SARS-CoV-2 Reverse Genetics Reveals a Variable Infection Gradient in the Respiratory Tract

Published:May 26, 2020DOI: https://doi.org/10.1016/j.cell.2020.05.042

  • A SARS-CoV-2 infectious cDNA clone and reporter viruses are generated
  • SARS-CoV-2 and SARS-CoV neutralization assays show limited cross neutralization
  • SARS-CoV-2 shows a gradient infectivity from the proximal to distal respiratory tract
  • Ciliated airway cells and AT-2 cells are primary targets for SARS-CoV-2 infection

Summary
The mode of acquisition and causes for the variable clinical spectrum of coronavirus disease 2019 (COVID-19) remain unknown. We utilized a reverse genetics system to generate a GFP reporter virus to explore severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pathogenesis and a luciferase reporter virus to demonstrate sera collected from SARS and COVID-19 patients exhibited limited cross-CoV neutralization. High-sensitivity RNA in situ mapping revealed the highest angiotensin-converting enzyme 2 (ACE2) expression in the nose with decreasing expression throughout the lower respiratory tract, paralleled by a striking gradient of SARS-CoV-2 infection in proximal (high) versus distal (low) pulmonary epithelial cultures. COVID-19 autopsied lung studies identified focal disease and, congruent with culture data, SARS-CoV-2-infected ciliated and type 2 pneumocyte cells in airway and alveolar regions, respectively. These findings highlight the nasal susceptibility to SARS-CoV-2 with likely subsequent aspiration-mediated virus seeding to the lung in SARS-CoV-2 pathogenesis. These reagents provide a foundation for investigations into virus-host interactions in protective immunity, host susceptibility, and virus pathogenesis.


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

  1. Nicholas J. Matheson, Paul J. Lehner. https://science.sciencemag.org/content/369/6503/510
Key phases of disease progressionSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) binds to angiotensin-converting enzyme 2 (ACE2). Initial infection of cells in the upper respiratory tract may be asymptomatic, but these patients can still transmit the virus. For those who develop symptoms, up to 90% will have pneumonitis, caused by infection of cells in the lower respiratory tract. Some of these patients will progress to severe disease, with disruption of the epithelial-endothelial barrier, and multi-organ involvement.

Comprehensive review of coronavirus disease 2019 (COVID-19)

Shaylika Chauhan, Biomedical Journal, Available online 1 June 2020. https://doi.org/10.1016/j.bj.2020.05.023

Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was first identified in December 2019 in Wuhan, the capital of China’s Hubei province and has rapidly spread all over the world. The World Health Organization (WHO) declared the outbreak to be a Public Health Emergency of International Concern on 30 January 2020 and recognized it as a pandemic on 11 March 2020. The number of people diagnosed with COVID-19 worldwide crossed the one million mark on April 2, 2020; two million mark on April 15, 2020; three million mark on April 27,2020 and the four million mark on May 9,2020. Despite containment efforts, more than 187 countries have been affected with more than 4, 178,346 cases in the world with maximum being in USA (1, 347,936) followed by 227,436 in Spain and 224, 422 in United Kingdom as of May, 2020. COVID-19 is the latest threat to face mankind cutting across geographical barriers in a rapidly changing landscape. This review provides an update on a rapidly evolving global pandemic. As we face the threat of emerging and re-emerging infectious diseases, this is a stark reminder to invest in population health, climate change countermeasures, a global health surveillance system and effective research into identifying pathogens, their treatment and prevention and effective health delivery systems.


COVID-19 May Be a Blood Vessel Disease:

Endothelial cell infection and endotheliitis in COVID-19.

Zsuzsanna Varga, et al. The Lancet. April 20, 2020 DOI:https://doi.org/10.1016/S0140-6736(20)30937-5

Our findings show the presence of viral elements within endothelial cells and an accumulation of inflammatory cells, with evidence of endothelial and inflammatory cell death. These findings suggest that SARS-CoV-2 infection facilitates the induction of endotheliitis in several organs as a direct consequence of viral involvement (as noted with presence of viral bodies) and of the host inflammatory response. In addition, induction of apoptosis and pyroptosis might have an important role in endothelial cell injury in patients with COVID-19. COVID-19-endotheliitis could explain the systemic impaired microcirculatory function in different vascular beds and their clinical sequelae in patients with COVID-19. This hypothesis provides a rationale for therapies to stabilise the endothelium while tackling viral replication, particularly with anti-inflammatory anti-cytokine drugs, ACE inhibitors, and statins.7891011 This strategy could be particularly relevant for vulnerable patients with pre-existing endothelial dysfunction, which is associated with male sex, smoking, hypertension, diabetes, obesity, and established cardiovascular disease, all of which are associated with adverse outcomes in COVID-19.

COVID-19: Vascular Manifestations of Disease

COVID-19: Vascular Manifestations of Disease, 6 jul. 2020
Speaker: John S. Pellerito, MD, FAIUM, FACR, FSRU Date Aired: 6/24/2020

COVID-19 on Wikipedia

https://en.wikipedia.org/wiki/Coronavirus_disease_2019

SARS-CoV-2 and the COVID-19 disease: a mini review on diagnostic methods.

Rev. Inst. Med. trop. S. Paulo vol.62  São Paulo  2020  Epub June 29, 2020. https://doi.org/10.1590/s1678-9946202062044