Temporal and Spatial Distribution of Toxoplasma gondii Differentiation into Bradyzoites and Tissue Cyst Formation In Vivo

Abstract

During Toxoplasma gondii infection, a fraction of the multiplying parasites, the tachyzoites, converts into bradyzoites, a dormant stage, which form tissue cysts localized mainly in brain, heart, and skeletal muscles that persist for several years after infection. At this stage the parasite is protected from the immune system, and it is believed to be inaccessible to drugs. While the long persistence of tissue cysts does not represent a medical problem for healthy individuals, this condition represents a major risk for patients with a compromised immune system, who can develop recrudescent life-threatening T. gondii infections. We have investigated for the first time the dynamics and the kinetics of tachyzoite-to-bradyzoite interconversion and cyst formation in vivo by using stage-specific bioluminescent parasites in a mouse model. Our findings provide a new framework for understanding the process of bradyzoite differentiation in vivo. We have also demonstrated that complex molecules such as D-luciferin have access to tissue cysts and are metabolically processed, thus providing a rationale for developing drugs that attack the parasite at this developmental stage.Toxoplasma gondii is transmitted to humans by the ingestion of either undercooked meat containing tissue cysts or poorly washed vegetables contaminated with oocysts from cat feces. The infection normally progresses as a mild, self-resolving disease. Initially T. gondii multiplies rapidly inside cells of different tissues and organs in the form of tachyzoites. Within 2 to 3 weeks, infected individuals develop a potent immune response that effectively controls the growth of the parasite. Before being eliminated by the immune system, some of the tachyzoites develop into a dormant stage, the bradyzoites, which multiply at a much lower rate than tachyzoites and become progressively enclosed in a dense matrix surrounded by a thick wall, the tissue cyst (11,33,46). At this stage the parasite is much less vulnerable to attack by the immune system. Tissue cysts can persist for several years in the brain, the heart, and the skeletal muscle of individuals who had been previously infected with T. gondii (34,46,49). Tissue cysts do not cause major pathological damage, and parasites are eventually released as result of stochastic reactivation of the bradyzoites (14) yet are promptly eliminated by the immune system. Therefore, in healthy individuals the persistence of T. gondii cysts in tissues and organs does not represent a cause for concern. However, several conditions may appear later in life that impair the function of the immune system and its ability to control the reactivation of T. gondii tissue cysts. These include infectious diseases such as human immunodeficiency virus infection (28-30) and treatment with immunosuppressive and chemotherapeutic agents commonly given to transplant and cancer patients, respectively (3,18,22,27,32,45). Reactivation of tissue cysts in these individuals leads to the recrudescence of T. gondii infection (15), a life-threatening co...

Toxoplasma gondii infection and behaviour – location, location, location?

“…Indeed, a study that assessed the tissue cyst density systematically in brain regions found an increased cyst density in the amygdalar regions based on haematoxylin and eosin staining (Vyas et al, 2007); although, in this study, T. gondii tissue cysts were found in most brain regions and observations in our laboratory and others have found cysts in numerous brain regions in infected mice. Bioluminescent imaging of T. gondii that express luciferase under the control of a bradyzoite-specific gene promoter found the principal luminescence to be in the cerebral cortex, colliculi, cerebellum and olfactory bulbs (Di Cristina et al, 2008). McLeod and colleagues (Hermes et al, 2008) used a similar approach to Vyas and colleagues (Vyas et al, 2007), but did not specifically focus on the amygdala, and found increased cyst numbers in both the cortex and the diencephalon, the region containing the thalamus (Hermes et al, 2008).…”

Deneysel Kronik Toksoplazmoz Fare Modeli: Beyin Lezyonlarının Davranış Değişiklikleri ile İlişkilendirilmesi

“…Doku kistlerinin beyindeki spesifik ve seçici lokalizasyonu, davranış manipülasyonuna sebep olabilecek potansiyel mekanizmalar içinde direkt etkiler arasında sayılmaktadır (28). Bulbus olfaktoryus, amigdala, nükleus akümbens, serebral korteks, beyincik, medulla oblongata, bazal gangliyon, hippokampus çevresi gibi bölgelerin etken tarafından daha sıklıkla tercih edildiği önceki çalışmalarda ortaya konmuştur (8,24,29). Bu çalışmada, doku kistleri ve lezyon şiddeti özellikle ammon boynuzu, perihipokampal bölge ve amigdaloid komplekste daha yüksek oranda gözlenmiştir.…”

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“…The parasite tissue burden was measured by quantitative PCR. Infection with RH strain parasites develops rapidly and is typically fatal on approximately day 8 postinoculation, which is prior to the initiation of the chronic phase of infection (days 10 to 12 for cystogenic strains [15]). As shown in Fig.…”