Localized recrudescence of Toxoplasma infections in the central nervous system of immunocompromised mice assessed by in vivo bioluminescence imaging

Dellacasa-Lindberg, Isabel; Hitziger, Niclas; Barragán, Antonio

doi:10.1016/j.micinf.2007.06.003

Cited by 68 publications

(73 citation statements)

References 30 publications

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“…Monitoring by BLI of mice infected with H3F33 revealed that during the first days postinfection, R-Luc photon emission was localized mainly in the abdomen. This pattern is similar to that previously observed when mice were infected with tachyzoites expressing firefly luciferase (8,10,20,36). Autopsies carried out shortly after BLI analysis revealed that the signal was localized to the adipose tissue surrounding the ab- dominal organs.…”

Section: Discussionsupporting

confidence: 87%

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

et al. 2008

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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...

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Section: Discussionsupporting

confidence: 87%

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

et al. 2008

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“…Tachyzoites from the T. gondii line CTGluc (type III) (8) and the green fluorescent protein (GFP)-expressing line PTG-GFPluc (type II) (13) were maintained by serial 2-day passaging in human foreskin fibroblast (HFF) monolayers. HFFs were propagated in Dulbecco's modified Eagle's medium (DMEM; Invitrogen) with 10% fetal bovine serum (FBS), gentamicin (20 g/ml; Gibco), glutamine (2 mM; Gibco), and HEPES (0.01 M; Gibco), referred to as complete medium (CM).…”

Section: Methodsmentioning

confidence: 99%

“…The Regional Animal Research Ethical Board approved all protocols involving animals. A reactivation model with immunosuppressed adult mice infected with the type III T. gondii strain CTGluc was described previously (8). Briefly, male BALB/c wild-type (wt) mice were infected intraperitoneally (i.p.)…”

Section: Methodsmentioning

confidence: 99%

“…IFN-␥R Ϫ/Ϫ mice were infected i.p. with 0.5 ϫ 10 3 CTGluc parasites and treated with sulfadiazine sodium salt (Sigma-Aldrich) ad libitum as previously described (8).…”

Section: Methodsmentioning

confidence: 99%

“…Brains were dissected, frozen in liquid nitrogen on O.C.T. compound (Tissue-Tek; Sakura), and prepared as previously described (8). Astrocytes were detected using a primary rat anti-glial fibrillary acidic protein antibody (anti-GFAP) (1:500; Zymed Laboratories) and secondary Alexa Fluor 594-conjugated chicken anti-rat IgG (1:400; Molecular Probes).…”

Section: Methodsmentioning

confidence: 99%

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Migratory Activation of Primary Cortical Microglia upon Infection with Toxoplasma gondii

et al. 2011

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Disseminated toxoplasmosis in the central nervous system (CNS) is often accompanied by a lethal outcome.Studies with murine models of infection have focused on the role of systemic immunity in control of toxoplasmic encephalitis, while knowledge remains limited on the contributions of resident cells with immune functions in the CNS. In this study, the role of glial cells was addressed in the setting of recrudescent Toxoplasma infection in mice. Activated astrocytes and microglia were observed in the close vicinity of foci with replicating parasites in situ in the brain parenchyma. Toxoplasma gondii tachyzoites were allowed to infect primary microglia and astrocytes in vitro. Microglia were permissive to parasite replication, and infected microglia readily transmigrated across transwell membranes and cell monolayers. Thus, infected microglia, but not astrocytes, exhibited a hypermotility phenotype reminiscent of that recently described for infected dendritic cells. In contrast to gamma interferon-activated microglia, Toxoplasma-infected microglia did not upregulate major histocompatibility complex (MHC) class II molecules and the costimulatory molecule CD86. Yet Toxoplasma-infected microglia and astrocytes exhibited increased sensitivity to T cell-mediated killing, leading to rapid parasite transfer to effector T cells in vitro. We hypothesize that glial cells and T cells, besides their role in triggering antiparasite immunity, may also act as "Trojan horses," paradoxically facilitating dissemination of Toxoplasma within the CNS. To our knowledge, this constitutes the first report of migratory activation of a resident CNS cell by an intracellular parasite.

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Animal Models for Toxoplasma gondii Infection

Subauste

2012

CP in Immunology

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Toxoplasma gondii is a protozoan of worldwide distribution. This unit describes murine models of acute T. gondii infection, toxoplasmic encephalitis, and Toxoplasma retinochoroiditis. T. gondii infection in SCID mice allows the study of T cell-independent mechanisms of defense. The uracil auxotroph strain cps1-1 and temperature-sensitive mutant strains of T. gondii allow studies of immunization and adoptive transfer. In vivo study of parasite host-interaction is possible with the use of parasites that express fluorescent proteins and model antigens, plus the use of transgenic mice that express the appropriate T cell receptor and fluorescently labeled leukocytes. Parasites that express bioluminescent markers make it possible to study the dynamics of infection in real time using bioluminescence imaging. Support protocols present methodology for evaluation of progression of infection and immune response to the parasite, the maintenance of T. gondii tissue cysts and tachyzoites, as well as preparation of T. gondii lysate antigens.

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Localized recrudescence of Toxoplasma infections in the central nervous system of immunocompromised mice assessed by in vivo bioluminescence imaging

Cited by 68 publications

References 30 publications

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

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

Migratory Activation of Primary Cortical Microglia upon Infection with Toxoplasma gondii

Animal Models for Toxoplasma gondii Infection

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