Toxoplasma gondii lacks the enzymes required for de novo arginine biosynthesis and arginine starvation triggers cyst formation

Fox, Barbara A.; Gigley, Jason P.; Bzik, David J.

doi:10.1016/j.ijpara.2003.12.001

Cited by 163 publications

(156 citation statements)

References 34 publications

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“…All strains that were used or developed in this study are listed in Table 1. Parasites were maintained by serial passage in diploid human foreskin fibroblasts (HFF) at 35°C (40). PFU assays were performed over 8 days (41) unless otherwise stated.…”

Section: Methodsmentioning

confidence: 99%

Nonreplicating, Cyst-Defective Type II Toxoplasma gondii Vaccine Strains Stimulate Protective Immunity against Acute and Chronic Infection

Fox

Bzik

2015

Infect Immun

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Live attenuated vaccine strains, such as type I nonreplicating uracil auxotroph mutants, are highly effective in eliciting lifelong immunity to virulent acute infection by Toxoplasma gondii. However, it is currently unknown whether vaccine-elicited immunity can provide protection against acute infection and also prevent chronic infection. To address this problem, we developed nonreverting, nonreplicating, live attenuated uracil auxotroph vaccine strains in the type II ⌬ku80 genetic background by targeting the deletion of the orotidine 5=-monophosphate decarboxylase (OMPDC) and uridine phosphorylase (UP) genes. Deletion of OMPDC induced a severe uracil auxotrophy with loss of replication, loss of virulence in mice, and loss of the ability to develop cysts and chronic infection. Vaccination of mice using type II ⌬ku80 ⌬ompdc mutants stimulated a fully protective CD8؉ T celldependent immunity that prevented acute infection by type I and type II strains of T. gondii, and this vaccination also severely reduced or prevented cyst formation after type II challenge infection. Nonreverting, nonreplicating, and non-cyst-forming ⌬ompdc mutants provide new tools to examine protective immune responses elicited by vaccination with a live attenuated type II vaccine.T oxoplasma gondii is an obligate intracellular parasite with an extremely broad host range inclusive of most birds and virtually all mammals (1). T. gondii chronically infects approximately one-third of the human population (2). Three major strain types are found in North America and Europe, and these type I, II, or III strains differ with respect to their virulence traits in mice (3). Type I strains are considered to be highly virulent, type II strains have low virulence, and type III strains are considered to be avirulent. Following acute infection by type II strains of T. gondii, a chronic infection is established. Chronic infection is characterized by slow-growing bradyzoite forms within tissue cysts in brain, muscle, and eye (4), and infection is considered to be lifelong (5, 6). Reactivated infection during AIDS or immune suppression may cause a severe and difficult to treat toxoplasmic encephalitis (7) or recurrent ocular toxoplasmosis (8). Vaccination against Toxoplasma is difficult due to the existence of multiple antigenically distinct strain types and multiple antigenically distinct developmental stages. Toxoplasma also can effectively escape immunity by the development of a chronic encysted stage that is not easily cleared by immune responses.Antigen-based vaccine formulations provide only a partially protective immunity and do not prevent the establishment of tissue cysts and chronic infection following exposure to T. gondii (9). Immunization with T. gondii extracts or killed noninvasive parasites also fails to elicit significant immunity to reinfection with T. gondii (10, 11). Suboptimal vaccine priming using antigen-based vaccine formulations is not surprising in view of the requirement for populations of CD8 ϩ and CD4 ϩ T cells that produce the inter...

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Section: Methodsmentioning

confidence: 99%

Nonreplicating, Cyst-Defective Type II Toxoplasma gondii Vaccine Strains Stimulate Protective Immunity against Acute and Chronic Infection

Fox

Bzik

2015

Infect Immun

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“…T. gondii is an auxotroph for tryptophan [19][20][21], arginine [22,23], polyamines [24], purines [25,26], cholesterol [27,28], iron [23,29], and other essential nutrients [30]. Although parasites surrounded by the PVM are protected against the acidification from the fusion of endocytic vesicle, this non-fusion state deprives parasites of an abundant source of nutrients from the host's endocytic and exocytic system.…”

Section: Subversion Of Host Organelles Cytoskeleton and Lysosomesmentioning

confidence: 99%

Host cell manipulation by the human pathogen Toxoplasma gondii

Laliberté

Carruthers

2008

Cell. Mol. Life Sci.

158

123

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Toxoplasma gondii is an obligate intracellular parasite that can infect virtually any nucleated cell. During cell invasion Toxoplasma creates a subcellular compartment termed the parasitophorous vacuole, which acts as an interface between the parasite and host cytoplasm, and in many cases serves as a platform for modulation of several host cell functions that support parasite replication and infection. Spatial reorganization of host organelles and the remodeling of the cytoskeleton around the parasitophorous vacuole are observed early following entry and recent evidence suggests this interior redecorating promotes nutrient acquisition by the parasite. New findings also reveal that T. gondii manipulates signaling pathways of the host cell by deploying parasite kinases and a phosphatase, including at least two that infiltrate the host nucleus. T. gondii infection additionally controls several cellular pathways to establish an anti-apoptotic environment in a variety of cell types, and to subvert immune cells as a conduit for dissemination. In this review we discuss these recent developments in understanding how T. gondii achieves widespread success as a human and animal parasite by manipulating its host.

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“…The vacuole membrane consists of parasite and host lipids and a subset of parasite proteins but is largely devoid of host cell proteins (57,80). The parasitophorous vacuole membrane (PVM) serves as a molecular sieve through which T. gondii scavenges host cell nutrients, including certain amino acids, nucleic acid precursors, and lipids, such as cholesterol (12,16,24,25,74). During invasion and creation of the PVM, apically oriented organelles (hence the term "apicomplexan" for this group of protozoa) called micronemes and rhoptries are discharged, followed later by release of dense granules (11,35).…”

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confidence: 99%

An Inside Job: Hacking into Janus Kinase/Signal Transducer and Activator of Transcription Signaling Cascades by the Intracellular Protozoan Toxoplasma gondii

Denkers

Bzik²,

Fox³

et al. 2012

Infect Immun

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The intracellular protozoan Toxoplasma gondii is well known for its skill at invading and living within host cells. New discoveries are now also revealing the astounding ability of the parasite to inject effector proteins into the cytoplasm to seize control of the host cell. This review summarizes recent advances in our understanding of one such secretory protein called ROP16. This molecule is released from rhoptries into the host cell during invasion. The ROP16 molecule acts as a kinase, directly activating both signal transducer and activator of transcription 3 (STAT3) and STAT6 signaling pathways. In macrophages, an important and preferential target cell of parasite infection, the injection of ROP16 has multiple consequences, including downregulation of proinflammatory cytokine signaling and macrophage deviation to an alternatively activated phenotype.

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Toxoplasma gondii lacks the enzymes required for de novo arginine biosynthesis and arginine starvation triggers cyst formation

Cited by 163 publications

References 34 publications

Nonreplicating, Cyst-Defective Type II Toxoplasma gondii Vaccine Strains Stimulate Protective Immunity against Acute and Chronic Infection

Nonreplicating, Cyst-Defective Type II Toxoplasma gondii Vaccine Strains Stimulate Protective Immunity against Acute and Chronic Infection

Host cell manipulation by the human pathogen Toxoplasma gondii

An Inside Job: Hacking into Janus Kinase/Signal Transducer and Activator of Transcription Signaling Cascades by the Intracellular Protozoan Toxoplasma gondii

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