SARS-CoV-2, the coronavirus behind the COVID-19 pandemic, seems to provoke a muted antiviral reaction in human cells and in ferrets, according to a study posted to bioRxiv on March 24. The authors of the study, which is not yet peer-reviewed, propose that this distinctive transcriptional response may be responsible for the coronavirus’s high fatality rate.
“The value of really looking at how the host is responding to this virus is obviously very high and can inform [future work on] drugs,” says Carolina Lopez, who studies how viruses stimulate the immune system at University of Pennsylvania and who did not participate in the study.
Benjamin tenOever, a microbiologist at the Icahn School of Medicine at Mount Sinai in New York, and his group were already studying respiratory viruses when SARS-CoV-2 hit the scene, so they incorporated it into their ongoing work. To compare the coronavirus to seasonal respiratory viruses, they infected a lung cancer cell line with influenza A virus (IAV), respiratory syncytial virus (RSV), or SARS-CoV-2 and sequenced RNA from infected cells. They found that, like IAV and RSV, SARS-CoV-2 was able to replicate in the cells, and that the coronavirus exhibited a transcriptional response that was similar in magnitude to IAV and less robust than RSV.
When they looked at which genes were upregulated in response to viral infection, they found that SARS-CoV-2 spurred the expression of a suite of host genes that was more similar to RSV’s transcriptional program than to IAV’s. But SARS-CoV-2 didn’t appear to induce two important antiviral genes that both RSV and IAV do: those that code for type I and type III interferons, which are part of the gene program that acts as a call to arms to alert a cell’s neighbors to the presence of a viral intruder. The coronavirus did boost the expression of two unique cytokines, secreted factors that have been previously shown to be associated with inflammation in the lungs.
The researchers hypothesized that the modest response in the lung cancer cell line could be because these cells do not express the main receptor, known as ACE2, that SARS-CoV-2 uses to get in, so they tried infecting primary human lung cells, which do have ACE2, and sequencing RNA to assess gene expression in infected and mock-infected cells. The primary human lung cells had a similar transcriptional response as the lung cancer cells, including undetectable levels of type I and III interferon transcripts.
At this point, they wanted to try an animal model. Mouse were out, tenOever explains, because they don’t have a compatible ACE2 receptor. But his group and their collaborators in Randy Albrecht’s lab at Mount Sinai already had a lot of data on flu in ferrets, which provided a ready comparison. Ferrets are “the gold standard for influenza experimentation . . . because they get very similar symptoms. They get a fever; they get a runny nose. They feel a little malaise, and then they recover,” tenOever says. Plus, a report that a COVID-19–positive patient passed the virus to her dog indicated that the ACE2 receptor present in the order Carnivora, which includes both dogs and ferrets, was probably compatible with SARS-CoV-2.
When the researchers infected ferrets with SARS-CoV-2, they saw that the ferrets did get sick with a fever and shed viral particles, meaning that the virus was capable of replicating. They compared the genes expressed in cells collected by squirting a little saline up the animals’ noses after SARS-CoV-2 and IAV infections and found that the coronavirus antiviral response was diminished compared to the response to IAV.
“It’s a very underwhelming response,” says tenOever.
Since they posted the preprint, the authors have continued to monitor the antiviral response in the ferrets, and they see the similar transcriptional responses over time. “The ones that are there are consistent. The ones that are absent that should be there are consistent, and it’s unclear whether or not the virus is actively blocking certain arms of that response.” That’s possible, he adds, because there are host shut-off mechanisms that the virus that caused the 2003 SARS outbreak, SARS-CoV, uses, and SARS-CoV-2 may do the same thing.
“I’m curious how this corresponds to the other zoonotic coronaviruses. That’s really the big question,” says Emma Loveday, who studies viral infections at Montana State University and did not participate in the work. The next step would be to compare SARS-CoV-2 to SARS-COV and the coronavirus responsible for Middle East respiratory syndrome to determine whether this muted response is a unique aspect of the novel coronavirus or something that’s seen with all of them, she adds.
tenOever theorizes that the snapshot of what they’ve seen in cells and animals may explain why older people seem to have more severe disease after SARS-CoV-2 infection. It’s already known that the immune system becomes less effective with age. People under 50 probably have a pretty strong immune system, he says, so even if they only mount half the response that would be expected to a respiratory virus, that’s probably sufficient to neutralize the virus.
The most interesting thing is that “there are some genes that they identify that they don’t see in the other viruses,” Lopez says. She cautions that it can be complicated to compare the magnitude of host transcriptional reactions to different viruses that are like “pears and apples” side by side, but when it comes to SARS-CoV-2, she says, “everything that comes out right now is valuable. It’s informative in one way or another.”
D. Blanco-Melo et al., “SARS-CoV-2 launches a unique transcriptional signature from in vitro, ex vivo, and in vivo systems,” bioRxiv, doi:10.1101/2020.03.24.004655, 2020.
Abby Olena is a freelance journalist based in Alabama. Find her on Twitter @abbyolena.