Comprehensive analysis of Toxoplasma gondii migration routes and tissue dissemination in the host

Abstract

Toxoplasma gondii is a highly adaptable intracellular parasite capable of infecting a wide range of warm-blooded animals, including humans. Following the ingestion of cysts and oocysts, the parasites rapidly emerge and transmigrate through the bloodstream, initiating a complex infection process. Despite reports on the parasite's dissemination, the mechanisms behind its migration remain unclear. Recent advances using innovative 3D models and various host systems are beginning to shed light on the migratory routes and strategies employed by T. gondii. This review compiles current knowledge on the migration and dissemination of T. gondii, from its initial interactions in the gut to its invasion of immune-privileged organs. This review provides a comprehensive understanding of how T. gondii establishes its infection crossing the most impermeable biological barriers within the host.

Fig 1. Mouse peritoneal macrophage invaded by a tachyzoite of T. gondii.

T, tachyzoite; N, nucleus of host cell; PV, parasitophorous vacuole; m, host mitochondria. Thin section micrographed in a Transmission Electron Microscope. Scale bar = 1 μm.

Fig 2. Toxoplasma gondii crossing the blood–brain barrier.

Toxoplasma gondii appears to cross the blood–brain barrier (BBB) via two, probably overlapping steps. First, it hijacks phagocytic immune cells like a “Trojan-horse”, transporting the parasite to brain capillaries where it is either released nearby or transported directly through them while still hidden within migrating leukocytes. Second, once free tachyzoites contact the endothelial layer, they enter the central nervous system (CNS) by transiently loosening TJ (paracellular pathway) or by infecting and lysing endothelial cells after intracellular replication (transepithelial pathway). Figure created with BioRender.com.

Fig 3. Toxoplasma gondii and its reported human sequelae or its potential associated manifestations.

The silhouette represents a gender-neutral individual to emphasize its relevance at the population level. This ubiquitous intracellular parasite disseminates beyond the intestine and establishes chronic cysts in multiple organs. Epidemiological studies link latent infection to metabolic disorders (higher seropositivity in type 1 diabetes) [87,88] and a 1.7-fold increased risk in metabolic-syndrome [89] and to several solid tumors, such as glioma [90], colorectal cancer [93] and hepatocellular carcinoma [94]. T. gondii remains a major cause of congenital neuroocular disease [100,111] and, in immunocompromised hosts, of encephalitis [64]. Its remarkable tissue-invasive characteristics are also being repurposed in genetically modified “live-vector” strains for drug delivery and tumor immunotherapy [26]. Figure created with BioRender.com.

Fig 4. Studying Toxoplasma gondii infection by using microphysiological devices: modeling a human intestine.

The microphysiological system simulates the intestinal environment, allowing the investigation of parasite early infection, stage conversion, migration through intestinal epithelial cells, its impact on the intestinal barrier, and subsequent spread to other tissues. This model enables the analysis of immune responses and therapeutic interventions. Figure created with BioRender.com.