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Researcher Tariq Rana explains, “I was expecting to find Zika using multiple integrins, or other cell surface molecules also used by other viruses. But instead we found Zika uses αvβ5, which is unique. When we further examined αvβ5 expression in brain, it made perfect sense because αvβ5 is the only integrin member enriched in neural stem cells, which Zika preferentially infects. Therefore, we believe that αvβ5 is the key contributor to Zika's ability to infect brain cells.” Study Two
In the second experiment, which was published in the journal Cell Stem Cell , the scientists used one specific antibody against each of the many integrins to find out which inhibitor would act most powerfully. Researcher Jeremy Rich describes the results: “When we blocked other integrins, there was no difference. You might as well be putting water on a cell. But with αvβ5, blocking it with an antibody almost completely blocked the ability of the virus to infect brain cancer stem cells and normal brain stem cells.”
They then used two methods to inhibit the integrin - using a blocking antibody and disabling its encoding gene.
They observed that both methods prevented Zika infection, and prolonged survival of treated mice compared to exposed untreated mice. Using glioblastoma cells from surgical patients, they also found that inhibition of this integrin blocked Zika virus infection of the cell.
At this point the stories converge, because the first team also used two experimental cancer drugs called cilengitide and SB273005 in mice to block the αvβ5 integrin. The mice thus treated were then exposed to Zika virus. After 6 days of daily treatment, the researchers found that there was only half as much of the virus in the brains of the treated mice as in the brains of controls.
The findings not only add to the knowledge about the virus but also open up a new field of possibilities in antiviral strategies – blocking the entry of other similar viruses into specific tissues by inhibiting integrins, according to Rana, whose team is now working on developing a unique mouse model. This animal will not have αvβ5 integrin in the cells of the brain. This will prove once for all that this molecule is essential for the entry and replication of the virus in brain cells. αvβ5 integrin and brain cancer
Talk of serendipity! When Rich first saw the effect of Zika virus on the developing brain, shrinking it drastically, he saw something different – a possible way to kill glioblastoma cells, a goal he has been pursuing for years. This led to a 2017 study which showed that the Zika virus prefers to infect and kill glioblastoma cells. This observation was exciting because glioblastomas are not only very aggressive tumors that have a high mortality rate but are also poorly responsive to standard therapies. This is the major reason for their poor outcomes, with most glioblastomas, if not all, being found to recur after treatment.
The current study by Rich explains why glioblastoma stem cells are preferred by the Zika virus to other brain cells. The scientists found that there are two parts to the αvβ5 integrin, namely, -- αv and β5. Both are expressed at high levels by glioblastomas. However, the first subunit is typically expressed by stem cells, while the second is linked to cancer cells. The complete molecule is essential for glioblastoma cells to survive.
For this reason, the Zika virus preferentially infects and kills glioblastoma stem cells compared to either normal brain stem cells or other types of brain cell. In other words, says Rich, “It turns out that the very thing that helps cancer cells become aggressive cancer stem cells is the same thing Zika virus uses to infect our cells.”
By transplanting human glioblastomas into 3D brain cell cultures or brain organoids, they tested their theory in a more realistic way. They found the Zika virus selectively removed glioblastoma stem cells from the organoids, but this was reversed simply by blocking αvβ5 integrin. Since this inhibition blocked the removal of the cancer cells, it prevented anticancer effects.
The researchers have thus leveraged their findings by exploiting it to block virus entry into brain cells and also how to use this integrin to shrink cancer cells in the brain. They would like to increase the specificity of brain cell destruction by engineering viral genes.
Future research will be twofold: engineering the Zika virus to improve the safety profile in its use in brain tumors and look for drugs that block the integrin to prevent Zika infection. Journal references: Integrin αvβ5 Internalizes Zika Virus during Neural Stem Cells Infection and Provides a Promising Target for Antiviral Therapy Wang, Shaobo et al., https://www.cell.com/cell-reports/fulltext/S2211-1247%2819%2931491-3 Zika Virus Targets Glioblastoma Stem Cells through a SOX2-Integrin αvβ5 Axis Zhu, Zhe et al., https://www.cell.com/cell-stem-cell/fulltext/S1934-5909%2819%2930471-0
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