An international team of academic and pharmaceutical scientists have tapped into publically available large-scale ‘Omics’ databases to identify new targets to treat influenza — the virus that causes annual epidemics and occasional pandemics.
The study, published today in Cell Host and Microbe, reflects a breakthrough approach using advanced computational designs to identify new factors that can be targeted to prevent viruses from spreading.
Research teams from Switzerland, Germany and the U.S. analyzed datasets from independent genomic and proteomic study publications on Influenza A virus host molecules. Thanks to the comprehensive analysis of these ‘OMIC’ databases, the researchers identified 20 previously unrecognized host proteins required for Influenza A virus replication.
One protein, UBR4, was singled out as a pivotal host protein that the virus uses to bud off from the host cell membrane and form spherical vesicles that transmit the virus within and between individuals.
“Traditionally, physicians have treated the flu with drugs that directly block the influenza virus,” said Sumit Chanda, Ph.D., co-senior author and director of the Immunity and Pathogenesis Program at Sanford Burnham Prebys Medical Discovery Institute (SBP). “Although these drugs have been helpful, many patients fail to respond because viruses, especially influenza A virus (IAV), can mutate, rendering them resistant to available drugs. Our research efforts are focused on finding unalterable host molecules — the ones within our bodies — that viruses hijack to spread and create full blown infections.”
The study showed that blocking UBR4 in human cells (in vitro) and mice (in vivo) reduced IAV replication and pathogenesis, establishing proof-of-concept of the strategy to target UBR4 as an influenza treatment.
“These unchangeable host proteins are vital for the replication of the viruses,” explains Professor Silke Stertz from the Institute of Medical Virology at the University of Zurich. “We can now use these to stop the virus from spreading further.”
The research team also created a website with open access for scientists to cull additional host-targets to develop the next-generation of anti-influenza drugs.
“‘Big data’ is no longer merely a catchphrase — it is a real tool to help scientists address the world’s most serious public health threats,” said Adolfo Garcia-Sastre, Ph.D., director of the Global Health and Emerging Pathogens Institute at the Icahn School of Medicine at Mount Sinai. “Our work illustrates how the computational analysis of large datasets from multiple independent studies can reveal novel host factors and networks involved in virus replication as potential targets for therapeutic intervention.”
The research team has created a simplified, user-friendly web portal of the integrated data that reflects the biochemical landscape of essential influenza-host interactions. The site enables customized queries and analysis tools to find host proteins likely to play a role in influenza infection.