Mycobacterium tuberculosis infection of human neural progenitor cells alters their functions

Abstract Central nervous system tuberculosis (CNS-TB) is the most dangerous form of extrapulmonary tuberculosis. However, the current understanding of infectious mechanisms and anti-mycobacterial immunity within the brain parenchyma is limited due to the absence of an ideal human CNS-TB model. In this study, we developed a novel human in vitro model for the study of CNS-TB by infecting 3D neural organoids and 2D neural progenitor cells (NPC) with Mycobacterium tuberculosis (Mtb). Here we report that the subset of the NPC population can be phagocytized by the apoptotic cell binding receptors. Internalized Mtb bacilli, co-localized within late endosomal and phagolysosomal compartments as well as in the cytoplasm of the NPCs. Mtb infection of NPC induced an elevated cell death and limited proliferation of the infected NPCs Additionally a strong type-1 interferon (IFN) responses were detected in Mtb-infected NPCs by the RNA-sequencing and by immunohistochemistry. We demonstrated that the treatments with anti-IFNα neutralization antibodies could partially rescue Mtb-induced NPC death and proliferation defects. Our findings suggest that these novel neural organoids and NPC-based in vitro platforms provide a new platform for elucidating CNS-TB pathogenesis and can be ultimately used for testing novel anti-mycobacterial treatment strategies for the human CNS-TB. "Supported by grants from NIH (R56AI162164-01)