Toxoplasma gondii-A Gastrointestinal Pathogen Associated with Human Brain Diseases

Abstract

Serious psychiatric disorders such as schizophrenia, bipolar disorder, and major depression are important causes of mortality and morbidity worldwide. While these are primarily diseases involving altered brain functioning, numerous studies have documented increased rates of gastrointestinal inflammation and dysfunction in many individuals with these disorders. Toxoplasma gondii is an apicomplexan protozoan intracellular parasite with a widespread distribution in both developed and developing countries. Toxoplasma organisms enter the ecosystem through the shedding of oocysts by Toxoplasma-infected felines. In almost all cases of postnatal human infection, Toxoplasma enters its hosts through the intestinal tract either by the ingestion of oocysts or by the consumption of meat from food animals which themselves were infected by Toxoplasma oocysts. It had previously been thought that most cases of Toxoplasma infection in immune competent children and adults were inapparent and asymptomatic. However, recent studies cast doubt on this concept as exposure to Toxoplasma has been associated with a range of acute and chronic symptoms. Of particular note has been the finding of an increased rate of a range of neurological and psychiatric disorders associated with serological evidence of Toxoplasma exposure. A role of Toxoplasma infection in brain diseases is also supported by the consistent finding of altered cognition and behavior in animal models of infections. Much of the attention relating to the role of Toxoplasma infection in neuropsychiatric disorders has focused on the brain, where Toxoplasma tissue cysts can persist for extended periods of time. However, recent discoveries relating to the role of the gastrointestinal tract in cognition and behavior suggest that Toxoplasma may also increase susceptibility to human brain diseases through immune activation, particularly involving the gastrointestinal mucosa. The study of the pathways relating to the pathobiology and immunology of Toxoplasma infection may provide insights into the pathogenesis of a range of human neuropsychiatric disorders as well as into cognitive functioning in otherwise healthy individuals.

Keywords: Cognitive functioning; Gut–blood barrier; Intestinal inflammation; Parasitic infections; Psychiatric disorders; Schizophrenia; Toxoplasma.

Figure 1. Life Cycle of Toxoplasma gondii

The only known definitive hosts for Toxoplasma gondii are members of family Felidae (domestic cats and their relatives). Unsporulated oocysts are shed in the cat’s feces . Although oocysts are usually only shed for 1–2 weeks, large numbers may be shed especially in kittens of your cats undergoing their first infection. Oocysts take 1–5 days to sporulate in the environment and become infective. Intermediate hosts in nature (including birds, rodents, and farm animals) become infected after ingesting soil, water or plant material contaminated with oocysts . Oocysts transform into tachyzoites shortly after ingestion. These tachyzoites localize in neural and muscle tissue and develop into tissue cyst bradyzoites . Cats become infected after consuming intermediate hosts harboring tissue cysts . Cats may also become infected directly by ingestion of sporulated oocysts although this is a less common form of infection. Animals bred for human consumption and wild game may also become infected with tissue cysts after ingestion of sporulated oocysts in the environment . Humans can become infected by any of several routes:eating undercooked meat of animals harboring tissue cysts consuming food or water contaminated with cat feces or by contaminated environmental samples such as fecal-contaminated soil or changing the litter box of a pet cat . More rarely humans can become infected through blood transfusion or organ transplantation transplacentally from mother to fetus . In the human host, the parasites form tissue cysts, most commonly in skeletal muscle, myocardium, brain, and eyes; these cysts may remain throughout the life of the host. Diagnosis is usually achieved by serology, although tissue cysts may be observed in stained biopsy specimens, particularly in immune compromised individuals . Diagnosis of congenital infections can be achieved by detecting T. gondii DNA in amniotic fluid using molecular methods such as PCR (Adapted From http://www.cdc.gov/parasites/toxoplasmosis/biology.html)

Figure 2

Immunofluorescent visualization of intracellular tachyzoites of T.gondii strain RH shown 26 hours after infection of human fibroblasts. The tachyzoites are reacted with rabbit antibody to the Toxoplasma p30 (SAG1) protein and then with anti-rabbit antibodies labelled with Alexa Fluor 594. Host cell nuclei are visualized using 4',6-diamidino-2-phenylindole (DAPI). The tachyzoites thus are stained red and the fibroblast nucleus (N) is stained blue. Tachyzoites typically replicate by endodyogeny. Thus a cluster of 2 tachyzoites( )is indicative of one cycle of replication, 4 tachyzoites of two cycles (4) and cluster of 8 tachyzoites (8) representing 3 cycles of replication. A single tachyzoite (1) represents one that has not yet undergone a cycle of replication (Figure courtesy of Claudia Bordón. Johns Hopkins School of Medicine)

Figure 3

A section of brain from chronically infected mice showing two T. gondii bradyzoite tissue cysts (green), at 400x magnification. Note that the tissue cyst on the left is younger than the one on the right because of the difference in cyst size.

Figure 4

Meta-Analysis of published studies describing associations between Toxoplasma exposure and Schizophrenia or Related Disorders. Red boxes indicate studies published before 2007 and summarized in Torrey et al, 2007. Blue boxes indicate studies published between 2007 and 2012 and summarized in Torrey et al, 2012. Yellow diamonds indicate pooled odds ratios. (Reprinted from Torrey et al (2012))