MDSC-Mediated Regulation of Th9 and CD8+ T Cells Orchestrates Neurocognitive Pathology in Experimental Cerebral Malaria 2308438

Introduction Cerebral malaria (CM), a catastrophe of Plasmodium infection, is driven by skewed host immune responses and is coupled with lasting cognitive impairment. IFN-γ and Granzyme B—mediated neuroinflammation contributes to neuronal injury, yet the immune—metabolic mechanisms coupling myeloid regulation to neurotransmitter imbalance remain unclear. This study investigates the reciprocal interaction of myeloid-derived suppressor cells (MDSCs) and Th9 cells during experimental cerebral malaria (ECM), and how this immune axis disrupts dopamine homeostasis, BDNF signaling, and COMT regulation. Methods ECM was induced in rodents using Plasmodium berghei ANKA. MDSC and Th9 populations were analyzed by flow cytometry. IL-9 neutralization and MDSC were depleted in vivo to assess reciprocal regulation. IFN-γ and Granzyme B levels, dopamine content, BDNF expression, COMT regulation, and glial activation were quantified by flowcytometer, HPLC and qRT-PCR. Results IL-9 elevated expansion and pro-inflammatory programming of MDSCs, particularly PMN-MDSCs. MDSCs, through IL-1β secretion, promoted Th9 differentiation, forming a feed-forward loop. Depleting IL-9 during ECM reduced MDSC proliferation and activation, while depleting MDSCs subverted Th9 frequency. Increased IFN-γ and Granzyme B from CD8+ T cells impeded dopamine synthesis via oxidative stress, tyrosine hydroxylase suppression, and dopaminergic neuronal injury. Dopamine loss impaired BDNF transcription and induced maladaptive COMT upregulation. Conclusion Our study established IL-9—MDSC—Th9 immune axis as a core driver of neuroinflammation and dopamine dysregulation during ECM. Immune-mediated disruption of dopamine—BDNF—COMT signaling provides a mechanistic link between inflammation and cognitive dysfunction, highlighting IL-9 as a potential adjunct therapeutic target in cerebral malaria. Funding Source ICMR (Sanction No: EMDR/SG/15/2023-1532 Dated: 04.04.2024)