Take a walk on the host side

Posted by Hari Montañez Brull, Heyrhyoung Lyoo, Kristina Lanko on January 16, 2017

Genome manipulation is currently revolutionizing biology. CRISPR/Cas, an antiviral defense system in bacteria, is now in use for this purpose. In the virology field, we can identify important host factors for virus replication with CRISPR/Cas-based screening.

Together with specific guide RNAs (which have a sequence complementary to that of the target gene), CRISPR/Cas can disrupt (knock out) specific genes of interest. For example, if you put CRISPR/Cas and a guide RNA targeting gene A in cells, you will have cells without A gene expression. Once pools of knockout cells have been created, cells surviving a viral infection can be selected. These cells are likely to have mutations in genes that are necessary for viral replication and the identity of these genes can be revealed by next-generation sequencing.

CRISPR/Cas-based screening for identification of important host factors for virus

This method of host factor identification has recently been applied to several important human pathogens infecting millions of people worldwide (such as the Yellow fever, Dengue, and Zika viruses). Recently, the host cell factors used by West Nile virus to induce cell death were identified. Those proteins are part of a quality-control mechanism for cellular protein synthesis (ERAD pathway): if a potentially toxic protein is produced, it gets cleared from the cell by ERAD. Some of those factors came up in screens using different viruses, such as the Zika, Dengue and Yellow fever viruses. Therefore, it seems useful to further investigate those factors and determine their roles in different viral infections.

Identification of host factors helps us to better understand how viruses work, and the more we know, the more elaborated our antiviral strategies can become. Elucidating mechanisms of virus-host interactions could lead to the development of a new class of powerful and revolutionary drugs, which could target host proteins, complexes, or pathways needed for viruses to infect the host. The ultimate success here would be to find a common host factor on which multiple viruses rely during their replication, and create a drug targeting this factor, a so called “broad-spectrum antiviral”. Having such host factor-directed antiviral compounds would not only be cost-effective, it is also very likely that such drugs would be effective against emerging viruses related to the ones they were initially developed for.