Doctoral Senior Reseach Fellow University of Calcutta KOLKATA, West Bengal, India
Introduction/Rationale: 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.
