Toxoplasma gondii

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Taxonomic lineage

cellular organisms - Eukaryota - Alveolata - Apicomplexa - Coccidia - Eucoccidiorida - Eimeriorina - Sarcocystidae - Toxoplasma - Toxoplasma gondii

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Brief facts

• Toxoplasma gondii is an obligate intracellular parasite classified in the phylum Apicomplexa, which includes numerous important human and animal pathogens such as Plasmodium species, Cryptosporidium species, Neospora caninum, etc. (click here for more examples).
• Toxoplasma gondii is capable of infecting a wide variety of mammals and birds. This single-celled protozoan organism might cause a disease known as toxoplasmosis and is arguably the most successful protozoan parasite on Earth. Between 15 and 85% of the world adult human population is chronically infected with Toxoplasma gondii depending on geographical location.
• The invasive stages of apicomplexans are characterized by the presence of an apical complex composed of specialized cytoskeletal and secretory organelles: micronemes (involved in attachement and penetration), rhoptries (required for creation of a transient structure, moving junction, and the establishment of parasitophorous vacuole (PV)), and dense granules (secrete proteins throughout most of parasite stages). Parasitophorous vacuole (PV) is a unique compartment delimited from the host cell cytoplasm by PV membrane (PVM), which prevents T. gondii degradation by the host cell endocytic machinery and enables parasite intracellular propagation.
• Cats (Felis catus, domestic cat at GeoChemBio: taxonomy, brief facts, digestive system, development) are primary hosts of Toxoplasma gondii. About sexual cycle of the parasite and its distribution by cats' feces please see section Developmental stages below.
• Toxoplasmosis is a potentially fatal disease of the developing human fetus and immunocompromised (e.g., AIDS and transplant) patients and can cause severe ocular disease in otherwise healthy individuals.
• Most infections remain asymptomatic and treatment is not prescribed, however, toxoplasmosis is strongly linked with development of psychosis, depression, and anxiety disorders, reckless behavior and impulsivity in youth. Unfortunately, all above mentioned disorders are quite common and their etiology often is not explored fully.
• Experiments on rats and mice, natural prey of cats, had shown that infected rats and mice exhibit hyperactivity, fearlessness toward cat urine ordor, and novelty seeking behavior - types of conduct that most likely make them victims of cat predation. It is speculated that the pathogen targets brain of an intermediate host to increase its exposure and vulnerability to its natural predators. Although some hosts, such as humans, cannot be considered to become a prey of a cat, it can be postulated that all hosts can be affected by similar pathways.
• A functional immune system of the host suppresses T. gondii and makes it to encyst in various tissues including brain. Therefore, healthy host is a key condition for persistence of T. gondii. In an immunodeficient host, tachyzoite growth causes tissue damage, and persistent infection is not established. Furthermore, when healthy but chronically infected host becomes immunocompromized, bradyzoites transform into tachyzoites, causing cerebral injuries. There is no available drug that can reach the parasite encysted in the brain tissue.
• According to most recent studies, it seems that these pathogens can secrete protein kinases into host cells to subvert host-cell signalling pathways and that this explains many of the differences in virulence among the three dominant clonal lineages.
• Recent population genetic studies have identified a remarkably limited number of Toxoplasma gondii genotypes in nature, the vast majority of which fall into one of only three distinct lineages. They can be associated with different types of toxoplasmosis as a disease (ocular, brain, muscle, necrosis, etc.).
• Genetic analysis of strains indicates that Toxoplasma gondii sexual recombination between different strains of the parasite is very rare in natural populations of the host (felines).

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Infection pathways

• from mother to fetus during pregnancy
• inhaling oocysts (from litter boxes of domestic cats, from soil)
• contamination of hands with feline feces while gardening, playing in sandboxes, etc.
• ingestion of toxoplasma cysts contained in contaminated undercooked meat

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Predominant genotypes of T. gondii

• Type I is highly virulent in mice and, perhaps, in human.
• Type II predominates in infections of immunocompromised patients; relatively avirulent in mouse. Type II strains are most often associated with human toxoplasmosis, especially in Europe.
• Type III is not highly virulent in mouse, and causes chronic infections in humans.

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Developmental stages

• Sexual This part of the life cycle takes place only in members of the Felidae family (domestic and wild cats), after ingestion of flesh of infected animal (any warm-blooded animal including birds).
  • Enteroepithelial
    stage After ingestion of tissue cysts, the parasites invade the cat enterocytes, undergo several rounds of division and differentiate into microgametocytes and macrogametocytes.
    • Division Proliferation of the parasites in the cat enterocytes.
    • Differentiation Parasites differentiate into sexual structures, microgametocytes and macrogametocytes.
    • Zygote The gametocytes fuse to form a zygote or oocyst that is shed into the environment with the cat feces.
  • Fecal stage
    • Meiosis The oocyst undergoes meiosis, producing an octet of highly infectious sporozoites that are resistant to environmental damage and may persist for years in a moist environment.
• Asexual Asexual reproduction begins after ingestion of the cat feces by a secondary host such as a mouse.
• Acute infection
  stage Sporozoites differentiate into the rapidly dividing tachyzoite form, which establishes and sustains the acute infection.
• Chronic infection
  stage A chronic phase of the disease ensues, as the tachyzoite changes into a slowly dividing form known as the bradyzoite.
• Resting stage Latent bradyzoite tissue cysts persist for the life of the host mainly within the muscles and brain. The cysts are very difficult to eradicate entirely because they rest inside the host cells.

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Tissues

• Cyst A small thick-walled sac that encloses dormant bradyzoites; usually resides in muscle or brain tissues (resting stage). stage
• Oocyst Zygote produced by gametocytes fusion. Mature oocyst consists of wall surrounding two sporocysts, each of which is comprised of a sporocyst wall surrounding four sporozoites (fecal stage)
• Unsporulated oocyst
• Sporulated oocyst Mature oocyst containing sporozoites.
• Sporozoite Highly infectious form of T. gondii produced by meiosis of the oocyst; resistant to environmental damage and may persist for years in a moist environment.
• Tachyzoite Sporozoites differentiate into tachyzoites - motile haploid, asexually reproducing form of the parasite - that establish and sustain the acute infection; upon host cell penetration tachyzoites form the parasitophorous vacuole (PV). PV membrane (PVM) surrounds dividing parasites and protects them from acidification by host's endocytic vesicles; T. gondii presents three organelles that are involved in host's cells invasion, formation of PV, nutrient acquisition, and, above all, subversion of host's defenses, including suppression of apoptosis: microneme proteins (MICs), rhoptry proteins (ROPs), and dense granules.
• Bradyzoite A slowly dividing form of the parasites; latent bradyzoite tissue cysts persist for the life of the host, re-emerging occasionally, thus sustaining chronic infection.

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Appendix 1: Neurological and behavioral abnormalities in mice due to chronic toxoplasmosis

Hermes G, Ajioka JW, Kelly KA, Mui E, Roberts F, Kasza K, Mayr T, Kirisits MJ, Wollmann R, Ferguson DJ, Roberts CW, Hwang JH, Trendler T, Kennan RP, Suzuki Y, Reardon C, Hickey WF, Chen L, McLeod R.
Neurological and behavioral abnormalities, ventricular dilatation, altered cellular functions, inflammation, and neuronal injury in brains of mice due to common, persistent, parasitic infection. J Neuroinflammation. 2008 Oct 23;5:48.

Appearance of eleven-month-old Specific Pathogen Free (SPF) mice that are uninfected and chronically infected with T. gondii.
(A) Eleven month old uninfected Swiss Webster mouse.
(B) Eleven month old infected female mouse from the same SPF colony ten months after acquisition of T. gondii infection. Note hunched body position, poor grooming, piloerection, reduced body mass, and tail wounding.
(C) Chronically infected SPF mouse with abnormal body position.

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References

Articles

• Striepen B, Jordan CN, Reiff S, van Dooren GG. Building the perfect parasite: cell division in apicomplexa. PLoS Pathog. 2007 Jun;3(6):e78.

  

  Apicomplexa Are Intracellular Parasites (A) Highly simplified apicomplexan life cycle. Apicomplexans are haplonts, and meiosis (sporogony) immediately follows fertilization. Fertilization might occur within a host cell or extracellularly, giving rise to an oocyst or, less frequently, an invasive stage zygote (ookinete).
  (B) Schematic representation of a zoite (not all structures are present in all apicomplexans). AP, apicoplast; AR, apical rings; CC, centrocone; CE, centrosome; CO, conoid; DG, dense granule; ER, endoplasmic reticulum; G, Golgi; IMC, inner membrane complex; MI, mitochondrion; MN, microneme; MT, subpellicular microtubule; NU, nucleus; RH, rhoptry.
  (C) Zoites actively invade the cells of their hosts, establishing a specialized parasitophorous vacuole (PV) (in some species the parasite lyses the vacuole and develops freely in the cytoplasm).
  

• Saeij JP et al. Polymorphic secreted kinases are key virulence factors in toxoplasmosis. Science. 2006 Dec 15;314(5806):1780-3. PMID: 17170306
• Sibley LD, Boothroyd JC. Virulent strains of Toxoplasma gondii comprise a single clonal lineage. Nature. 1992 Sep 3;359(6390):82-5. PMID: 1355855
• Laliberté J. and Carruthers VB. Host cell manipulation by the human pathogen Toxoplasma gondii. Cell Mol Life Sci. 2008 Jun;65(12):1900-15. PMID: 18327664
• Yolken RH, Torrey EF. Are some cases of psychosis caused by microbial agents? A review of the evidence. Mol Psychiatry. 2008 May;13(5):470-9. Epub 2008 Feb 12. PMID: 18268502
• Webster JP. The effect of Toxoplasma gondii on animal behavior: playing cat and mouse. Schizophr Bull. 2007 May;33(3):752-6. Epub 2007 Jan 11. PMID: 17218613
• Lafferty KD. Look what the cat dragged in: do parasites contribute to human cultural diversity? Behav Processes. 2005 Mar 31 PMID: 15792708
• Dlugonska H. Toxoplasma rhoptries: unique secretory organelles and source of promising vaccine proteins for immunoprevention of toxoplasmosis. J Biomed Biotechnol. 2008;2008:632424. PMID: 18670609

Websites

• James W. Ajioka, Jennifer M. Fitzpatrick and Christopher P. Reitter (2001) Toxoplasma gondii genomics: shedding light on pathogenesis and chemotherapy.

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