It is a new study that has revealed this intricate dance between the SARS-CoV-2 virus and human proteins. It proves that the virus relies on 69 unique proteins to hijack host cell machinery to replicate, mutate, and spread. Judd Hultquist and his collaborators carried out the work. As the above overview indicates, each of these proteins plays crucial roles in multiple stages of the viral life cycle. Those results were published today in partnership with PLOS Biology, one of the world’s premiere biology journals. Ultimately, they may pave the way for award-winning antiviral therapies that target host pathways rather than directly attacking the virus.
The study pinpoints ten proteins that are indispensable for the virus to invade host cells. It further uncovers 32 proteins required for the replication of the SARS-CoV-2 genome and 27 proteins necessary for the assembly of new viral particles. This comprehensive understanding of the protein interactions involved in the viral life cycle offers a potential pathway for developing effective antiviral therapies.
Identifying Key Proteins
Hultquist, an assistant professor of Medicine in the Division of Infectious Diseases and Microbiology-Immunology, who led a genome-wide siRNA screen. The long-term aim was to translocate new, better proteins. This approach allowed scientists to methodically focus on every gene in the genome. Through this, they revealed novel biological mechanisms and defined host factors that are key for productive SARS-CoV-2 replication.
“SARS-CoV-2, like any virus, needs to enter the cell, start replicating its genome, and then start making all of the building blocks needed to make new progeny viruses,” – Judd Hultquist
Determining which human proteins the virus hijacks throughout its infection cycle has been a major hurdle. Scientists have been, and are still, trying to untangle this tricky interplay. Hultquist noted that we didn’t quite know before how all these cellular processes help the virus to replicate.
“For a lot of these processes, the virus uses our own cellular architecture, but we had an incomplete understanding of exactly which human proteins the virus was using for which stages of its replication cycle,” – Judd Hultquist
Uncovering Cellular Pathways
The research highlights three key cellular pathways responsible for enabling SARS-CoV-2 replication. The first pathway is how cells talk to each other and grow. Understanding the role of PKR is critical for understanding and altering how cells react to viral infections. Our second pathway involves the building block of cellular energy production. It depicts how the virus steals the host cell energy supply to fuel its viral reproduction machine. The third pathway is focused on inflammation and cell stress responses. These variables all can significantly impact a host’s viral disease resistance.
Such insights simultaneously deepen our appreciation of viral biology and highlight potential points for therapeutic intervention.
“Our strategy of individually targeting each gene in the genome allowed us to uncover a lot of new biology and host factors that uniquely impacted the late stages of viral replication,” – Judd Hultquist
Training Future Scientists
One of the most remarkable things about this study is the overall diversity they achieved. More than 50% of the contributing writers are current graduate students, medical students, and postdoc researchers. Their participation in this work offered them tangible experience in basic research and scientific thought processes.
“Over half of the authors on this paper are graduate students, medical students, and postdocs who had the opportunity through this work to participate in fundamental research and be trained in scientific thinking. This type of education is critical for training the next-generation of scientists and doctors, and it was only made possible by the support we had from federal grants and agencies,” – Judd Hultquist
The training offered through this research equips young scientists with essential skills, fostering the next generation of professionals prepared to tackle future public health challenges.
Future Directions
Hultquist and his team are particularly bullish on what lies ahead. Their goal is to advance their research by finding existing drugs that can hit several strains of coronaviruses, including SARS-CoV-2. Some compounds under investigation are already in clinical trials for cancer treatment and are being explored as potential antiviral agents for HIV.
“These drugs are actually in clinical trial for the treatment of cancer and are being actively explored as part of a strategy to cure HIV, so it was quite exciting to see that they might also act as antiviral drugs against SARS-CoV-2,” – Judd Hultquist
Perhaps most importantly, the implications of this research go beyond SARS-CoV-2. By better understanding how certain proteins affect the viral life cycle, researchers hope to create new broad-spectrum antiviral medications. This makes them potentially very effective against all coronaviruses.
“In addition, we’re focused on understanding mechanistically how several of these proteins influence the viral life cycle of SARS-CoV-2 and other related coronaviruses,” – Judd Hultquist