Our built-in protection from coronavirus infection

Zoonotic coronaviruses, as exemplified by the COVID-19 pandemic, are a major threat to global health. Here, we identify LY6E as a host-encoded antiviral gene that impairs cellular entry by six viruses from the Coronaviridae family, including SARS-CoV-2.

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Written by Katrina Mar and Stephanie Pfaender.

The global outbreak of SARS-CoV-2 significantly altered daily life as we know it. At the time of writing this post, more than 13 million cases have been reported worldwide with nearly 600,000 fatalities. Most efficacious drugs approved for clinical treatment of COVID-19 target viral proteins or inflammation instigated by an aberrant host immune response. However, a ‘silver bullet’ treatment for COVID-19 remains elusive.

Coronaviruses are known for their ability to infect humans. The endemic human coronaviruses (HCoV-229E, -OC43, -HKU1, and -NL63) annually circulate and cause a significant proportion of common colds. Zoonotic coronaviruses, which have spilled over from animal reservoirs to humans, can cause life-threatening infections as first observed with SARS-CoV in 2003, followed by MERS-CoV in 2012, and now SARS-CoV-2 in 2019.

Interferons, a family of cytokines produced by virally infected host cells, protect neighboring cells from infection by stimulating production of antiviral interferon stimulated genes (ISGs). Most coronavirus infections in cell culture and in mouse models are impaired by interferon pretreatment. Clinical studies investigating interferon for treatment of COVID-19 are currently underway, underscoring an urgent need to understand the antiviral factors involved in the protective state induced by interferon.

In 2017, we began our study to identify ISGs that inhibit coronavirus infection. Our study began when co-first author Stephanie Pfaender from the lab of Volker Thiel visited Rockefeller University to collaborate with Lefteris Michailidis and Charlie Rice. Stephanie and Lefteris screened a library of ISGs for antiviral activity towards HCoV-229E and identified LY6E, which also inhibited all tested members of Coronaviridae, including MERS-CoV, SARS-CoV, and the model coronavirus mouse hepatitis virus (MHV). The ability of LY6E to reduce infection by multiple coronaviruses indicated that the ISG targeted a shared pathway, which Stephanie later found to be spike protein-mediated membrane fusion.

We were surprised that LY6E exhibited antiviral activity, as John Schoggins had previously generated and screened the same ISG library as a postdoc in Charlie’s lab and discovered that LY6E enhanced infection by yellow fever virus and influenza A virus. In 2012, viral enhancement by LY6E became the focus of co-first author Katrina Mar’s dissertation. In 2018, Charlie visited UTSW as an invited speaker and expanded the collaboration over lunch. Several months later, Katrina showed that Ly6e was critical for mice to survive infection with the coronavirus MHV.

The initial reports of COVID-19 came while we were preparing the manuscript in late 2019. As one of the first labs to obtain SARS-CoV-2 for cell culture infections, we showed that LY6E also blocked entry and spike-mediated membrane fusion of SARS-CoV-2.

The emergence of SARS-CoV, MERS-CoV, and SARS-CoV-2 over the past 17 years demonstrates that zoonotic coronaviruses threaten global health. Given the lack of knowledge regarding circulating animal coronaviruses and rapid increases in factors that promote zoonotic infections (globalization, industrialization, and climate change), a global pandemic caused by another zoonotic coronavirus is imminent. Our study provides a potential target for a host-based therapy that boosts the body’s own antiviral protection against members of the Coronaviridae family. Exploiting the exact mechanism of action might provide novel antiviral treatment strategies to better prepare for future coronavirus outbreaks.

Check out our paper here:

https://www.nature.com/articles/s41564-020-0769-y

Katrina Mar

Postdoctoral Fellow, University of Texas Southwestern

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