Zika Virus Hijacks Human Cells to Supercharge Its Infectious Power

Virologists from the Department of Veterinary Biosciences at Ohio State University in Columbus have identified the underlying biological mechanism that makes the Zika virus infectious. According to the World Health Organization, the Zika virus, primarily transmitted to humans by Aedes aegypti mosquitoes, has caused outbreaks in Africa, the Americas, Asia, and the Pacific since 2007. Although global case numbers have declined since 2017, transmission continues at low levels in the Americas and other endemic regions.

Zika Uses Multiple Proteins to Hijack Host Cell Maintenance Systemc & Suppress Antiviral Defenses

The new study has uncovered how the Zika virus enhances its ability to infect host cells. Researchers found that Zika hijacks the host cells’ internal maintenance system, used to eliminate unneeded molecules, to suppress specific surface proteins that the virus initially uses to enter the cells.These proteins not only facilitate viral entry but also play a role in triggering the host’s antiviral response. To prevent that response, the virus dampens the proteins’ activity by manipulating the cell’s own health-regulating process, allowing infection to proceed unchecked.

While other viruses like HIV are known to silence host receptors to gain entry, Zika stands out for using at least three of its own proteins to carry out this task, according to Shan-Lu Liu, senior author of the study and a professor of virology in the Department of Veterinary Biosciences at The Ohio State University.

“That’s the most interesting part: It’s amazing that not only one, but several Zika proteins can do this,” said Liu, also a professor in the Department of Microbial Infection and Immunity. “We looked at two Zika virus strains and examined three physiologically relevant cell types. With both strains, we could see the downregulation in all three cell types. It looks like this is an important mechanism.”

Previous studies have identified specific cell surface proteins, known as PS receptors, as key entry points for various viruses, including Zika. This study focused on two such receptors, AXL and TIM-1, which have been previously associated with Zika infection. Liu and his team aimed to uncover how the virus maintains infection after entering cells through these receptors.

To investigate this, the researchers conducted cell culture experiments using both African and Asian strains of the Zika virus. They tested the virus in three types of human cells linked to systems commonly affected by Zika: lung epithelial cells, trophoblasts (which support embryo development), and glioblastoma brain cancer cells.

Zika Virus Co-opts Host Autophagy to Downregulate Entry Receptors 

The experiments revealed that Zika infection led to the downregulation of both AXL and TIM-1 receptors across all three cell types. While the researchers initially expected this suppression to occur through typical protein degradation pathways, they instead discovered that the virus harnesses a cellular self-maintenance process known as autophagy. As explained by Liu, autophagy is a fundamental physiological process that helps preserve cellular function by breaking down and recycling the cell’s own components. It’s often referred to as ‘self-eating’, where the host eliminates damaged organelles or misfolded proteins that could be harmful to the cell.

Researchers found that Zika manipulates host cells to suppress their own protective proteins, a viral adaptation that helps the virus regulate its infection process. Normally, AXL and TIM-1 would trigger the production of inflammatory molecules as part of the cell’s antiviral defense. Additionally, their continued presence could allow more Zika particles to enter already-infected cells, leading to a phenomenon known as superinfection. Viruses typically avoid this scenario, as overcrowding can kill host cells.

Further experiments showed that three Zika proteins on the virus’s membrane induce autophagy in host cells. “Normally, these proteins help viral entry or replication, but they also cause this downregulation, a previously unrecognized function,” said Liu. “It’s not entirely surprising, as viruses tend to encode proteins that either support their replication or help them manipulate the host environment.”

Liu said researchers need more studies but believes this mechanism also affects other pathogens. He further emphasized that the finding highlights the co-evolution of viral-host interactions. The more critical a host factor is to a virus, the more the virus will work to control it. As he explained, understanding these mechanisms is essential for improving preparedness against emerging or reemerging infectious diseases.

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Denisse Sandoval