Researchers at the University of Sydney, Australia, have uncovered a lung protein that blocks SARS-CoV-2 infection and could be a new pathway for the development of drugs to treat COVID-19. This protein, called the leucine-rich repeat-containing protein 15 (LRRC15), is an inbuilt receptor that binds SARS-CoV-2 without passing on the infection, according to research was published Thursday in PLOS Biology.
“Alongside two other groups, one at Oxford, the other at Brown and Yale, we found a new receptor in the LRRC15 protein that can stop SARS-CoV-2. We found that this new receptor acts by binding to the virus and sequestering it which reduces infection,” said Greg Neely, a professor at the Charles Perkins Centre and the School of Life and Environmental Sciences. “The fact that there’s this natural immune receptor that we didn’t know about, that’s lining our lungs and blocks and controls virus, that’s crazy interesting.”
LRRC15 was discovered by the investigators as a result of research that looked to provide a more comprehensive assessment of the host factors that regulate binding to SARS-CoV-2 spike protein beyond the known primary receptor ACE2.
The research team employed whole-genome CRISPR activation to help identify these different host interactions with SARS-CoV-2 and discovered that LRRC15, like ACE2, is a receptor for the virus. Unlike ACE2, however LRRC15 does not support infection. Further, its ability to stick to the virus and immobilize it protects other cells from becoming infected.
“We think it acts a bit like Velcro, molecular Velcro, in that it sticks to the spike of the virus and then pulls it away from the target cell types,” said Lipin Loo, a postdoctoral researcher in the Neely lab.
Matthew Waller, a PhD student who was part of the research team, added “Basically, the virus is coated in the other part of the Velcro, and while it’s trying to get to the main receptor, it can get caught up in this mesh of LRRC15.”
While LRRC15 is found in many tissue types in locations around the body, such as the skin, tongue, lung, fibroblasts, placenta, and lymph nodes, it becomes much more prevalent in the lungs after SARS-CoV-2.
“When we stain the lungs of healthy tissue, we don’t see much of LRRC15, but then in COVID-19 lungs, we see much more of the protein,” Loo said. “We think this newly identified protein could be part of our body’s natural response to combating the infection creating a barrier that physically separates the virus from our lung cells most sensitive to COVID-19.”
According to Loo, this recent research meshes with earlier research from Imperial College London which showed that lack of LRRC15 in the blood was indicative of more severe cases of COVID-19, a finding that helped frame the variable responses of individuals to the virus.
Another important finding of the research has implications in fibrosis—a scarring and thickening of lung tissue that can occur as a result of infection and inflammation—that can cause breathing problems.
“Since this receptor can block COVID-19 infection, and at the same time activate our body’s anti-virus response, and suppress our body’s fibrosis response, this is a really important new gene,” Neely said. “This finding can help us develop new antiviral and antifibrotic medicines to help treat pathogenic coronaviruses, and possibly other viruses or other situations where lung fibrosis occurs.”
Using their findings, the team is now taking a dual-pronged approach to researching therapeutic development to target LRRC15 that could work across multiple variants. One strategy would target the nose as a preventative treatment, the second would be aimed at treatments for the lungs for serious cases.