CVM Researcher Receives Large R15 Grant from NIH To Study Aspects of CCHFV
JAN. 2022 –
Western University of Health Sciences, College of Veterinary Medicine Professor of Virology, Mohammad Mir, PhD, received a $423,000 R15 grant from the NIH (in July 2021) to delineate the molecular mechanism by which the nucleocapsid protein (N-protein) of Crimean Congo hemorrhagic fever virus (CCHFV) favors the translation of viral mRNA during infection. The project is entitled “Demonstrating the mechanism of Nairovirus translation strategy”.
Dr. Mir’s project observes the importance of the Crimean Congo hemorrhagic fever as a zoonotic viral disease that is asymptomatic in infected livestock but poses a serious threat to humans. CCHFV is a tick born, highly contagious negative strand RNA virus that has a high mortality rate in humans and can trigger unwanted slaughter of infected livestock—at the present, there is no treatment for this viral disease. Dr. Mir admits that what interests him most about this project is that “the project will shed light on a conceptually new mechanism by which viruses preferentially translate their mRNA molecules in infected cells. This mechanism will reveal new targets for therapeutic intervention of CCHFV and many more viruses that cause serious and life-threatening illness in humans.”
The preliminary data of this project shows that the CCHFV N-protein can facilitate mRNA translation without the assembly of eIF4F complex at the mRNA 5’ cap. However, the structural integrity of individual components of this complex is required for N-protein mediated translation mechanism. This published data suggests that CHFV N- protein highly likely lures the host translation apparatus for the preferential translation of viral mRNA to boost the synthesis of viral proteins in the infected cell. Using multifaceted experimental avenues, Dr. Mir’s team (Dr. Ren and Austin Royster) will test the hypothesis that CCHFV N protein interacts with the components of eIF4F complex to selectively engage the 40S ribosomal subunits on the viral mRNA 5’ UTR (untranslated region). Since ribosome loading on mRNA is a critical rate limiting step in eukaryotic translation, CCHFV N protein likely helps the viral transcripts at this critical step by selectively engaging the host cell ribosomes on viral mRNA 5’ UTR. This selective ribosome loading likely helps viral transcripts by avoiding the competition from host cell transcripts for the same host translation machinery. It is his team’s plan to determine whether CCHFV N protein mediated translation strategy selectively facilitates the translation of viral mRNA in human lung cells.
In the short term, this project will provide critical insights into the pathogenesis of viral disease for which there is no cure by demonstrating the mechanics of N-protein mediated translation strategy. Dr. Mir has recognized that the Crimean Congo hemorrhagic fever is a global health problem. His proposed research ‘will help in the design of therapeutic counter measures for this viral illness—ultimately benefitting the general public on a global scale’.
The short-term goal of this project seeks to develop an antiviral drug for the treatment of CCHF, .while the long-term goal will be to develop an antiviral drug for the treatment of CCHF. As this viral infection causes a global health problem due to the lack of FDA approved vaccine and effective therapeutic agents for both humans and animals, the development of an antiviral therapeutic stands to benefit both the general public and a diverse animal population effected by the virus. Additionally, apart from direct public health relevance, this grant application will meet the healthcare needs of US military service members employed at geographical regions pandemic to the CCHF virus disease.
This has indeed been a hefty task for Dr. Mir, who highlighted that DOD grants are highly competitive and undergo a highly stringent three-tier review process which includes a trip through a review conducted by 25-30 infectious disease experts, resulting in only 10%-15% of the applications submitted being forwarded to the next process. Having been a part of the accepted applications, Dr. Mir was asked to submit a full proposal, which was in turn reviewed by three independent experts and discussed in a large study section composed of experts from diverse research backgrounds. Around 5% of applications receive the highest priority are scored to undergo internal review by the DOD—only the applications meeting the requirements of the Military Infectious Disease Research Program are finally selected for funding.