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1.
Genes (Basel) ; 11(6)2020 06 11.
Article in English | MEDLINE | ID: covidwho-602760

ABSTRACT

There is increasing evidence of gastrointestinal (GI) infection by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We surveyed the co-expression of SARS-CoV-2 entry genes ACE2 and TMPRSS2 throughout the GI tract to assess potential sites of infection. Publicly available and in-house single-cell RNA-sequencing datasets from the GI tract were queried. Enterocytes from the small intestine and colonocytes showed the highest proportions of cells co-expressing ACE2 and TMPRSS2. Therefore, the lower GI tract represents the most likely site of SARS-CoV-2 entry leading to GI infection.


Subject(s)
Betacoronavirus/metabolism , Enterocytes/metabolism , Lower Gastrointestinal Tract/metabolism , Peptidyl-Dipeptidase A/genetics , Serine Endopeptidases/genetics , Base Sequence , Cells, Cultured , Coronavirus Infections/pathology , Enterocytes/virology , Gastrointestinal Diseases/virology , Humans , Lower Gastrointestinal Tract/virology , Membrane Proteins/genetics , Membrane Proteins/metabolism , Pandemics , Peptidyl-Dipeptidase A/metabolism , Pneumonia, Viral/pathology , Sequence Analysis , Serine Endopeptidases/metabolism , Virus Internalization
2.
Nat Med ; 26(7): 1077-1083, 2020 07.
Article in English | MEDLINE | ID: covidwho-260261

ABSTRACT

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.


Subject(s)
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
3.
Sci Immunol ; 5(47)2020 05 13.
Article in English | MEDLINE | ID: covidwho-260039

ABSTRACT

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.


Subject(s)
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
4.
Science ; 369(6499): 50-54, 2020 07 03.
Article in English | MEDLINE | ID: covidwho-154670

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can cause coronavirus disease 2019 (COVID-19), an influenza-like disease that is primarily thought to infect the lungs with transmission through the respiratory route. However, clinical evidence suggests that the intestine may present another viral target organ. Indeed, the SARS-CoV-2 receptor angiotensin-converting enzyme 2 (ACE2) is highly expressed on differentiated enterocytes. In human small intestinal organoids (hSIOs), enterocytes were readily infected by SARS-CoV and SARS-CoV-2, as demonstrated by confocal and electron microscopy. Enterocytes produced infectious viral particles, whereas messenger RNA expression analysis of hSIOs revealed induction of a generic viral response program. Therefore, the intestinal epithelium supports SARS-CoV-2 replication, and hSIOs serve as an experimental model for coronavirus infection and biology.


Subject(s)
Betacoronavirus/physiology , Enterocytes/virology , Ileum/virology , Virus Replication , Betacoronavirus/ultrastructure , Cell Culture Techniques , Cell Differentiation , Cell Lineage , Cell Proliferation , Culture Media , Enterocytes/metabolism , Enterocytes/ultrastructure , Gene Expression , Humans , Ileum/metabolism , Ileum/ultrastructure , Lung/virology , Male , Organoids , Peptidyl-Dipeptidase A/genetics , Peptidyl-Dipeptidase A/metabolism , RNA, Messenger/genetics , RNA, Messenger/metabolism , Receptors, Virus/genetics , Receptors, Virus/metabolism , Respiratory Mucosa/virology , SARS Virus/physiology
5.
Rev Esp Enferm Dig ; 112(5): 383-388, 2020 05.
Article in English | MEDLINE | ID: covidwho-148632

ABSTRACT

Although SARS-CoV-2 may primarily enter the cells of the lungs, the small bowel may also be an important entry or interaction site, as the enterocytes are rich in angiotensin converting enzyme (ACE)-2 receptors. The initial gastrointestinal symptoms that appear early during the course of Covid-19 support this hypothesis. Furthermore, SARS-CoV virions are preferentially released apically and not at the basement of the airway cells. Thus, in the setting of a productive infection of conducting airway epithelia, the apically released SARS-CoV may be removed by mucociliary clearance and gain access to the GI tract via a luminal exposure. In addition, post-mortem studies of mice infected by SARS-CoV have demonstrated diffuse damage to the GI tract, with the small bowel showing signs of enterocyte desquamation, edema, small vessel dilation and lymphocyte infiltration, as well as mesenteric nodes with severe hemorrhage and necrosis. Finally, the small bowel is rich in furin, a serine protease which can separate the S-spike of the coronavirus into two "pinchers" (S1 and 2). The separation of the S-spike into S1 and S2 is essential for the attachment of the virion to both the ACE receptor and the cell membrane. In this special review, we describe the interaction of SARS-CoV-2 with the cell and enterocyte and its potential clinical implications.


Subject(s)
Betacoronavirus/pathogenicity , Coronavirus Infections/metabolism , Enterocytes/virology , Gastrointestinal Diseases/virology , Intestine, Small/virology , Peptidyl-Dipeptidase A/metabolism , Pneumonia, Viral/metabolism , Betacoronavirus/metabolism , Coronavirus Infections/virology , Enterocytes/metabolism , Gastrointestinal Diseases/metabolism , Humans , Intestine, Small/cytology , Intestine, Small/metabolism , Pandemics , Pneumonia, Viral/virology , Receptors, Angiotensin/metabolism , Respiratory Mucosa/physiology , Respiratory Mucosa/virology
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