Researchers at UC Berkeley’s Hsu Lab identified human lung proteins that can either promote or restrict infection from SARS-CoV-2.
According to campus public health postdoctoral scholar and lead study author Scott Biering, this research study focused on how SARS-CoV-2 interacts with mucin proteins, which are a major component of mucus. By using CRISPR-based technology on human epithelial cells, the researchers either inactivated or overexpressed every gene in the human genome to detect how certain ones interact with SARS-CoV-2.
After manipulating one gene in each cell and exposing the cells to the virus, the researchers waited to see which cells would survive, according to campus assistant specialist and lead study author Sylvia Sarnik. They then took the surviving cells and sequenced the genes to discover which knocked-out gene helped the cell survive.
“Mucins are important for maintaining homeostatic conditions, such as detecting injury and surface stresses,” Biering said. “We found many different mucin proteins were important for restricting the virus.”
Biering added that COVID-19 is associated with severe lung dysfunction that prevents the exchange of gasses, and some have proposed that a primary cause is the accumulation of mucus.
While Biering agreed that too much mucus may prevent someone from breathing properly, he said mucus is still a barrier that blocks SARS-CoV-2 from entering cells.
“Some proteins restrict the virus as a natural barrier, but some promote virus infection,” Biering said. “The key determinant is the content of mucus in a person’s body.”
According to Sarnik, there are two classes of mucins: membrane-anchored mucins called MUC1 and MUC4 and secreted mucins referred t0 as MUC5AC and MUC5B.
When the researchers upregulated the MUC1 and MUC4 in a lung cancer cell line, those mucins had an antiviral effect. Meanwhile, MUC5AC promoted the virus, Biering added.
“One interesting thing we found is that our lung cells activate mucin expression upon viral infection, and that this can broadly block diverse respiratory viruses,” campus assistant bioengineering professor Patrick Hsu said in an email. “However, this isn’t the case for all viruses, and we have some early evidence that some viruses may have taken advantage of this mechanism to actually improve their ability to infect the lung.”
Sarnik said after conducting a mechanistic investigation of mucins with other viruses, the researchers found that they could not generalize these findings to all viruses — even other coronaviruses — since each behave differently.
With further investigation into what mucins are good and bad, Biering hopes drugs can be made based on the expression of right and wrong mucins. For Sarnik, the paper opens the door to a better understanding of SARS-CoV-2, including better treatments and a more definite vaccine target.
“This is still a relatively new virus, so learning as much as possible about it is still very critical at this stage,” Sarnik said. “With new variants, this is not going away any time soon; the more we understand, the more we can investigate.”