A new cellular protection pathway has been identified that targets a vulnerability shared by several viruses including coronaviruses and Ebola. The vulnerability was identified by researchers at Benaroya Research Institute at Virginia Mason (BRI) and, assisted by researchers at Case Western Reserve University, Boston University School of Medicine and MRIGlobal, they found the cellular pathway can protect cells against infection by these viruses, including SARS-CoV-2.
The research has highlighted the role of two genes can play in protecting against viral infections, which could potentially be leveraged in new treatments and therapies against viral infectious diseases, by inhibiting virus fusion to prevent the viruses from gaining entry to cells.
Initially, the researchers used a transposon-mediated gene-activation screen to identify genes that could potentially provide protection against the Ebola virus. The new approach allowed the researchers to identify resistance mechanisms against Ebola and other dangerous pathogens.
The researchers found the gene MHC class II transactivator (CIITA) induces resistance in human cell lines by activating the gene, CD74.One form of the CD74 gene, called p41, disrupts the processing of proteins on the surface of the Ebola virus using proteases called Cathespins, and by doing so, stop the virus from gaining entry into cells. CD74 p41 was also found to work against SARS-CoV-2, by blocking the Cathepsin-dependent entry pathway.
“CIITA induces resistance by activating expression of the p41 isoform of invariant chain CD74, which inhibits viral entry by blocking cathepsin-mediated processing of the Ebola glycoprotein (EboGP),” explained the researchers.
CIITA was thought to play an important role in communication between immune cells, in a conventional mediated immune response by T cells and B cells. The additional role of providing protection against viruses by blocking their entry into cells was not previously known.
“Many viruses, including coronaviruses, use cathepsin proteases to help them infect cells. Fortunately, when SARS-CoV-2 emerged, I had recently moved to Case Western, and was able to use their specialized BSL3 laboratories to show the CD74 pathway also blocked endosomal entry by this virus. Thus, this anti-viral mechanism has evolved to work against many different viruses,” said Anna Bruchez, Ph.D., Instructor in Pathology, Case Western Reserve University, and study co-author.
“We really don’t understand the cellular mechanisms that block viral infections which has limited our ability to effectively respond to pandemics, including this year’s coronavirus,” said Lynda M. Stuart, M.D., Ph.D., Deputy Director, Bill & Melinda Gates Foundation, BRI Affiliate Investigator and co-author on the study.
The research identifies one mechanism used by cells to prevent viral infections, which could potentially be leveraged in new therapies for a range of viral infectious diseases.
You can read more about the study in the paper – MHC class II transactivator CIITA induces cell resistance to Ebola virus and SARS-like coronaviruses – which was recently published in the journal Science. DOI: 10.1126/science.abb3753