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Recent:   

How does SARS-CoV-2 cause COVID-19?

Matheson et al., Science, doi:10.1126/science.abc6156
Jul 2020  
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Review discussing how the viral receptor ACE2 regulates SARS-CoV-2 cell entry, tissue tropism, and COVID-19 disease progression. The presence of a furin cleavage site in the SARS-CoV-2 spike protein expands cell tropism compared to SARS-CoV. Expression of ACE2 and the TMPRSS2 protease is highest in the upper respiratory tract, enabling efficient transmission of SARS-CoV-2 before symptom onset. Severe COVID-19 is characterized by breakdown of the lung epithelial-endothelial barrier and may be driven by persistent viral replication and/or immune-mediated damage.
Matheson et al., 31 Jul 2020, peer-reviewed, 2 authors. Contact: pjl30@cam.ac.uk, njm25@cam.ac.uk.
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Abstract: INSIGHTS | P E R S P E C T I V E S VIEWPOINT: COVID-19 How does SARS-CoV-2 cause COVID-19? The viral receptor on human cells plays a critical role in disease progression By Nicholas J. Matheson1,2 and Paul J. Lehner1 V 1 Department of Medicine, Cambridge Institute for Therapeutic Immunology and Infectious Disease (CITIID), University of Cambridge, Cambridge, UK.2NHS Blood and Transplant, Cambridge, UK. Email: pjl30@cam.ac.uk; njm25@cam.ac.uk 510 without targeting ACE2, so other factors must also be important. As a respiratory virus, SARS-CoV-2 must initially enter cells lining the respiratory tract. Single-cell sequencing and RNA in situ mapping of the human respiratory tract show ACE2 and TMPRSS2 expression to be highest in ciliated nasal epithelial cells, with lesser amounts in ciliated bronchial epithelial cells and type II alveolar epithelial cells (6). This translates to greater permissivity of upper versus lower respiratory tract epithelial cells for SARS-CoV-2 infection in vitro and fits disease pathology: Upper respiratory tract symptoms are common early in disease, with nasopharyngeal and throat swabs positive for SARS-CoV-2 at clinical presentation (7). In contrast to SARS-CoV, infectivity of patients with SARS-CoV-2 peaks before symptom onset (8). Indeed, presymptomatic transmission makes SARS-CoV-2 impossible to contain through case isolation alone and is a key driver of the pandemic (8). This alteration in the pattern of disease may relate to the acquisition of the furin cleavage site in spike or increased binding affinity for ACE2 in SARSCoV-2, compared with SARS-CoV (9). If the main role of ACE2 is to cleave angiotensin II, it is unclear why expression in lung tissue is more prominent in epithelial than in endothelial cells. Furthermore, the Human Cell Atlas highlights ACE2 expression in intestinal enterocytes, rather than in the lungs. This distribution may reflect nonenzymatic roles of ACE2, such as chaperoning amino acid transporters. Indeed, SARSCoV-2 infection of the gastrointestinal (GI) tract is common, with viral RNA detectable in stool in up to 30% of COVID-19 patients. This likely contributes to the frequency of GI symptoms. Conversely, whereas fecal-oral transmission of coronaviruses is thought to be prominent among bats, it appears to be a minor transmission route for SARS-CoV-2 in humans, perhaps because colonic fluid inactivates the virus. Whether extrapulmonary ACE2 expression and concomitant viral infection account for other clinical manifestations of SARS-CoV-2 is unclear. The association between SARS-CoV-2 infection and anosmia (loss of smell) may reflect ACE2 and TMPRSS2 expression in sustentacular cells, which maintain the integrity of olfactory sensory neurons. Olfactory epithelial cells also express NRP1 and could provide a direct route to the brain (4). sciencemag.org SCIENCE 31 JULY 2020 • VOL 369 ISSUE 6503 Published by AAAS iruses enter cells and initiate infection by binding to their cognate cell surface receptors. The expression and distribution of viral entry receptors therefore regulates their tropism, determining the tissues that are infected and thus disease pathogenesis. Severe acute respiratory syndrome coronavirus 2 (SARSCoV-2) is the third human coronavirus known to co-opt the peptidase angiotensinconverting enzyme 2 (ACE2) for cell entry (1). The interaction between SARS-CoV-2 and ACE2 is critical to determining both..
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