S184. IN SILICO PREDICTION OF T-CELL-MEDIATED MOLECULAR MIMICRY IN TOXOPLASMOSIS AND SCHIZOPHRENIA

BACKGROUND: Exposure to Toxoplasma gondii (TOXO) has been consistently associated with the development of schizophrenia, but the neurobiological mechanism through which this occurs is not well elucidated. Emerging data has broadly implicated the adaptive immune system as a possible pathway from TOXO infection to schizophrenia. In order to explore the hypothesis that crossreactive T cells could help mediate this relationship, we built upon the genetic analysis from our psychiatrically-enriched Ashkenazi Jewish cohort using an in silico approach to predict HLA reactivity to TOXO epitopes, with the aim of identifying host proteins that could be susceptible to T-cell-mediated molecular mimicry. METHODS: We used netMHCpan v4.0 to generate a library of 2182 oligopeptides from the TOXO proteome that were predicted to be strongly antigenic for individuals with HLA-C*04:01, an allele of interest since our analysis indicated that the odds ratio for TOXO infection were in the opposite direction for those with schizophrenia compared to controls. A predicted binding affinity less than 500 nM was used to identify epitopes that were likely to be biologically relevant. Epitopes identified by this approach were compared with human peptides for local sequence similarity using BLAST optimized for short peptide sequences in order to identify host proteins that could mimic TOXO antigens. Ingenuity Pathway Analysis was then used to interpret and synthesize possible biological relationships between predicted autoantigens and schizophrenia. RESULTS: Our pipeline identified 38 candidate proteins for molecular mimicry at a threshold of P<.05 after correcting for multiple testing. A number of these genes have been strongly linked to schizophrenia through genetic studies, including HSPA9, PSMA4, and ZDHHC5. Pathway and gene ontology analysis revealed that these genes were involved in networks of regulation of gene expression as well as ubiquitination, which participates in antigen presentation. DISCUSSION: Using an in silico approach, we identified 38 human proteins that could be targeted by a crossreactive T cell autoimmune response after exposure to TOXO. Several of these candidate proteins are highly relevant for genetic risk of schizophrenia and participate in molecular pathways that mediate antigen processing. CD8+ T cells contribute to autoimmunity through cytokine release and have been implicated in the relationship between TOXO exposure and schizophrenia. Though these results will need experimental confirmation, we hope that they will spur further research on the role of the adaptive immune system in toxoplasmosis and schizophrenia.