Characterization of the cribriform plate lymphatics in CNS Mtb infection 4556

Description CNS TB represents a severe, often life-threatening manifestation of Mycobacterium tuberculosis (Mtb) infection, characterized by significant neurological complications and high mortality. Development of cerebral edema leads to negative outcomes in CNS TB. Lymphatic drainage is crucial to remove metabolic waste products, reduce cranial pressure and present antigens in CNS inflammation. We have previously shown that meningeal lymphatic vessels near the cribriform plate (CP) undergo lymphangiogenesis during EAE-induced neuroinflammation and interact with leukocytes, creating an immunoregulatory niche. Here we show after CNS Mtb infection DCs enter the brain through the choroid plexus, followed by the recruitment of T cells, leading to IFNγ-mediated responses. We found infected DCs interacting with lymphatic endothelial cells (LEC) at the CP, indicating this region is an important drainage route and a possible immune regulatory check point. We measured lymphangiogenesis at the CP one-week post infection, which was inhibited by VEGFR-3 blockade, which also led to reduced IFNγ production by Mtb-specific CD4 T cells in the CNS. Using scRNAseq, we identified and compared LEC populations from Mtb-infected and sham-treated animals, which will lead to further understanding of the infection-mediated changes and immune regulatory functions of this lymphatic niche. Funding Sources Supported by NIH NS123449 to M.S., NIH NS126595 and NS108497 to Z.F.