Unique proteomic signature of JCPyV-infected human astrocytes: from cells to extracellular vesicles

JC polyomavirus (JCPyV) is the causative agent of progressive multifocal leukoencephalopathy (PML), a severe, and often fatal, demyelinating disease of the central nervous system. While PML has traditionally been characterized as a lytic infection of oligodendrocytes, more recent findings suggest an important role for astrocytes during the initial stages of disease. Here, using human induced pluripotent stem cell-derived astrocytes coupled with a multiparametric approach, we show that astrocytes are readily infected with JCPyV that strongly impacts their biology, inducing a unique proteomic signature. Furthermore, the changes observed mirror elements of ex vivo findings in PML brain lesions, including dysregulation of the cell cycle and activation of the DNA damage response. We also demonstrate that this signature is extended to extracellular vesicles (EVs) while being strikingly different from that of inflammatory conditions. Thus, our results support the relevance of using brain-derived EVs as a means to gain mechanistic insights into JCPyV pathophysiology in the brain and pave the way towards the identification of new biomarkers for the early stratification of patients at risk of developing PML.