Viral propagation in glial cells in progressive multifocal leukoencephalopathy

• Applicant: Professorin Dr. Imke Metz
• Subject Area: Molecular and Cellular Neurology and Neuropathology
• Term: since 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 541767224

Progressive multifocal leukoencephalopathy (PML) is a devastating opportunistic CNS infection caused by JC polyoma virus (JCPyV). The incidence shows a dramatic increase due to the use of novel powerful immunomodulatory therapies for diseases such as multiple sclerosis. No specific antiviral therapies are available. PML is a human-specific disease, and JCPyV shows a strict tissue specificity with productive infection and tissue damage only found in the CNS. PML leads to severe and diverse neurological symptoms and has a dire prognosis. Thus, there is an urgent need to better understand PML pathogenesis and to identify novel treatments. This study aims to identify cell populations and molecular mechanisms that initiate lesion development and that support viral spread and lesion enlargement. In addition, we will analyze mechanisms of cell death and survival of glial cell populations. Here we will focus on interferons and interferon-stimulated genes in different glial cell populations, as well as the therapeutic application of type I interferons. The best way to study human disease is in human tissue, and thus we will make use of human autopsy and biopsy tissue from PML patients from our large tissue bank including > 100 PML patients. However, in vitro models are urgently needed to supplement human studies. Thus far, PML research has been hampered by a lack of biologically relevant PML models, as JCPyV only infects human cells. To overcome this limitation, we will generate human-induced brain organoids from pluripotent stem cells, and infect these with a prototypic JCPyV variant (MAD1 strain) that causes PML. Brain organoids are composed of human-derived interconnected neurons, astrocytes and oligodendrocytes, and in previous work we were able to show that they are a promising tool for modelling JCPyV infection. Our study will provide data on which cell populations and molecular mechanisms need to be targeted to avoid viral spreading, and thus identify potential therapeutic approaches. Our findings will contribute to a better understanding of which mechanisms contribute to PML pathology, as well as how they may be overcome by endogenous and exogenous interferons, a potential treatment option for PML patients.

• DFG Programme: Research Grants