University of Cambridge scientists this week demonstrate dramatic differences in the ability of Zika Virus to attack parallel stem cell populations in the developing brain and in malignant brain tumours. The mechanisms uncovered could be important for preventing birth defects and for treating brain tumours in the future.
Dr. Harry Bulstrode, working as part of a team in Professor David Rowitch’s lab at the Wellcome-MRC Cambridge Stem Cell Institute (CSCI), compared Zika Virus levels on infection of glioblastoma brain tumour samples donated by patients, alongside developing human brain tissue, which is highly vulnerable to Zika.
The research, published (28 September) in Neuron, found that the virus targets brain stem cells effectively in both developing brain and brain tumours. However, whereas brain tumours are rich in immune cells which coordinate effective stem cell antiviral responses, in early brain development these cells are rare or absent, leaving developing brain stem cells defenceless.
Based on these findings, the team used interferon signalling molecules produced by brain tumour immune cells to protect developing brain stem cells from Zika Virus. Conversely drugs blocking these signals enabled Zika Virus to target brain tumour stem cells effectively.
Dr Bulstrode said of the research, “This paper is exciting because it shows how the body’s own immune cells help brain tumours escape treatment with viruses, and suggests ways in which we can overcome this.”
Background
Zika virus is a flavivirus spread by mosquitoes. In 2015 novel Zika strains associated with an epidemic outbreak in Asia and South America were associated with microcephaly, a failure of forebrain development, in babies born to mothers infected during pregnancy.
Microcephaly has been shown to reflect selective Zika targeting of brain stem cells present in the developing brain. These cells are rare or absent in the adult human brain, but similar gene expression programs are found in stem cells in malignant brain tumours. With this in mind, in 2017 Dr. Bulstrode secured Cancer Research UK Pioneer Award funding to investigate the application of Zika Virus as an anti-cancer ‘oncolytic’ treatment in brain tumours, which formed the basis for this study.
The team, comprised of scientists working at the Cambridge Stem Cell Institute and elsewhere, as well as neurosurgeons based at Addenbrooke’s Hospital, showed that the immune response to Zika virus can be stimulated in brain tissue through the use of interferons, a family of proteins which play essential roles in immunoregulation.
Conversely, inhibition of the pathway that is crucial in mediating the effects of interferons lowers the resistance to Zika virus infections. The latter is of particular importance because of Zika’s potential to be used in anti-cancer therapy: by finding a way to lower a tumour’s resistance to the infection, scientists would be able to increase efficacy of oncolytic treatment.
Dr Gergely commented "Our team's ability to compare developing brain and tumour tissues side-by-side provided us with a unique insight into both the identity of cells targeted by Zika virus and the vital role played by the tissue microenvironment in controlling infection."
Professor Rowitch said “Our study helps explain why the human developing brain is vulnerable as it lacks enough protective microglia, a cell type that can fight viruses. It further suggests ways to use interferon signalling to build resilience in brain cells from our lab studies, a finding that could eventually help in the clinic.”
Details
During their research, the scientists compared rates of infection in foetal brain tissue and adult brain tumour tissue at 72 hours and 7 days post infection in order to determine vulnerability of cells in different states. They found that virus levels in developing brain tissue were typically 10-100 times higher than that of the glioblastoma tissue.
Using RNA-Sequencing to compare Zika infection in human developing brain and brain tumour tissues for the first time, the team found a signature of microglial cell infiltration that correlated with the ability of tumours to fight off infection. They went on to show that treatment with the interferons produced by these microglia could protect developing brain stem cells from infection, and that blocking the interferon response could enhance Zika targeting of brain tumour stem cells.
The use of human brain tissue rather than mouse was key to the study given that mice with normal immune systems are not susceptible to Zika Virus.
Dr Bulstrode said, “We could not have based this work on traditional cell line and mouse models. Instead we refined state-of-the-art techniques to directly analyse human developing brain as well as tumour tissue.”
In the future, Dr Bulstrode hopes to build on this work at CSCI in virus targeting of stem cells, both in brain tumours and degenerative brain disease.