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SSRN ; 2020.
Article | WHO COVID | ID: covidwho-693565


The outbreak of COVID-19 caused by the SARS-CoV-2 virus has created an unparalleled disruption of global behavior and a significant loss of human lives To minimize SARS-CoV-2 spread, understanding the mechanisms of infection from all possible viral entry routes is essential As aerosol transmission is thought to be the primary route of spread, we sought to investigate whether the eyes are potential entry portals for SARS-CoV-2 While virus has been detected in the eye, in order for this mucosal membrane to be a bone fide entry source SARS-CoV-2 would need the capacity to productively infect ocular surface cells  As such, we conducted RNA sequencing in ocular cells isolated from adult human cadaver donor eyes as well as from a pluripotent stem cell-derived whole eye organoid model to evaluate the expression of ACE2 and TMPRSS2, essential proteins that mediate SARS-CoV-2 viral entry We also infected eye organoids and adult human ocular cells with SARS-CoV-2 and evaluated virus replication and the host response to infection We found the limbus was most susceptible to infection, whereas the central cornea exhibited only low levels of replication Transcriptional profiling of the limbus upon SARS-CoV-2 infection, found that while type I or III interferons were not detected in the lung epithelium, a significant inflammatory response was mounted Together these data suggest that the human eye can be directly infected by SARS-CoV-2 and thus is a route warranting protection Funding: The National Eye Institute (NEI), Bethesda, MD, USA, extramural grant 1R21EY030215-01 and the Icahn School of Medicine at Mount Sinai supported this study

Cell Stem Cell ; 27(1): 125-136.e7, 2020 07 02.
Article in English | MEDLINE | ID: covidwho-610467


SARS-CoV-2 has caused the COVID-19 pandemic. There is an urgent need for physiological models to study SARS-CoV-2 infection using human disease-relevant cells. COVID-19 pathophysiology includes respiratory failure but involves other organ systems including gut, liver, heart, and pancreas. We present an experimental platform comprised of cell and organoid derivatives from human pluripotent stem cells (hPSCs). A Spike-enabled pseudo-entry virus infects pancreatic endocrine cells, liver organoids, cardiomyocytes, and dopaminergic neurons. Recent clinical studies show a strong association with COVID-19 and diabetes. We find that human pancreatic beta cells and liver organoids are highly permissive to SARS-CoV-2 infection, further validated using adult primary human islets and adult hepatocyte and cholangiocyte organoids. SARS-CoV-2 infection caused striking expression of chemokines, as also seen in primary human COVID-19 pulmonary autopsy samples. hPSC-derived cells/organoids provide valuable models for understanding the cellular responses of human tissues to SARS-CoV-2 infection and for disease modeling of COVID-19.

Betacoronavirus/physiology , Coronavirus Infections/virology , Induced Pluripotent Stem Cells/metabolism , Models, Biological , Organoids/virology , Pneumonia, Viral/virology , Tropism , Animals , Autopsy , Cell Line , Coronavirus Infections/pathology , Hepatocytes/pathology , Hepatocytes/virology , Humans , Induced Pluripotent Stem Cells/virology , Liver/pathology , Mice , Pancreas/pathology , Pancreas/virology , Pandemics , Peptidyl-Dipeptidase A/metabolism , Pneumonia, Viral/pathology , Virus Internalization
Cell ; 181(5): 1036-1045.e9, 2020 05 28.
Article in English | MEDLINE | ID: covidwho-72372


Viral pandemics, such as the one caused by SARS-CoV-2, pose an imminent threat to humanity. Because of its recent emergence, there is a paucity of information regarding viral behavior and host response following SARS-CoV-2 infection. Here we offer an in-depth analysis of the transcriptional response to SARS-CoV-2 compared with other respiratory viruses. Cell and animal models of SARS-CoV-2 infection, in addition to transcriptional and serum profiling of COVID-19 patients, consistently revealed a unique and inappropriate inflammatory response. This response is defined by low levels of type I and III interferons juxtaposed to elevated chemokines and high expression of IL-6. We propose that reduced innate antiviral defenses coupled with exuberant inflammatory cytokine production are the defining and driving features of COVID-19.

Betacoronavirus/physiology , Coronavirus Infections/immunology , Pneumonia, Viral/immunology , RNA Viruses/immunology , Animals , Cells, Cultured , Chemokines/genetics , Chemokines/immunology , Coronavirus Infections/genetics , Disease Models, Animal , Host-Pathogen Interactions , Humans , Immunity, Innate , Inflammation/virology , Interferons/genetics , Interferons/immunology , Pandemics , Pneumonia, Viral/genetics , RNA Viruses/classification , Transcription, Genetic