Reexamining Chronic Toxoplasma gondii Infection: Surprising Activity for a "Dormant" Parasite

Abstract

Purpose of review: Despite over a third of the world's population being chronically infected with Toxoplasma gondii, little is known about this largely asymptomatic phase of infection. This stage is mediated in vivo by bradyzoites within tissue cysts. The absence of overt symptoms has been attributed to the dormancy of bradyzoites. In this review, we reexamine the conventional view of chronic toxoplasmosis in light of emerging evidence challenging both the nature of dormancy and the consequences of infection in the CNS.

Recent findings: New and emerging data reveal a previously unrecognized level of physiological and replicative capacity of bradyzoites within tissue cysts. These findings have emerged in the context of a reexamination of the chronic infection in the brain that correlates with changes in neuronal architecture, neurochemistry, and behavior that suggest that the chronic infection is not without consequence.

Summary: The emerging data driven by the development of new approaches to study the progression of chronic toxoplasma infection reveals significant physiological and replicative capacity for what has been viewed as a dormant state. The emergence of bradyzoite and tissue cyst biology from what was viewed as a physiological "black box" offers exciting new areas for investigation with direct implications on the approaches to drug development targeting this drug-refractory state. In addition, new insights from studies on the neurobiology on chronic infection reveal a complex and dynamic interplay between the parasite, brain microenvironment, and the immune response that results in the detente that promotes the life-long persistence of the parasite in the host.

Keywords: Bradyzoite; CNS infection; Glycosylation; Tissue cyst; Toxoplasma.

Fig. 1

Distribution of key glycans in tissue cysts. A distinguishing feature of Toxoplasma gondii tissue cysts is the high level of glycosylation. Left panel lectin staining with FITC-conjugated Dolichos biflorus (DBA-recognizing GalNAc) lectin labels the tissue cyst wall and the intra-cyst matrix (green). In contrast, Concanavalin A (ConA-recognizing mannose and glucose, and an indicator of N-linked glycosylation) selectively stains structures within the bradyzoites and in the matrix (red) but is excluded from the tissue cyst wall (merge). Right panel the distribution of amylopectin granules within bradyzoites detected using Schiff reagent (red) overlaid on a differential interference contrast of a purified tissue cyst reveals an uneven distribution of amylopectin within the tissue cyst with clusters of bradyzoites exhibiting high levels of amylopectin (outlined in green) adjacent to areas with low amylopectin levels (outlined in yellow)

Fig. 2

Evidence of replication and patterns of replication within tissue cysts. Tissue cysts and the bradyzoites within them have been viewed as dormant non-replicative entities. Replication by endodyogeny and cytokinesis in toxoplasma can be detected using antibodies against components of the inner membrane complex (IMC) including TgIMC3. Top panel the intensity of TgIMC3 is highest in developing daughter parasites and recently emerged parasites. Following emergence, the TgIMC3 signal loses intensity and can thus serve as a marker for the recency of replication. Bottom panel actively replicating bradyzoites within tissue cysts can be detected based on the level of TgIMC3 labeling. Evidence for sporadic replication (left panel, arrowheads), clustered replication (outlined in yellow) with a region where replication is not occurring (outlined in red) are seen in most cases. In several cases, highly synchronized replication whereby all the bradyzoites within tissue cyst were dividing at the same time is observed. Together, these findings suggest that the tissue cysts are dynamic entities containing replication competent bradyzoites