Researchers in the laboratory of Steve Goldman, MD, PhD, Co-Director of University of Rochester Center for Translational Neuromedicine, are delving deeper into the science behind progressive multifocal leukoencephalopathy (PML), a disease caused by the JC virus, which commonly affects multiple sclerosis patients and others with compromised immune systems. The team aims to improve the ways by which scientists study PML and test for new treatments.
Until now, scientists have been trying to make advances in PML research using inadequate models of disease. “The JC virus is an example of an infection that specifically targets glia, the brain’s support cells,” said Dr. Goldman, in a news release from the university. He further explained, “Because this virus only infects human glia and not brain cells in other species, it has eluded our efforts to better understand this disease. To get around this problem, we have developed a new mouse model that allows us to study human glia in live animals.”
The work, published in “Human Glial Chimeric Mice Reveal Astrocytic Dependence of JC Virus Infection,” in Journal of Clinical Investigation, was made possible through a mouse model created by Dr. Goldman and Maiken Nedergaard, MD, DMSc. The mice had brains consisting of both animal neurons and human glia cells (astrocytes and oligodendrocytes). These mice happened to be smarter due to the presence of human cells, but more importantly, the mice had glia cells that could be infected with the JC virus.
Using this model, Dr. Goldman and colleagues have completely turned around previous beliefs. Previously, researchers determined the JC virus attacks oligodendrocytes, preventing axon myelination. Dr. Goldman showed the initial targets of the JC virus are astrocytes, as well as glial progenitor cells. Attacking astrocytes allows the JC virus to replicate and mutate before “exploding” the cell and spreading infection by a domino effect.
“We have been looking at the wrong cell population,” stated Dr. Goldman. “Astrocytes seem to be the main target of the virus, and oligodendrocytes are essentially innocent bystanders caught in the crossfire.” As astrocytes die, other cells are affected because astrocytes are a vital support cell of the nervous system. Without functional astrocytes and oligodendrocytes, the brain loses myelin production and cannot replace myelin lost from causes such as multiple sclerosis.
The researchers were able to further show that JC virus propagation among astrocytes in mice was sufficient to cause PML. The disease evolved upon active infection with JC virus that mutated the capsid protein VP1. The team now has a more biologically-relevant model to study human-specific gliotropic viruses such as JC virus. Potential treatments that specifically target astrocytes will be used in these mouse models to improve PML management.