Decoy Cells Trick SARS-CoV-2, Reduce Cytokines In Vitro
Scientists have summoned every trick in the book to develop a COVID-19 treatment over the last few months, from stem cells and synthetic antibodies to common over-the-counter medications and tried-and-true steroids. Some have even attempted to lure SARS-CoV-2 away from human cells by using molecular decoys. But few have tried to distract the novel coronavirus with fake human cells. Scientists reported in PNAS last week (October 6) that genetically engineered cells can bind and neutralize the coronavirus in vitro. They envision that such cellular decoys could be deployed to combat infections.
“It’s a very elegant study,” says Karolinska Institute molecular toxicologist Bengt Fadeel, who was not involved in this study. “Provided that you know the receptor of a given virus, you could, in principle, adopt this approach to intercept any virus.”
Xiaoyuan Chen, a senior investigator at the National Institute of Biomedical Imaging and Bioengineering at the National Institutes of Health (NIH), pivoted from developing nanotechnology to diagnose and treat cancers to study SARS-CoV-2 when the virus began spreading around the world early this year. He had seen previous reports of using decoy receptors to trick pathogens such as HIV and was curious if the emerging technique might work against SARS-CoV-2.
To find out, Chen and his collaborators at Wuhan University fused membranes from human monocytic THP-1 cells, a cell line derived from leukemia, with membranes from human embryonic kidney cells that overproduce the ACE2 receptors that SARS-CoV-2 grabs hold of to infiltrate cells. Chen says they hoped that, if the hybrid vesicles were injected in vivo, the virus would ignore unmodified human cells and instead home in on the decoys. Once attached to the engineered cells’ ACE2, the virus would be absorbed and neutralized, according to Chen.
By embedding monocytic membranes, which have cytokine receptors, into the engineered vesicles, the decoys can bind with inflammatory cytokines such as IL-6, preventing them from building up and causing cytokine storms, overreactive immune responses thought to contribute to more severe COVID-19.
The idea of a decoy to thwart SARS-CoV-2 infection is not a new one. One team of scientists created a decoy using engineered, free-floating ACE2 receptors that bind especially well with the virus. Their decoys, which the developers propose can “significantly block early stages of SARS-CoV-2 infections,” are now in a Phase 2 clinical trial run by Apeiron Biologics. In a July preprint, pharmacologist Gaurav Sahay of Oregon State University described a method that delivers engineered mRNA that codes for ACE2 to the liver of mice using lipid nanoparticles, causing ACE2 decoys to be translated and secreted into the blood. He found that the method successfully led to an increase of ACE2 decoys in vivo and they inhibited a modified, nonpathogenic version of SARS-CoV-2 in vitro.
Chen’s new spin on the concept is to couple the decoys with cytokine receptors. “The combination of [ACE2 and cytokine receptors in] the vesicle structure is something new,” says Sahay, who was not involved in Chen’s study. “It’s a very exciting development.”
Researchers tested the nanodecoys by incubating both SARS-CoV, responsible for the 2003 SARS outbreak, and SARS-CoV-2, which causes COVID-19, in human and monkey cells, and found that the decoys significantly inhibited viral infection, regardless of cell or virus type.
To test whether the decoys could work outside a petri dish, researchers induced acute lung inflammation in mice by having them inhale lipopolysaccharide, an irritant. Four hours later, the mice inhaled the nanodecoys, and after eight hours, the researchers collected fluid from the mice’s lungs. They found that the decoys successfully mopped up cytokines compared to mice that did not receive decoys.
“This study is rather straightforward,” says Chen. “It’s surprising that such a simple approach is able to neutralize the virus, at least at the cellular level, and in vivo neutralize cytokines within hours. For COVID-19, a rapid response is essential, and these nanodecoys do just that.”
While these results suggest that these decoys can neutralize cytokines in mice’s lungs, their ability to block a SARS-CoV-2 infection was not tested in mice. Chen cited a shortage of the transgenic mice bearing human ACE2 that would be needed to conduct such experiments.
Mice that received the nanodecoys showed no adverse reaction to the treatment, which is encouraging, says Fadeel, but he says he wonders if that would hold true in humans as well, particularly because the engineered cells use material from human cancer cells. “I would be cautious about administering small bits of cancer cells, especially into the lungs,” he says.
Sahay also notes that cell membranes in the lungs, arteries, heart, kidney, and intestines produce ACE2 for a reason—it cleaves angiotensin, a protein that raises blood pressure. He questions if the decoys might impair the body’s ability to regulate blood pressure, as angiotensin may bind to the decoys.
Neither Chen nor his colleagues at Wuhan University currently have plans to test the decoys in humans, but he filed a patent for their design through the NIH. “It’s a very simple approach—almost too simple,” says Chen. “That’s the beauty of this study.”