Zika virus infection can stunt neonatal brain development, a condition known as microcephaly, in which babies are born with abnormally small heads. To determine how best to prevent and treat the viral infection, scientists first need to understand how the pathogen gets inside brain cells.
Employing different approaches to answer different questions, two research teams at University of California San Diego School of Medicine independently identified the same molecule v5 integrin as Zika virus key to entering brain stem cells.
In a pair of papers published January 16, 2020 by Cell Press, the researchers also found ways to take advantage of the integrin to both block Zika virus from infecting cells and turn it into something good: a way to shrink brain cancer stem cells.
Integrins are molecules embedded in cell surfaces. They play important roles in cell adherence and communication, and are known to be involved in cancer progression and metastasis. Several other integrins are known entry points for other viruses, including adenovirus, foot-and-mouth disease virus and rotavirus, but v5 was not previously known for its role in viral infections.
One team, led by Tariq Rana, PhD, professor and chief of the Division of Genetics in the Department of Pediatrics at UC San Diego School of Medicine and Moores Cancer Center, used CRISPR gene editing to systematically delete every gene in a 3D culture of human glioblastoma (brain cancer) stem cells growing in a laboratory dish. Then they exposed each variation to Zika virus to determine which genes, and the proteins they encode, are required for the virus to enter the cells. The virus was for the first time labeled with green fluorescent protein (GFP) to allow the researchers to visualize viral entry into the cells.
3D human brain organoids. Left: normal, uninfected. Center: infected with Zika virus. Right: infected with Zika virus and treated with cilengitide, which protects the cells from destruction by the virus.
Their study, published in Cell Reports, uncovered 92 specific human brain cancer stem cell genes that Zika virus requires to infect and replicate in the cells. But one gene stood out, the one that encodes v5 integrin.
Integrins are well known as molecules that many different viruses use as doorknobs to gain entry into human cells, Rana said. 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 v5, which is unique. When we further examined v5 expression in brain, it made perfect sense because v5 is the only integrin member enriched in neural stem cells, which Zika preferentially infects. Therefore, we believe that v5 is the key contributor to Zikas ability to infect brain cells.
The second study, published in Cell Stem Cell, was led by Jeremy Rich, MD, professor in the Department of Medicine at UC San Diego School of Medicine and director of neuro-oncology and of the Brain Tumor Institute at UC San Diego Health. Knowing that many viruses use integrins for entry into human cells, Richs team inhibited each integrin with a different antibody to see which would have the greatest effect.
When we blocked other integrins, there was no difference. You might as well be putting water on a cell, said Rich, who is also a faculty member in the Sanford Consortium for Regenerative Medicine and Sanford Stem Cell Clinical Center at UC San Diego Health. But with v5, blocking it with an antibody almost completely blocked the ability of the virus to infect brain cancer stem cells and normal brain stem cells.
Richs team followed up by inhibiting v5 in a glioblastoma mouse model with either an antibody or by deactivating the gene that encodes it. Both approaches blocked Zika virus infection and allowed the treated mice to live longer than untreated mice. They also found that blocking the v5 integrin in glioblastoma tumor samples removed from patients during surgery blocked Zika virus infection.
Ranas team also blocked v5 in mice, treating them daily with cilengitide or SB273005, two experimental cancer drugs that target the integrin. Six days after Zika virus infection, the brains of their drug-treated mice contained half as much virus as mock-treated mice.
The neat thing is that these findings not only help advance the Zika virus research field, but also opens the possibility that we could similarly block the entry of multiple viruses that use other integrins with antibodies or small molecule inhibitors, Rana said.
Rana and team are now engineering a mouse model that lacks v5 integrin in the brain a tool that would allow them to definitively prove the molecule is necessary for Zika viral entry and replication.
Rich is a neuro-oncologist who specializes in diagnosing and treating patients with glioblastoma, a particularly aggressive and deadly type of brain tumor. When he first saw how the Zika virus shrinks brain tissue, it reminded him of what he hopes to achieve when hes treating a patient with glioblastoma. In 2017, he and collaborators published a study in which they determined that Zika virus selectively targets and kills glioblastoma stem cells, which tend to be resistant to standard treatments and are a big reason why glioblastomas recur after surgery and result in shorter patient survival rates.
Richs latest study helps account for the virus preference for glioblastoma stem cells over healthy brain cells. The v5 integrin is made up of two separate subunits v and 5. The team found that glioblastoma stem cells produce a lot of both the v subunit (associated with stem cells) and 5 subunit (associated with cancer cells). Together, these units form the v5 integrin, which, the team discovered, plays an important role in glioblastoma stem cell survival. Those high levels of v5 integrin also help explain why, in the study, glioblastoma stem cells were killed by Zika virus at much higher rates than normal stem cells or other brain cell types.
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, Rich said.
To see how this might play out in a more realistic model of human disease, Richs team partnered with an expert in human brain disease modeling Alysson Muotri, PhD, professor at UC San Diego School of Medicine, director of the UC San Diego Stem Cell Program and a member of the Sanford Consortium for Regenerative Medicine, and team. Pinar Mesci, PhD, a postdoctoral researcher in Muotris lab, generated a new brain tumor model, where human glioblastoma tumors were transplanted into human brain organoids, laboratory mini-brains that can be used for drug discovery. The researchers discovered that Zika virus selectively eliminates glioblastoma stem cells from the brain organoids. Inhibiting v5 integrin reversed that anti-cancer activity, further underscoring the molecules crucial role in Zika virus ability to destroy cells.
Now Richs team is partnering with other research groups to perform targeted drug studies. In addition to searching for drugs to block Zika virus, as Ranas group is doing, Rich is interested in genetic modifications to the virus that could help better target its destruction to brain cancer cells, while leaving healthy cells alone.
While we would likely need to modify the normal Zika virus to make it safer to treat brain tumors, we may also be able to take advantage of the mechanisms the virus uses to destroy cells to improve the way we treat glioblastoma, Rich said. We should pay attention to viruses. They have evolved over many years to be very good at targeting and entering specific cells in the body.
Zika virus was perhaps best known in 2015-16, when a large outbreak affected primarily Latin America, but also several other regions of the world. While that particular epidemic has passed, Zika virus has not gone away. Smaller, local outbreaks continue and this past summer, the first few cases of native Zika virus infection were recorded in Europe. Scientists warn Zika could continue to spread as climate change affects the habitat range of the mosquito that carries it. The virus can also be transmitted from pregnant mother to fetus, and via sexual contact. More than half of all people on Earth are at risk for Zika virus infection, and there is no safe and effective treatment or vaccine.
Co-authors of Ranas study, published January 16, 2020 in Cell Reports, include: Shaobo Wang, Qiong Zhang, Shashi Kant Tiwari, Gianluigi Lichinchi, Edwin H. Yau, Hui Hui, Wanyu Li, UC San Diego; and Frank Furnari, UC San Diego and Ludwig Institute for Cancer Research.
This research was funded, in part, by the National Institutes of Health (grants AI125103, CA177322, DA039562, DA046171 and DA049524).
Co-authors of Richs study, published January 16, 2020 in Cell Stem Cell, also include: Zhe Zhu, Jean A. Bernatchez, Xiuxing Wang, Hiromi I. Wettersten, Sungjun Beck, Alex E. Clark, Qiulian Wu, Sara M. Weis, Priscilla D. Negraes, Cleber A. Trujillo, Jair L. Siqueira-Neto, David A. Cheresh, UC San Diego; Ryan C. Gimple, Leo J.Y. Kim, UC San Diego and Case Western Reserve University; Simon T. Schafer, Fred H. Gage, Salk Institute for Biological Studies; Briana C. Prager, UC San Diego, Case Western Reserve University and Cleveland Clinic; Rekha Dhanwani, Sonia Sharma, La Jolla Institute for Allergy and Immunology; Alexandra Garancher, Robert J. Wechsler-Reya, Sanford Burnham Prebys Medical Discovery Institute; Stephen C. Mack, Baylor College of Medicine, Texas Childrens Hospital; Luiz O. Penalva, Childrens Cancer Research Institute; Jing Feng, Zhou Lan, Rong Zhang, Alex W. Wessel, Michael S. Diamond, Hongzhen Hu, Washington University School of Medicine; Sanjay Dhawan, and Clark C. Chen, University of Minnesota.
The research was funded, in part, by the National Institutes of Health (grants CA217065, CA217066, CA203101, CA159859, CA199376, NS097649-01, CA240953-01, NS096368, R01DK103901,R01AA027065, MH107367, N5105969, CA045726, CA050286, CA197718, CA154130, CA169117, CA171652, NS087913, NS089272), California Institute for Regenerative Medicine (CIRM, grants FA1-00607, DISC209649) and International Rett Syndrome Foundation.
Disclosures: Tariq Rana is a co-founder of, member of the scientific advisory board for, and has equity interest in ViRx Pharmaceuticals. Alysson Muotri is a co-founder and has equity interest in TISMOO, a company dedicated to genetic analysis focusing on therapeutic applications customized for autism spectrum disorder and other neurological disorders. David Cheresh is a co-founder of TargeGen and AlphaBeta Therapeutics, a new but currently unfunded company developing an antibody to integrin v5 involved in cancer treatment. The terms of these arrangements have been reviewed and approved by UC San Diego in accordance with its conflict of interest policies. In addition, Michael Diamond, of Washington University School of Medicine, is a consultant for Inbios and Atreca and serves on the Scientific Advisory Board of Moderna.
Follow this link:
Zika Virus' Key into Brain Cells ID'd, Leveraged to Block Infection and Kill Cancer Cells - UC San Diego Health
- Advances in regenerative medicine-based approaches for skin ... - March 9th, 2025
- Regenerative Medicine: Case Study for Understanding and Anticipating ... - March 9th, 2025
- Top 3 Grants in Regenerative Medicine: February 2025 - RegMedNet - March 9th, 2025
- Editorial: Tissue Engineering and Regenerative Medicine: Advances, Controversies, and Future Directions by Frontiers in Bioengineering and... - March 9th, 2025
- Malaysia To Host 7th World Conference On Exercise And Regenerative Medicine - BERNAMA - March 9th, 2025
- Advancing Regenerative Medicine: A Comprehensive Outlook on the Global Cell Therapy Market - openPR - March 9th, 2025
- Worlds First 3D-Printed Penis Implant Successfully Restores Function in Pigs and Rabbits - The Daily Galaxy --Great Discoveries Channel - March 9th, 2025
- AskBio Receives FDA Regenerative Medicine Advanced Therapy designation for Parkinsons disease investigational gene therapy - Bayer - February 24th, 2025
- What is Regenerative Medicine? | Regenerative Medicine | University of ... - February 24th, 2025
- The quest for a communication device that tells cells to regenerate the body - Big Think - February 24th, 2025
- Transforming the future of regenerative medicine - Reuters - February 24th, 2025
- Breakthrough Alzheimer's Treatment Gets Official WHO Recognition - Major Milestone for Rare Disease Therapy - StockTitan - February 24th, 2025
- Regenerative Medicine Pioneer with 35-Year Track Record Takes Scientific Helm at ZEO ScientifiX - StockTitan - February 24th, 2025
- 101 Guide to Regenerative Medicine Types | Applications, Challenges - February 7th, 2025
- Regenerative Medicine | What is it? | ASCPM - February 7th, 2025
- Regenerative medicine and advanced therapy | NIST - February 7th, 2025
- Therapeutic Reprogramming toward Regenerative Medicine - February 7th, 2025
- Novel living biomaterial aims to advance regenerative medicine - February 7th, 2025
- UC Irvine-led discovery of new skeletal tissue advances regenerative ... - February 7th, 2025
- Top 3 Grants in Regenerative Medicine: January 2025 - RegMedNet - February 7th, 2025
- Advancements in lung regeneration: from bench to bedside - February 7th, 2025
- Entos Pharmaceuticals Awarded $4 Million USD in Funding from the California Institute for Regenerative Medicine (CIRM) for its Congenital Generalized... - February 7th, 2025
- Adia Nutrition Officially Enters $15.1 Billion Global Stem Cell Market with Domestic Treatments by Successful Opening of First Florida Location -... - February 7th, 2025
- Cell therapy weekly: iPSC therapy IND for Phase III trial cleared - RegMedNet - February 7th, 2025
- Creative Medical Technology Holdings Expands Collaboration with Greenstone Biosciences to Accelerate iPSCelz - EIN News - February 7th, 2025
- Placental Stem Cell Therapy Solution Market Size And Booming - openPR - February 7th, 2025
- Stem Cells Applications in Regenerative Medicine and Disease ... - December 6th, 2024
- Ageing of stem cells reduces their capacity to form tumours - Nature.com - December 6th, 2024
- Master of Science in Regenerative Medicine and Entrepreneurships FUSION program information session - The Daily | Case Western Reserve University - December 6th, 2024
- BioRestorative Therapies Announces Notice of Allowance of - GlobeNewswire - December 6th, 2024
- Stem Cell Therapy Strategic Business Report 2024 - - GlobeNewswire - December 6th, 2024
- University of Colorado Anschutz Medical Campus-Led Team Receives Up to $46 Million to Develop Innovative Treatment to Cure Blindness - University of... - December 6th, 2024
- Affimed Announces Acimtamig and AlloNK Combination Granted Regenerative Medicine Advanced Therapy (RMAT) Designation by the U.S. Food and Drug... - December 6th, 2024
- Navigating the hope and hype of regenerative medicine - October 14th, 2024
- Cell and Gene Therapy Investment Ticks Up After Hard Few Years - BioSpace - October 14th, 2024
- Crackdowns on Unproven Stem Cell Therapies Worked Abroad - Medpage Today - October 14th, 2024
- How Regenerative Medicine can help you get out of pain without surgery - WJLA - October 14th, 2024
- Regenity Biosciences Receives 510(k) Clearance for RejuvaKnee, a Groundbreaking Regenerative Meniscus Implant Device to Redefine the Standard of Care... - October 14th, 2024
- Buy, Sell, Hold: Cell and Gene Therapy - BioPharm International - October 14th, 2024
- Mayo Clinic offers unique regenerative medicine procedure for knee and ... - September 13th, 2024
- Regenerative Medicine to the Rescue - Cleveland Clinic - September 13th, 2024
- Regenerative medicine applications: An overview of clinical trials - September 13th, 2024
- The Progression of Regenerative Medicine and its Impact on Therapy ... - September 13th, 2024
- Immune cell injection significantly boosts healing of bone, muscle & skin - September 13th, 2024
- Regenerative Medicine Foundation - September 13th, 2024
- BridgeBio Receives FDAs Regenerative Medicine Advanced Therapy (RMAT ... - September 13th, 2024
- Tissue engineering and regenerative medicine approaches in colorectal ... - September 13th, 2024
- Tubular scaffolds boost stem cell-driven bone regeneration in skull defects - Phys.org - September 13th, 2024
- Finding the right path(way) to reduce fat accumulation in the liver - Medical University of South Carolina - September 13th, 2024
- NAMRU EURAFCENT Signs Agreement with Egypt Center for Research and Regenerative Medicine - DVIDS - September 13th, 2024
- BridgeBio Receives FDAs Regenerative Medicine Advanced Therapy (RMAT) Designation for BBP-812 Canavan Disease Gene Therapy Program - StockTitan - September 13th, 2024
- BioNexus Gene Lab Corp. Signs Strategic Partnership MOU with Shenzhen Rongguang Group to Advance Cancer Screening, Precision Medicine, and... - September 13th, 2024
- Neurona Therapeutics Receives $3.8 Million CIRM Grant for the Development of Next Generation Neural Cell Therapy Candidate - Yahoo Finance - September 13th, 2024
- Aging is associated with functional and molecular changes in distinct hematopoietic stem cell subsets - Nature.com - September 13th, 2024
- Cellino Awarded $25M in Funding from the Advanced Research Projects Agency for Health (ARPA-H) - Business Wire - September 13th, 2024
- HepaTx Enters Collaboration with Mayo Clinic to Advance Cell Therapy Technology for Liver Disease to Clinical Trials - Longview News-Journal - September 13th, 2024
- Obsidian Therapeutics Receives FDA Regenerative Medicine Advanced Therapy (RMAT) Designation for OBX-115 for the Treatment of Advanced Melanoma -... - September 4th, 2024
- Regenerative Medicine in Orthopedic Surgery: Expanding Our Toolbox - Cureus - September 4th, 2024
- Somite.ai takes pre-seed to $10M as it eyes to become the OpenAI of stem cell biology - CTech - September 4th, 2024
- Longeveron Announces Positive Type C Meeting with U.S. FDA Regarding Pathway to BLA for Lomecel-B in Hypoplastic Left Heart Syndrome (HLHS) - Yahoo... - September 4th, 2024
- Study Explores Potential Of 3D Printed Regenerative Breast Implants - Forbes - September 4th, 2024
- Nikon Announces New Image Analysis Functions to Empower Drug Discovery Research for Cancer, Neurological Disease, and Regenerative Medicine - PR... - September 4th, 2024
- Trinity researcher scores 800,000 to boost regenerative medicine - SiliconRepublic.com - September 4th, 2024
- Seeing the future: Zebrafish regenerates fully functional photoreceptor cells and restores its vision - EurekAlert - September 4th, 2024
- Regenerative Medicine Industry Projected to Surge to USD 73,084.2 Million by 2033, Growing at an 18.5% CAGR - Future Market Insights - September 4th, 2024
- What is regenerative medicine? | Northwell Health - July 2nd, 2024
- Science Saturday: A regenerative reset for aging - July 2nd, 2024
- Science Saturday: A year of new directions and advancements for ... - March 29th, 2024
- Diverse ways regenerative medicine is advancing health care - March 29th, 2024
- Stem cell-based regenerative medicine - PMC - National Center for ... - February 27th, 2024
- Regenerative medicine | NIST - February 10th, 2024
- San Jose blood stem cell donor meets 15-year-old whose life he saved in Los Angeles - The Mercury News - May 17th, 2023
- Regenerative medicine: Current therapies and future directions - April 23rd, 2023
- What Is Regenerative Medicine? | Goals and Applications | ISCRM - April 23rd, 2023
- Important Patient and Consumer Information About Regenerative Medicine ... - April 23rd, 2023
- Regenerative medicine can be a boon for those with Drug-Resistant Tuberculosis - Hindustan Times - April 23rd, 2023
- About Regenerative Medicine - Center for Regenerative ... - Mayo Clinic - April 7th, 2023
- Regenerative Medicine | National Institutes of Health (NIH) - April 7th, 2023
- Porcine Vaccine Market is estimated to be US$ 4.41 billion by 2030 with a CAGR of 7.50%during the forecast - EIN News - April 7th, 2023
- Advancing Safe and Effective Regenerative Medicine Products - March 21st, 2023