Representative image of DNA sequencing.
Credit: Pixabay Photo
Bengaluru: Despite extensive research on SARS-CoV-2 in the past three years, several questions remain unanswered when it comes to the biology of the virus.
This single-stranded RNA virus belongs to the same family as SARS and MERS viruses.
Its ability to evade the host’s immune responses has played a key role in its virulence, allowing it to spread at great speeds.
In a new study, researchers at the Indian Institute of Science (IISc) attempted to learn more about which proteins in the virus antagonise the host’s immune system and identified a viral protein called ORF6 as the main culprit. They elucidated the details of how this protein paralyses cellular innate immunity through multiple mechanisms.
The study, published in the journal Cellular and Molecular Life Sciences, was carried out by Oyahida Khatun, Mansi Sharma, Rohan Narayan, and Shashank Tripathi from the Centre for Infectious Disease Research (CIDR), IISc.
During infection, the body’s early antiviral responses are orchestrated by Interferons (IFNs), triggering specific signalling events that pose a critical hurdle for viruses.
Among the identified proteins, ORF6 emerged as the most potent inhibitor of IFN induction and signalling.
While consistent with previous research on ORF6 function, this study provided further clarification by revealing that ORF6 directly interacts with a specific host viral sensor called RIG-I, responsible for recognising viral RNA in infected cells.
The presence of the SARS-CoV-2 ORF6 protein resulted in reduced levels of RIG-I and the degradation of an enzyme called TRIM25, crucial for activating RIG-I and controlling viral infection.
Consequently, ORF6 also obstructed the expression of antiviral genes downstream of RIG-I by blocking the nuclear import of transcription factors involved in this process.
This is analogous to disabling the ignition (RIG-I) and applying the brakes (inhibiting antiviral gene expression) to halt the cellular antiviral response.
Furthermore, the researchers proposed the possibility of removing genes coding for ORF6 and other IFN antagonists from the SARS-CoV-2 viral genome as a potential strategy for developing live vaccines.