Research Projects

Toxoplasma gondii, a neurotropic parasite infecting nearly one-third of the global population, is strongly associated with neuropsychiatric and cognitive disorders, including schizophrenia, depression, epilepsy, and Alzheimer’s disease [1,2]. While established mechanisms involve neurotransmitter disruption, mitochondrial dysfunction, and chronic neuroinflammation via glial activation and T-cell infiltration [3–5. Alterations in sleep–wake cycles have been consistently observed in T. gondii-infected mice as well as in IgG-positive humans. Furthermore, since T. gondii infection leads to tryptophan depletion in the brain due to immune activation and shunting of tryptophan into the kynurenine pathway, this may directly impair serotonin and melatonin synthesis, as tryptophan is their essential precursor. This biochemical shift could underlie both the neurotransmitter imbalance and sleep disturbances seen in infected hosts. Our preliminary data show that chronic T. gondii infection disrupts circadian regulation by selectively upregulating BMAL1 and downregulating CLOCK in brain and peripheral tissues. This misalignment is pathophysiologically significant: BMAL1 deficiency in microglia increases oxidative stress and proinflammatory cytokines [7], while CLOCK dysfunction impairs neurotransmitter clearance and weakens blood–brain barrier (BBB) integrity, exacerbating cognitive deficits [8]. A novel aspect of our study is the role of the gut microbiome in the infection–circadian–neuroinflammation axis. The gut microbiota itself exhibits diurnal oscillations in composition, abundance, and metabolic activity, which are entrained by host circadian cues such as feeding–fasting cycles, melatonin, and glucocorticoids. These oscillations, in turn, influence peripheral circadian clocks via microbial metabolites like short-chain fatty acids (SCFAs) and secondary bile acids, which act as signaling molecules and epigenetic modulators of clock gene expression. T. gondii infection disrupts microbial diversity and rhythmicity, particularly by altering the availability of key metabolites and affecting host epithelial and immune clocks. This dysbiosis likely contributes to circadian misalignment, amplifies neuroinflammation, and exacerbates behavioral impairments in infected hosts. In addition, the parasite reprograms host tryptophan metabolism. Our data show parasite-induced colonic inflammation activates IDO1, accelerating tryptophan catabolism into kynurenine and reducing serotonin precursor availability [12]. Combined with BBB dysfunction, this impairs brain serotonin levels, worsening neurotransmitter imbalance. Concurrent dysbiosis reduces gut-derived indoles, undermining intestinal and BBB integrity, while elevated LPS enhances systemic and neuroinflammation, promoting neurotoxic kynurenine production and cognitive decline [13,14]. To capture systemic microbial translocation from parasite-induced gut barrier loss, we will perform blood metagenomics. This will identify circulating pathobionts that disseminate to distal organs, compromise BBB integrity, and contribute to neuroinflammation. These microbial signatures offer critical insight into the gut–blood–brain axis and how they drive circadian and cognitive dysfunction. T. gondii also alters mitochondrial metabolism, shifting key intermediates (e.g., lactate, succinate, BCAAs) that influence circadian regulators and immune cell plasticity [15,16]. As circadian transcription factors modulate antigen presentation and T-cell differentiation, disrupted metabolism links circadian misalignment to chronic brain inflammation [17,18]. This project will dissect how T. gondii-driven dysbiosis, metabolic reprogramming, and circadian disruption converge to cause neuroinflammation and cognitive decline, aiming to develop microbiota-based and metabolic interventions that restore circadian health and cognitive resilience.