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Toxoplasma gondii is a ubiquitous parasite infecting up to 30% of the population worldwide. Most individuals infected with T. gondii harbor a chronic infection that persists for the lifetime of the host with the parasite located predominantly in neural and muscular tissue. In some immune competent hosts however, chronic infection is associated with neurological disorders including schizophrenia, depression, suicidal behavior, headaches and cryptogenic epilepsy. There are three strains of T. gondii, designated type I, type II and type III, with evidence indicating type I strains are more virulent in humans, causing more severe clinical outcomes. Astrocytes are the predominant glial cell in the brain and can serve as a host cell for tachyzoite and bradyzoite stages in the brain. In this study we have used a transcriptional approach to dissect the host response to virulent type I RH strain vs. a virulent type II Me49 strain, in murine astrocytes. The results showed the type I strain induces a distinctly different host cell response in astrocytes inducing larger changes in gene expression levels and affecting different host cell pathways as compared to the type II strain. Type I vs. type II strains showed some common responses that may represent the ‘core’ response to parasite infection with host immune response genes the dominant pathway affected by both strains. However Toxoplasma strains show clear differences in modulation of some of these core host responses and importantly in some pathways related to pathogenesis of the nervous system. Neurobiological processes significantly affected by type I strain infection included effects on neurodevelopmental processes and nerve impulse transmission, including many gene homologues associated with Schizophrenia. The strain-specific effects could help explain the different clinical outcomes of Toxoplasma infections in humans and specifically, the distinct neurological complications such as Schizophrenia that occurs in the latent infection in some immune competent individuals.