Two cell subjournals reveal the mechanism of Zika virus invading brain stem cells, which may be used to treat fatal brain cancer

January 26, 2020 / Biovalley BIOON / - -- the most famous time for Zika virus may be from 2015 to 2016, when a large-scale Zika virus epidemic mainly affected Latin America, but also affected several other regions of the world Although the epidemic has passed, the Zika virus has not disappeared Smaller local outbreaks continue, and last summer several cases of local Zika virus infection were recorded in Europe Scientists have warned that the virus could continue to spread as climate change affects the habitat of mosquitoes carrying the Zika virus Zika virus can also be transmitted from a pregnant mother to a fetus or through sexual contact More than half of the people on earth are at risk of Zika virus infection, and there are no safe and effective drugs or vaccines Zika virus infection can stunt brain development in newborns, leading to a condition called microcephaly In this disease, the baby's head is abnormally small at birth To determine how best to prevent and treat the virus infection, scientists need to first understand how the pathogen enters brain cells In two new studies, two teams from the University of California, San Diego School of medicine independently identified the same molecule - α V β 5 integrin - as the key for Zika virus to invade brain stem cells They also found a way to use the integrin to stop Zika virus infecting cells and make them work: by reducing brain cancer stem cells Integrins are molecules embedded on the surface of cells They play an important role in cell adhesion and communication and are known to be involved in cancer progression and metastasis Several other integrins are known entry points of other viruses, such as adenovirus, foot-and-mouth disease virus and rotavirus, but the previous role of α V β 5 in virus infection is not known Looking for key molecules in the first new study, Dr Tariq Rana of the University of California, San Diego School of medicine and his team used CRISPR gene editing to systematically remove every gene from human glioblastoma stem cell (GSC), a brain cancer stem cell, which was cultured in three dimensions in a laboratory dish They then exposed each GSC cell variant to Zika virus to determine which genes and their encoded proteins were necessary for the virus to invade GSC cells For the first time, the virus was labeled with green fluorescent protein (GFP), allowing the researchers to visualize the virus invading these cells The related research results were published online in the Journal of cell reports on January 16, 2020 The title of the paper is "integrin α V β 5 internalizes Zika virus during neural stem cells infection and provides a promising target for antivirus therapy" Picture from cell reports, 2020, DOI: 10.1016/j.celrep.2019.11.020 Rana's team found 92 specific human brain cancer stem cell genes needed for Zika virus to invade and replicate in the cells However, one of the most important genes is the gene encoding α V β 5 integrin "It's well known that integrins are molecules that many different viruses use to invade human cells," Rana said I was hoping to find out that Zika virus uses multiple integrins, or other cell surface molecules that are also used by other viruses However, we found that Zika virus uses α V β 5, which is quite unique When we further study the expression of α V β 5 in the brain, it is fully understandable that this is because α V β 5 is the only integrin member enriched in neural stem cells, while Zika virus prefers to infect neural stem cells Therefore, we think that α V β 5 is the key factor for Zika virus to infect brain cells Blocking Zika virus infection in the second new study, Dr Jeremy rich of the University of California, San Diego School of medicine and his team used different antibodies to inhibit each integrin in order to see which antibody had the best inhibition effect, given that many viruses used integrins to invade human cells The related research results were published online in the Journal of cell stem cell on January 16, 2020 The title of the paper is "Zika virus targets glioblastoma stem cells through a Sox2 integrin α V β 5 axis" "When we block other integrins, there's no difference in effect," rich said But blocking α V β 5 with antibodies can almost completely block the ability of the virus to infect brain cancer stem cells and normal brain stem cells " Rich's team then used antibodies to inhibit α V β 5 in a mouse model of glioblastoma, or inactivate the gene that encodes it Both methods prevent Zika infection and allow these treated mice to live longer than untreated mice They also found that blocking α V β 5 in glioblastoma tumor samples taken from patients during surgery blocked Zika virus infection In addition, rich's team treated mice daily with cilengitide or sb273005, an experimental anticancer drug targeting at α V β 5 integrin, to block α V β 5 in their bodies Six days after Zika infection, the treated mice had half as many Zika viruses in their brains as the blank control mice "Interestingly, these findings not only help advance the study of Zika virus, but also provide the possibility for us to similarly block multiple virus invasions using other integrins by using antibodies or small molecular inhibitors," Rana said Rich's team is now developing a mouse model that lacks the α V β 5 integrin in the brain, which will allow them to confirm definitively that the molecule is necessary for Zika virus invasion and replication Rich is a neurooncologist who is good at diagnosis and treatment of glioblastoma patients Glioblastoma is a very aggressive and fatal brain tumor When he first observed how Zika virus causes brain tissue atrophy, he thought about the effect he hoped to achieve in treating glioblastoma patients In 2017, he and his collaborators determined in a study that Zika virus selectively targeted and killed glioblastoma stem cells (Journal of experimental medicine, 2017, DOI: 10.1084 / JEM 20171093) Since the brain cancer stem cells are resistant to standard treatment, it is also an important reason for the recurrence of glioblastoma and the lower survival rate of patients Rich's new study helps explain that Zika virus prefers glioblastoma stem cells to healthy brain cells α V β 5 integrins are composed of two independent subunits, α V and β 5 Rich's team found that glioblastoma stem cells produce a large number of α V subunits (related to stem cells) and β 5 subunits (related to cancer cells) at the same time They found that the integrins formed by these subunits play an important role in the survival of glioblastoma stem cells These high levels of α V β 5 integrins also help explain why in this new study, the proportion of glioblastoma stem cells killed by Zika virus is much higher than that of normal brain stem cells or other brain cell types "It turns out that the molecule that makes cancer cells into aggressive cancer stem cells is what Zika virus uses to infect our cells," rich said To understand how this might play a role in human disease models, the rich team worked with Dr alysson muotri, a brain disease modeling expert at the University of California, San Diego School of medicine Pinar mesci, a postdoctoral researcher in muotri laboratory and co-author of this paper, has constructed a new brain tumor model, in which human glioblastoma tumor is transplanted into human brain like organs The researchers found that Zika virus selectively eliminated glioblastoma stem cells from human brain like organs Inhibition of α V β 5 integrins reverses this antitumor activity, which further highlights that this molecule plays a key role in the ability of Zika virus to destroy cells Today, rich's team is working with other research teams on targeted drugs In addition to finding drugs to block Zika like Rana's team, rich is also interested in genetic modification of the virus, which allows it to better target brain cancer cells without affecting healthy cells "Although we may need to genetically modify the normal Zika virus to make it safer to treat brain tumors, we may also be able to use the virus's cellular destruction mechanism to improve the way we treat glioblastoma," rich said We should pay attention to the virus They have evolved over the years and are very good at targeting and invading specific cells in the body " (bio Com) reference: 1 Shaobo Wang et al Integrity α V β 5 internalizes Zika virus during neural stem cells infection and provides a promising target for antivirus therapy Cell reports, 2020, DOI: 10.1016/j.celrep.2019.11.020 2 Zhe Zhu et al Zika virus targets glioblastoma stem cells through a Sox2 integrity α V β 5 axis Cell Stem Cell, 2020, doi:10.1016/j.stem.2019.11.016 3.Zhe Zhu et al Zika virus has oncolytic activity against glioblastoma stem cells Journal of Experimental Medicine, 2017, doi:10.1084/jem.20171093 4.Zika Virus’ Key into Brain Cells ID’d, Leveraged to Block Infection and Kill Cancer Cells https://ucsdnews.ucsd.edu/pressrelease/zika-virus-key-into-brain-cells-idd-leveraged-to-block-infection-and-kill-cancer-cells