Dissemination of Toxoplasma gondii to immunoprivileged organs and role of Toll/interleukin-1 receptor signalling for host resistance assessed by in vivo bioluminescence imaging

Hitziger, Niclas; Dellacasa, Isabel; Albiger, Barbara; Barragán, Antonio

doi:10.1111/j.1462-5822.2005.00517.x

Cited by 126 publications

(138 citation statements)

References 35 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: 65%

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: 65%

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

et al. 2008

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“…Tachyzoites were grown in vitro, mechanically lysed from host cells by passage through a 27-gauge needle, and washed twice with PBS supplemented with 1% FCS. Parasite numbers were determined by counting on a hemocytometer, and afterwards, injection of comparable numbers of viable parasites was verified by plaque assay and bioluminescence imaging (11,17). Two groups of six mice were infected with each of the five Toxoplasma strains, WT (A7), PUS1-shi, TBD8 comp , TBD8, and PUS1 KO.…”

Section: Methodsmentioning

confidence: 99%

A Pseudouridine Synthase Homologue Is Critical to Cellular Differentiation inToxoplasma gondii

et al. 2009

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Toxoplasma gondii is a haploid protozoan parasite infecting about one in seven people in the United States. Key to the worldwide prevalence of T. gondii is its ability to establish a lifelong, chronic infection by evading the immune system, and central to this is the developmental switch between the two asexual forms, tachyzoites and bradyzoites. A library of mutants defective in tachyzoite-to-bradyzoite differentiation (Tbd ؊ ) was created through insertional mutagenesis. This library contains mutants that, compared to the wild type, are between 20% and 74% as efficient at stage conversion. Two mutants, TBD5 and TBD8, with disruptions in a gene encoding a putative pseudouridine synthase, PUS1, were identified. The disruption in TBD8 is in the 5 end of the PUS1 gene and appears to produce a null allele with a 50% defect in differentiation. This is about the same switch efficiency as obtained with an engineered pus1 deletion mutant (⌬pus1). The insertion in TBD5 is within the PUS1 coding region, and this appears to result in a more extreme phenotype of only ϳ10% switch efficiency. Complementation of TBD8 with the genomic PUS1 allele restored wild-type differentiation efficiency. Infection of mice with pus1 mutant strains results in increased mortality during the acute phase and higher cyst burdens during the chronic infection, demonstrating an aberrant differentiation phenotype in vivo due to PUS1 disruption. Our results suggest a surprising and important role for RNA modification in this biological process.Toxoplasma gondii is an apicomplexan parasite that is unique in its wide host range and global presence. In humans, the prevalence rate ranges from 15% to 75%, depending on geographic region (26). This high prevalence is due, in part, to the ability of the parasite to efficiently initiate an infection using either of two developmental stages, each with its own mode of transmission. Chronic infection is also a result of the ability of Toxoplasma to successfully evade clearance by the host immune system. All of these phenomena are dependent on the complex but well-described developmental biology of this coccidian parasite.Toxoplasma disseminates within a host primarily through interconversion between two asexual stages, the tachyzoite and bradyzoite forms. One way that a new host can be infected is through ingestion of raw or undercooked tissue from an infected animal. Bradyzoite-containing cysts in the tissue break open due to the pepsin and acidic environment of the digestive tract, after which the bradyzoites within are released and invade through the intestinal epithelium. These bradyzoites quickly convert into tachyzoites, the rapidly dividing, diseasecausing form of the parasite, which spread throughout the infected individual. During parasite expansion, adaptive immunity is triggered; this efficiently clears the tachyzoites but not the encysted bradyzoites. This persistence of bradyzoites results in a chronic, lifelong infection that allows further dispersal of Toxoplasma. Thus, parasite differentiation r...

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“…Perhaps the best-described example of this interaction is in the gut, where Toxoplasma triggers the expression dendritic-cell-and monocyte-recruiting chemokines. While these cells are important for host resistance, the parasite also infects and uses them to disseminate in the host via a Trojan horse-like mechanism (95)(96)(97). In addition, early microarray studies demonstrated that a subset of the host genes modulated by infection were regulated as a result of secreted parasite-and/or host-derived factors being released into the culture medium following infection (45).…”

Section: Toxoplasma Modulation Of Uninfected Cells: Is the Parasite Smentioning

confidence: 99%

Toxoplasma gondii Development of Its Replicative Niche: in Its Host Cell and Beyond

Blader

Koshy

2014

Eukaryot Cell

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b Intracellular pathogens can replicate efficiently only after they manipulate and modify their host cells to create an environment conducive to replication. While diverse cellular pathways are targeted by different pathogens, metabolism, membrane and cytoskeletal architecture formation, and cell death are the three primary cellular processes that are modified by infections. Toxoplasma gondii is an obligate intracellular protozoan that infects ϳ30% of the world's population and causes severe and lifethreatening disease in developing fetuses, in immune-comprised patients, and in certain otherwise healthy individuals who are primarily found in South America. The high prevalence of Toxoplasma in humans is in large part a result of its ability to modulate these three host cell processes. Here, we highlight recent work defining the mechanisms by which Toxoplasma interacts with these processes. In addition, we hypothesize why some processes are modified not only in the infected host cell but also in neighboring uninfected cells.T oxoplasma gondii is a protozoan, obligate intracellular parasite that is considered one of the world's most successful pathogens (1). Multiple factors contribute to this success, including a complex life cycle in which the parasite can be transmitted by both vertical and horizontal means, efficient propagation within both its primary (felines) and intermediate hosts, extensive mechanisms to evade and disarm host immunity, an ability to form chronic lifelong infections in intermediate hosts, and a wide host tropism in which the parasite can infect most nucleated cells of warm-blooded animals (2). Central to most of these factors is that Toxoplasma has developed the means to replicate efficiently within the hostile intracellular environment of its host cell. In this review, we highlight recent data that have shed light on how parasite growth is achieved by the parasite interacting with its host cell to manipulate host signaling cascades, transcription, cell survival pathways, and membrane transport. In addition, we discuss how parasites interact with neighboring host cells and propose how this may contribute to establishing a permissive microenvironment to improve its overall success. In particular, we focus on those processes that are essential for the growth of all parasite strains and we refer readers to recent reviews that highlight how polymorphic parasite molecules contribute to Toxoplasma virulence (3-5). NUTRIENT ACQUISITIONAs an obligate intracellular parasite that resides within a nonfusogenic vacuole, Toxoplasma must satisfy its nutritional needs by scavenging essential nutrients from its host cell. These nutrients include carbon sources (glucose and glutamine) to fuel its energy demands, specific amino acids, lipids, and other nutrients. Below, we discuss each of these and highlight pathways and processes that are unique to the parasite that could serve as novel drug targets (Fig. 1). GLUCOSE AND GLUTAMINE POWER THE PARASITEToxoplasma expresses a full complement of glycolytic and tr...

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Dissemination of Toxoplasma gondii to immunoprivileged organs and role of Toll/interleukin-1 receptor signalling for host resistance assessed by in vivo bioluminescence imaging

Cited by 126 publications

References 35 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

A Pseudouridine Synthase Homologue Is Critical to Cellular Differentiation inToxoplasma gondii

Toxoplasma gondii Development of Its Replicative Niche: in Its Host Cell and Beyond

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