoV-2 infection and sustain robust viral replication. Development of gastrointestinal symptoms in some patients with COVID-19 and detection of viral RNA in fecal specimens suggest that SARS-CoV-2 might cause enteric, in addition to respiratory, infection3,4. Here we demonstrate active replication of SARS-CoV-2 in human intestinal organoids and isolation of infectious virus from the stool specimen of a patient with diarrheal COVID-19. Collectively, we established the first expandable organoid culture system of bat intestinal epithelium and present evidence that SARS-CoV-2 can infect bat intestinal cells. The robust SARS-CoV-2 replication in human intestinal organoids suggests that the human intestinal tract might be a transmission route of SARS-CoV-2.

Betacoronavirus/pathogenicity , Coronavirus Infections/pathology , Coronavirus Infections/transmission , Intestines/virology , Organoids/virology , Pneumonia, Viral/pathology , Pneumonia, Viral/transmission , Animals , Cell Differentiation , Cells, Cultured , Child, Preschool , Chiroptera/virology , Chlorocebus aethiops , Coronavirus Infections/virology , Enterocytes/pathology , Enterocytes/physiology , Enterocytes/virology , Female , Humans , Infant , Intestinal Mucosa/pathology , Intestinal Mucosa/virology , Intestines/pathology , Male , Organoids/pathology , Pandemics , Pneumonia, Viral/virology , Reverse Transcriptase Polymerase Chain Reaction , Vero Cells , Viral Load/genetics , Viral Load/methods , Viral Tropism/physiology
Sci Immunol ; 5(47)2020 05 13.
Article in English | MEDLINE | ID: covidwho-260039


Gastrointestinal symptoms and fecal shedding of SARS-CoV-2 RNA are frequently observed in COVID-19 patients. However, it is unclear whether SARS-CoV-2 replicates in the human intestine and contributes to possible fecal-oral transmission. Here, we report productive infection of SARS-CoV-2 in ACE2+ mature enterocytes in human small intestinal enteroids. Expression of two mucosa-specific serine proteases, TMPRSS2 and TMPRSS4, facilitated SARS-CoV-2 spike fusogenic activity and promoted virus entry into host cells. We also demonstrate that viruses released into the intestinal lumen were inactivated by simulated human colonic fluid, and infectious virus was not recovered from the stool specimens of COVID-19 patients. Our results highlight the intestine as a potential site of SARS-CoV-2 replication, which may contribute to local and systemic illness and overall disease progression.

Betacoronavirus/physiology , Enterocytes/virology , Membrane Proteins/metabolism , Serine Endopeptidases/metabolism , Virus Internalization , Animals , Cell Line , Duodenum/cytology , Enterocytes/pathology , Humans , Mice , Organoids/virology , Peptidyl-Dipeptidase A/metabolism , Rotavirus/physiology , Vesiculovirus/genetics