Coronavirus

Coronavirus infections historically were associated with mild upper respiratory tract diseases in infants, children, and adults. Human coronavirus (HCoV)-OC43 and HCoV-229E were associated with 15–30% of common colds in winter and occasionally linked with lower respiratory tract disease in populations with chronic underlying diseases. HCoV research was complicated by the lack of a reverse genetic system or animal model. These viruses propagated poorly, and the number of reagents was limited. However, coronaviruses are capable of rapid host switching and evolution in changing ecologies (1), suggesting that their diversity and role in human disease were underappreciated. The 21st century heralded the arrival of the more pathogenic coronaviruses, like severe acute respiratory syndrome (SARS)-CoV.

https://web.archive.org/web/20180604062832/https://www.pnas.org/content/102/23/8073

• The Genome Sequence of the SARS-Associated Coronavirus

• Feb, 2008 - Difference in Receptor Usage between Severe Acute Respiratory Syndrome (SARS) Coronavirus and SARS-Like Coronavirus of Bat Origin¹⁾

• Feb 6, 2020 - Persistence of coronaviruses on inanimate surfaces and their inactivation with biocidal agents²⁾

Humanized mice develop coronavirus respiratory disease Ralph Baric and Amy C. Sims PNAS June 7, 2005. 102 (23) 8073-8074; https://doi.org/10.1073/pnas.0503091102

In 2013, researchers at the Wuhan Institute of Virology published a paper saying that Dr. Zhengli Shi and EcoHealth Alliance's Dr. Peter Daszak found CoVs that were 95% identical to human SARS-CoV in Chinese horseshoe bats. Further, these CoVs “were able to use human angiotensin-converting enzyme 2 (ACE2) receptor for docking and entry.”³⁾

Between 2004 and 2020, there were at least four incidents in which a SARS-CoV leaked from a laboratory.⁴⁾ During the COVID-19 pandemic, debate has raged over a lab leak hypothesis.

MERS-CoV spike nanoparticles protect mice from MERS-CoV infection Vaccine. 2017 Mar 14;35(12):1586-1589. doi: 10.1016/j.vaccine.2017.02.012. Epub 2017 Feb 23. Authors - Christopher M Coleman 1 , Thiagarajan Venkataraman 1 , Ye V Liu 2 , Gregory M Glenn 2 , Gale E Smith 2 , David C Flyer 2 , Matthew B Frieman 3 Affiliations

1. University of Maryland, School of Medicine, 685 West Baltimore St, Baltimore, MD 21201, United States. 2. - Novavax, Inc., 22 Firstfield Rd, Gaithersburg, MD 20852, United States. 3. - University of Maryland, School of Medicine, 685 West Baltimore St, Baltimore, MD 21201, United States. Electronic address: mfrieman@som.umaryland.edu.

PMID: 28237499 PMCID: PMC5423355 DOI: 10.1016/j.vaccine.2017.02.012

Abstract

The Middle East respiratory syndrome coronavirus (MERS-CoV) was first discovered in late 2012 and has gone on to cause over 1800 infections and 650 deaths. There are currently no approved therapeutics or vaccinations for MERS-CoV. The MERS-CoV spike (S) protein is responsible for receptor binding and virion entry to cells, is immunodominant and induces neutralizing antibodies in vivo, all of which, make the S protein an ideal target for anti-MERS-CoV vaccines. In this study, we demonstrate protection induced by vaccination with a recombinant MERS-CoV S nanoparticle vaccine and Matrix-M1 adjuvant combination in mice. The MERS-CoV S nanoparticle vaccine produced high titer anti-S neutralizing antibody and protected mice from MERS-CoV infection in vivo.

Keywords: Coronavirus; MERS-CoV; Mouse model; Nanoparticle vaccine. Copyright © 2017 Elsevier Ltd. All rights reserved.⁵⁾

Coronavirus S protein-induced fusion is blocked prior to hemifusion by Abl kinase inhibitors J Gen Virol. 2018 May;99(5):619-630. doi: 10.1099/jgv.0.001047. Epub 2018 Mar 20. Authors - Jeanne M Sisk 1 , Matthew B Frieman 2 , Carolyn E Machamer 1

Abstract

Enveloped viruses gain entry into host cells by fusing with cellular membranes, a step that is required for virus replication. Coronaviruses, including the severe acute respiratory syndrome coronavirus SARS-CoV, Middle East respiratory syndrome coronavirus MERS-CoV and infectious bronchitis virus (IBV), fuse at the plasma membrane or use receptor-mediated endocytosis and fuse with endosomes, depending on the cell or tissue type.

The virus spike (S) protein mediates fusion with the host cell membrane. We have shown previously that an Abelson (Abl) kinase inhibitor, imatinib, significantly reduces SARS-CoV and MERS-CoV viral titres and prevents endosomal entry by HIV SARS S and MERS S pseudotyped virions. SARS-CoV and MERS-CoV are classified as BSL-3 viruses, which makes experimentation into the cellular mechanisms involved in infection more challenging.

Here, we use IBV, a BSL-2 virus, as a model for studying the role of Abl kinase activity during coronavirus infection. We found that imatinib and two specific Abl kinase inhibitors, GNF2 and GNF5, reduce IBV titres by blocking the first round of virus infection. Additionally, all three drugs prevented IBV S-induced syncytia formation prior to the hemifusion step. Our results indicate that membrane fusion (both virus-cell and cell-cell) is blocked in the presence of Abl kinase inhibitors. Studying the effects of Abl kinase inhibitors on IBV will be useful in identifying the host cell pathways required for coronavirus infection. This will provide an insight into possible therapeutic targets to treat infections by current as well as newly emerging coronaviruses.

Keywords: Abl kinase; Abl1; Abl2; GNF2; GNF5; IBV; MERS-CoV; SARS-CoV; cell-cell fusion; coronavirus; imatinib; virus-cell fusion. Publication types - Research Support, N.I.H., Extramural⁶⁾