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Flavivirus infection requires specific host genes

Electron microscope image of Zika virus (red) isolated from a microcephaly case in Brazil.NIAID

Flaviviruses—a family that includes the Zika, West Nile, Japanese encephalitis, dengue, and yellow fever viruses—are typically transmitted by mosquitoes or ticks. These viruses infect hundreds of millions of people each year. They cause a wide range of symptoms, such as fever, shock, meningitis, paralysis, birth defects, and death. 

Since viruses rely on their infected host to create viral particles that spread infection, a research team led by Dr. Michael S. Diamond at Washington University in Saint Louis, Missouri carried out a genome-wide screen to identify host genes necessary for flavivirus infections. Using the CRISPR/Cas9 genetic editing system, they individually removed more than 19,000 genes from human cells and screened for cells that survived West Nile Virus infection. The work was funded in part by NIH’s National Institute of Allergy and Infectious Diseases (NIAID). Results were published online in Nature on June 17, 2016.

The researchers identified 9 genes that, when removed, reduced West Nile infection in the cells. All are associated with the cell’s endoplasmic reticulum, where viral translation, replication, and assembly of viral particles takes place. Six of the genes also reduced infection of Zika, dengue, Japanese encephalitis, and yellow fever viruses when removed from human cells. Most showed similar effects when absent from insect cells tested for West Nile and dengue virus infections.

Two of the identified genes are components of the signal peptidase complex (SPC). The SPC processes proteins for entry into the endoplasmic reticulum. Genetically removing the Signal Peptidase Complex Subunit 1 (SPCS1) gene in human cells reduced levels of all flaviviruses tested (West Nile, dengue, Zika, yellow fever, Japanese encephalitis, and hepatitis C viruses), but had little effect on other viruses (alphavirus, bunyavirus, or rhabdovirus).

Three flavivirus proteins (C, prM, and E) are needed during the viral particle assembly process. These are cleaved from a single flavivirus precursor protein upon entering the endoplasmic reticulum. In cells lacking SPCS1, levels of prM and E were reduced and correlated with a lower number of viral particles. This suggests that SPCS1 may regulate protein processing of flaviviruses.

“Flaviviruses appear to be uniquely dependent on this particular gene to assemble their viral particles,” Diamond says. “In these viruses, this gene sets off a domino effect that is required to assemble and release the viral particle. Without it, the chain reaction doesn't happen, and the virus can’t spread.”

The findings suggest that SPCS1 could be a potential therapeutic target for stopping flavivirus infections. Notably, an accompanying study in Nature used a similar approach to screen for host factors needed by the dengue and Hepatitis C viruses. That study uncovered some of the same, as well as other, host factors necessary for viral replication. Together, these studies suggest several potential new targets for antiviral therapies.

— by Tianna Hicklin, Ph.D.