Background
Toxoplasma gondii, a zoonotic parasite, poses risks for people with HIV (PWH). Although its clinical impact is minimal in immunocompetent hosts, U.S. seroprevalence studies show a 20-30% infection rate. The parasite forms bradyzoites in brain and muscle tissue that can reactivate when CD4+ T cell counts drop in PWH, leading to severe disease. Additionally, T. gondii alters epigenetic pathways in brains of rodents, causing behavioral changes, and its seropositivity in humans is associated with neurobehavioral disorders and adult glioma development.
Methods
To investigate the epigenetic effects of T. gondii in the brains of PWH, we conducted a pilot case-control study comparing DNA methylation of CpG dinucleotides in the frontal cortex and basal ganglia of four PWH with confirmed latent T. gondii infection (via ELISA, histopathology, or quantitative PCR) to four IgG seronegative PWH without documented infection. Two of the participants self-reported prior T. gondii encephalitis. Brain tissues were obtained from the California NeuroAIDS Tissue Network (CNTN). We performed reduced representation bisulfite sequencing and assessed differential DNA methylation after deconvolution using Limma. Genes of interest were further analyzed for expression changes and correlation with survival in glioblastoma (GBM) using the Gene Expression Profiling Interactive Analysis (GEPIA).
Results
Participants were all virally suppressed non-hispanic caucasian cisgender men with an average age of 50 years (range 30-75) and average CD4+ T cell count of 56 cells/uL (range 27-87) at time of death. In basal ganglia, we identified 63 differentially methylated (DM) sites, with 13 up and 50 down, and in frontal cortex, we found 71 DM sites, with 37 up and 34 down (FDR <0.1, mean difference ≥ ±15%). 70% of DM sites were located in gene bodies, where DNA methylation is positively correlated with gene expression. Notably, approximately half of these genes are associated with gliomas, and expression changes in several of them correlate with decreased survival in GBM (Figure 1).
Conclusions
The epigenetic changes in human brains infected with T. gondii suggest that the parasite may influence DNA methylation as in other mammals. The correlation between differentially methylated genes and expression changes linked to GBM points to a potential connection between T. gondii infection and brain tumor development. These findings underscore the need for comprehensive prevention strategies against T. gondii for at risk populations.