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Barcoded viral tracing of single-cell interactions in central nervous system inflammation.

  • Author(s): Clark, Iain C
  • Gutiérrez-Vázquez, Cristina
  • Wheeler, Michael A
  • Li, Zhaorong
  • Rothhammer, Veit
  • Linnerbauer, Mathias
  • Sanmarco, Liliana M
  • Guo, Lydia
  • Blain, Manon
  • Zandee, Stephanie EJ
  • Chao, Chun-Cheih
  • Batterman, Katelyn V
  • Schwabenland, Marius
  • Lotfy, Peter
  • Tejeda-Velarde, Amalia
  • Hewson, Patrick
  • Manganeli Polonio, Carolina
  • Shultis, Michael W
  • Salem, Yasmin
  • Tjon, Emily C
  • Fonseca-Castro, Pedro H
  • Borucki, Davis M
  • Alves de Lima, Kalil
  • Plasencia, Agustin
  • Abate, Adam R
  • Rosene, Douglas L
  • Hodgetts, Kevin J
  • Prinz, Marco
  • Antel, Jack P
  • Prat, Alexandre
  • Quintana, Francisco J
  • et al.

Cell-cell interactions control the physiology and pathology of the central nervous system (CNS). To study astrocyte cell interactions in vivo, we developed rabies barcode interaction detection followed by sequencing (RABID-seq), which combines barcoded viral tracing and single-cell RNA sequencing (scRNA-seq). Using RABID-seq, we identified axon guidance molecules as candidate mediators of microglia-astrocyte interactions that promote CNS pathology in experimental autoimmune encephalomyelitis (EAE) and, potentially, multiple sclerosis (MS). In vivo cell-specific genetic perturbation EAE studies, in vitro systems, and the analysis of MS scRNA-seq datasets and CNS tissue established that Sema4D and Ephrin-B3 expressed in microglia control astrocyte responses via PlexinB2 and EphB3, respectively. Furthermore, a CNS-penetrant EphB3 inhibitor suppressed astrocyte and microglia proinflammatory responses and ameliorated EAE. In summary, RABID-seq identified microglia-astrocyte interactions and candidate therapeutic targets.

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