Neuro-immune-endocrine modulation of T-cell exhaustion in Central Nervous System parasitic diseases: insights from Toxoplasmosis and Neurocysticercosis.

Parasitic infections of the central nervous system (CNS) represent a considerable health burden in low- and middle-income countries. During chronic disease, parasites modulate host immunity to ensure long-term persistence while limiting collateral tissue damage. A key feature of this immune remodeling is the progressive T-cell dysfunction that may culminate in T-cell exhaustion, characterized by increased expression of inhibitory receptors (TIM-3, LAG-3, KLRG1), checkpoint molecules (PD-1, PD-L1), suppressor of cytokine signaling-1 (SOCS1), and arginase-1. This immune modulation is weakened by the neuroimmune endocrine (NIE) axis involving hormone release, cytokines, and neurotransmitters contributing to parasite survival. This review focuses on two parasitic CNS infections: Neurotoxoplasmosis (NT) induced by the intracellular protozoan Toxoplasma gondii and Neurocysticercosis (NCC) caused when cysticercus of the cestode Taenia solium lodge into the CNS. We present updated evidence on how these phylogenetically distant pathogens exploit the NIE network, describe the physiological consequences for the host, and highlight shared and distinct mechanisms behind T cell exhaustion. Finally, we address emerging immunotherapeutic strategies aimed at reversing exhaustion and restoring protective immunity.