Next Generation Antivirals, Cancer Immunotherapies May be on the Horizon

Targeting a newly identified regulator of the innate immune response may lead to the development of antiviral drugs, vaccine adjuvants, cancer immunotherapies, and autoimmune disease treatments.

In a study published in Nature Microbiology, investigators found that the protein K-homology splicing regulatory protein (KHSRP) weakens the immune response to viral RNA.

“Depleting KHSRP improve immune signaling and reduce viral replication in cell culture and in vivo, suggesting that drugs inhibiting the protein may have therapeutic value,” said senior author Sumit Chanda, PhD.

KHSRP physically interacts with the protein retinoic acid-inducible gene I (RIG-I) to “apply the brakes” to the innate immune response, which is the bodies’ first line of defense against pathogens.

By detecting viral RNA in the cytoplasm of cells, RIG-I receptors can initiate antiviral immunity, according to the authors. When the receptors bind viral RNA, they turn on signaling that results in the production of interferon and the induction of other antiviral responses. Additionally, RIG-I receptors coordinate signaling with other immune factors to modulate the adaptive immune response.

“We identified KHSRP by systematically testing every human proteins to identify those that impact RIG-I signaling,” said investigator Stephen Soonthornvacharin. “We found about 240 proteins, but we focused on KHSRP because it was the only one of the 240 that was found to inhibit the very early steps of RIG-I signaling.

“Molecules that block KHSRP’s actions could serve as adjuvants—–components that heighten the immune response––to vaccine against influenza or hepatitis C, as antiviral drugs, or even next-generation cancer immunotherapies.”

Among the 240 identified RIG-I regulators, the investigators found that 125 appeared to activate RIG-I.

“Findings drugs that inhibit these proteins may be a way to treat autoimmune conditions involving too much interferon, like type 1 diabetes or lupus,” Soonthornvacharin said. “Figuring out which ones are promising requires further investigation.”

The authors hypothesize that KHSRP may protect against autoimmunity.

“RIG-I normally recognizes RNA molecules that arise during viral infections, but it can also mistakenly sense RNA present in normal cells,” Chanda said. “Without KHSRP, the innate response could be erroneously turned on when there’s no virus. Increasing the activity of KHSRP might therefore be a way to treat autoimmunity.”

Key contributor to the research Sunnie Yoh, PhD, said they plan to figure out more details of how KHSRP regulates RIG-I.

“That’s information that will move us in the direction of developing therapies,” Yoh concluded.