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Zika virus (ZIKV), a neurotropic flavivirus transmitted by mosquitoes, is associated with severe neurodevelopmental defects including neonate microcephaly. Increased cell death of neural progenitors in developping brain is believed to be one of the the primary cause of these neurological disorders. Major rearrangements of the cytoplasm is induced upon ZIKV infection, notably to form the viral replication factories within the endoplasmic reticulum (ER) network. Besides ER, the ZIKV induced-morphological remodeling of other cellular organelles, such as mitochondria and lysosomes, was shown to perturb cellular processes including apoptosis and immunity, allowing infected cells to release higher amounts of ZIKV progeny. With aim to better decipher the interplay between these remodeled organelles during ZIKV infection, we first performed immunofluorescence assays on ZIKV-infected liver cells which showed an accumulation of enlarged lysosomes in the perinuclear area enriched in viral replication factories, underlying a physical hijacking of lysosomes by ZIKV for the benefit of its replication. Concordantly, live cell confocal imaging of ZIKV-infected cells revealed a decrease in the motility of peripheral lysososmes which was accompagnied by an increase in the duration of lysosomemitochondria contacts. This correlated with a significant decrease in the number of mitochondria-lysosomal contact sites as shown by proximity ligation assays detecting TOMM20-LAMP1 and GDAP1-LAMP1 tethering complexes. Similar phenotypes were observed in cells infected with West Nile virus, another neurotropic flavivirus suggesting a conserved spatial …