Inflammation manipulation and a complement-centered reboot of the Toxoplasma gondii model of schizophrenia.

Abstract

The protozoan parasite, Toxoplasma gondii, has evolved a creative skillset to engage and sustain itself within a diversity of warm-blooded hosts. Progression to adulthood requires residence in the definitive host, Felidae, a taxonomic family encompassing the beloved, sometimes maligned, housecat. Humans are intermediate hosts, primarily infected following ingestion of foodstuffs containing T. gondii tissue cysts or T. gondii oocysts shed by cats. Although most human cases are asymptomatic, acute inflammation and deadly encephalopathies can result if the infection is congenital, or the host is immunocompromised. Increasingly, presumably benign asymptomatic infections are being investigated for behavioral outcomes and complex brain disorders such as schizophrenia. While not typically considered an inflammatory disorder, reports of muted idiopathic inflammation-like comorbidities in schizophrenia persist and cannot be discounted by the usual covariants, medications and metabolic factors. T. gondii's survival success may depend on its ability to regulate host inflammation and satisfy its own life-stage requirements for both motility and quiescence. Within the setting of this fluctuating inflammatory environment putatively controlled by T. gondii, other gene and environmental forces are also at work. We consider a model of schizophrenia centered on complement gene variants and the unique capacity for this set of immune pathways to perpetrate and perpetuate neurobiological dysfunction. We examine T. gondii's connections to the gut, to chronic stress, how its relationship with schizophrenia has matured, and how the boundaries between what qualifies as gene and environment have become blurred as we enter a new era of the microbiome and more personalized medicine.