Cerebral complement C1q activation in chronic Toxoplasma infection

Abstract

Exposure to the neurotropic parasite, Toxoplasma gondii, causes significant brain and behavioral anomalies in humans and other mammals. Understanding the cellular mechanisms of T. gondii-generated brain pathologies would aid the advancement of novel strategies to reduce disease. Complement factor C1q is part of a classic immune pathway that functions peripherally to tag and remove infectious agents and cellular debris from circulation. In the developing and adult brain, C1q modifies neuronal architecture through synapse marking and pruning. T. gondii exposure and complement activation have both been implicated in the development of complex brain disorders such as schizophrenia. Thus, it seems logical that mechanistically, the physiological pathways associated with these two factors are connected. We employed a rodent model of chronic infection to investigate the extent to which cyst presence in the brain triggers activation of cerebral C1q. Compared to uninfected mice, cortical C1q was highly expressed at both the RNA and protein levels in infected animals bearing a high cyst burden. In these mice, C1q protein localized to cytoplasm, adjacent to GFAP-labeled astrocytes, near degenerating cysts, and in punctate patterns along processes. In summary, our results demonstrated an upregulation of cerebral C1q in response to latent T. gondii infection. Our data preliminarily suggest that this complement activity may aid in the clearance of this parasite from the CNS and in so doing, have consequences for the connectivity of neighboring cells and synapses.

A Double‐Edged Sword: Complement Component 3 in Toxoplasma gondii Infection

“…Although Xiao et al. (2016) have reported alterations in the level of C1q in T. gondii infected mice, this is the first study that directly identified C1q, C3, and C4b from the brain of infected KM mice.…”

“…Considering studies on the classical complement pathway in T. gondii infection, by using quantitative PCR, Xiao et al. (2016) first claimed that C1q activation is a part of the host immune response to T. gondii chronic infection, and primarily recognizes degenerate cysts as targets for the parasite elimination . In our study, we used iTRAQ strategy to confirm the variation of C1q in the KM mice with T. gondii infection.…”

The microbiome, immunity, and schizophrenia and bipolar disorder

“…Of particular importance would be the interaction of immune related risk genes such as those involved in the complement system (Xiao et al, 2016) with the composition of the microbiome. Animal models would also be useful to better define the effects of psychiatric medications on the composition of the microbiome in terms of both psychiatric activity and side effects such as weigh gain (Bahr et al, 2015).…”

PersistentToxoplasmaInfection of the Brain Induced Neurodegeneration Associated with Activation of Complement and Microglia

“…Studies show that Toxoplasma cysts can be found almost exclusively in neurons (19,20) and are controlled mainly by cell-mediated immunity provided by resident CNS and infiltrating peripheral immune cells (21). Moreover, a low-grade brain inflammation has been documented in rodent models of chronic Toxoplasma infection characterized by microglia and astrocyte activation (22,23), an increase in complement protein C1q (22,24), and ventricular dilatation (22). These findings raise concerns about the possibility of neurodegeneration in Toxoplasmainfected brain, as neuroinflammatory responses might persist for years if infection is not resolved.…”