Suicide prevention: disruption of apoptotic pathways by protozoan parasites

Carmen, John C.; Sinai, Anthony P.

doi:10.1111/j.1365-2958.2007.05714.x

Cited by 79 publications

(75 citation statements)

References 119 publications

(213 reference statements)

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“…Toxoplasma has been observed to subvert host response by dysregulation of apoptosis (48) and IFN-␥-induced STAT1 activation (49) as well as inhibition of dendritic cell maturation (50). All of these host responses have been shown to be influenced by STAT6 activation (17,24,51).…”

Section: Discussionmentioning

confidence: 99%

Toxoplasma Rhoptry Protein 16 (ROP16) Subverts Host Function by Direct Tyrosine Phosphorylation of STAT6

Ong

Reese

Boothroyd

2010

Journal of Biological Chemistry

200

179

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The obligate intracellular parasite, Toxoplasma gondii, modulates host immunity in a variety of highly specific ways. Previous work revealed a polymorphic, injected parasite factor, ROP16, to be a key virulence determinant and regulator of host cell transcription. These properties were shown to be partially mediated by dysregulation of the host transcription factors STAT3 and STAT6, but the molecular mechanisms underlying this phenotype were unclear. Here, we use a Type I Toxoplasma strain deficient in ROP16 to show that ROP16 induces not only sustained activation but also an extremely rapid (within 1 min) initial activation of STAT6. Using recombinant wild-type and kinase-deficient ROP16, we demonstrate in vitro that ROP16 has intrinsic tyrosine kinase activity and is capable of directly phosphorylating the key tyrosine residue for STAT6 activation, Tyr 641 . Furthermore, ROP16 co-immunoprecipitates with STAT6 from infected cells. Taken together, these data strongly suggest that STAT6 is a direct substrate for ROP16 in vivo.Toxoplasma gondii, a ubiquitous, intracellular parasite of the phylum Apicomplexa, infects an estimated one-third of the human population as well as a broad range of warm-blooded animals. Infection is typically asymptomatic and chronic; however, severe and even fatal disease can result from acute infections of congenitally infected or immunocompromised hosts. Strikingly, Toxoplasma-induced inflammatory pathology in adult immunocompetent patients has also been reported (1, 2).Understanding the host/parasite interactions that underpin these various disease manifestations has become an area of active investigation, and recent work has implicated as key players a set of polymorphic proteins that are secreted from the apical organelles known as rhoptries (3). One of these, a putative serine-threonine kinase known as ROP16, was revealed as a parasite factor responsible for many changes in host gene expression (4). Much of the effect of ROP16 on transcription was found to depend on sustained activation of STAT3 and STAT6, two host transcription factors that can negatively regulate Th1 inflammatory responses. ROP16 is thus poised to mediate the inflammatory status of the host, an intriguing role for a parasite effector because Th1-driven immunopathology, not just uncontrolled parasite growth and dissemination, has been proposed to be a significant contributor to the disease outcome (5).Although the potential significance of the ROP16 effect on STATs is clear, the molecular mechanism by which it accomplishes this sustained activation was not apparent from the initial studies. STAT activation requires phosphorylation at specific, conserved tyrosine residues; this phosphorylation, which induces dimerization and nuclear translocation of the STATs, is canonically initiated and maintained in the cytosol by either receptorassociated tyrosine kinases (such as the JAKs) or non-receptor tyrosine kinases (e.g. Src family kinases) (6). The duration of STAT activation is usually limited by negative feedback beca...

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Section: Discussionmentioning

confidence: 99%

Toxoplasma Rhoptry Protein 16 (ROP16) Subverts Host Function by Direct Tyrosine Phosphorylation of STAT6

Ong

Reese

Boothroyd

2010

Journal of Biological Chemistry

200

179

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“…As mentioned above, one such function (highly conserved in metazoans) is as a host response to infection (Fang 2004;Carmen and Sinai 2007;Wang and Ruby 2011).…”

Section: Towards a Cellular Basis For Differential Coral Bleachingmentioning

confidence: 99%

“…Apoptosis is a highly conserved mechanism of programmed cell death (Kerr et al 1972) that is regulated by caspase enzymes (Lasi et al 2010). It is an important mechanism of symbiont loss during coral bleaching (Dunn et al 2004;Weis 2008;Pernice et al 2011) and is also a pathogen-removal strategy in metazoans (Carmen and Sinai 2007). The modification of apoptotic pathways has already been proposed as a mechanism for differential host cell survival post-bleaching (Tchernov et al 2011), and the anemone A. pallida generates NO to differing degrees during heat stress depending on the dominant in hospite symbiont genotype (Perez 2007).…”

Section: Communicated By Biology Editor Dr Anastazia Banaszakmentioning

confidence: 99%

Differential nitric oxide synthesis and host apoptotic events correlate with bleaching susceptibility in reef corals

et al. 2014

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Coral bleaching poses a threat to coral reefs worldwide. As a consequence of the temperature-induced breakdown in coral-dinoflagellate symbiosis, bleaching can have extensive effects on reef communities. However, our understanding of bleaching at a cellular level is limited, and this is particularly true regarding differential susceptibility among coral species. Recent work suggests that bleaching may represent a host innate immune-like response to symbiont dysfunction that involves synthesis of the signalling compound nitric oxide (NO) and the induction of host apoptotic-like cell death. In this study, we examined the activity of apoptosis-regulating enzymes alongside oxidised NO accumulation (a proxy for NO synthesis) in the reef corals Acropora millepora, Montipora digitata, and Pocillopora damicornis during experimental thermal stress. P. damicornis was the most sensitive species, suffering mortality (tissue sloughing) after 5 days at 33°C but non-lethal bleaching after 9 days at 31.5°C. A. millepora bleached at 33°C but remained structurally intact, while M. digitata showed little evidence of bleaching. P. damicornis and A. millepora both exhibited evidence of temperature-induced NO synthesis and, after 5 days of heating, levels of oxidised NO in both species were fivefold higher than in controls maintained at 28.5°C. These responses preceded bleaching by a number of days and may have occurred before symbiont dysfunction (measured as chlorophyll a degradation and oxidised NO accumulation). In A. millepora, apparent NO synthesis correlated with the induction of host apoptotic-like pathways, while in P. damicornis, the upregulation of apoptotic pathways occurred later. No evidence of elevated NO production or apoptosis was observed in M. digitata at 33°C and baseline activity of apoptosis-regulating enzymes was negligible in this species. These findings provide important physiological data in the context of the responses of corals to global change and suggest that early events in the host may be important in the collapse of the coral-dinoflagellate symbiosis.

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“…Toxoplasma-infected cells are profoundly resistant to apoptosis along both the intrinsic mitochondrion-dependent pathway and the extrinsic death receptor pathway (11,12,32,33,66,67). Transcriptional data indicate that apoptosis-related genes activated by infection and regulated by NF-B play a critical role in the inhibition of apoptosis While it did not detect the modulation of Bcl2 family proteins (modulation is observed only at infection rates much higher than those used here [11]), our proteomic study revealed the modulation of 16 proteins implicated in apoptosis in the infected cell (indicated in Table 1).…”

Section: Vol 76 2008 Modulation Of the Host Cell Proteome By T Gonmentioning

confidence: 99%

Modulation of the Host Cell Proteome by the Intracellular Apicomplexan ParasiteToxoplasma gondii

et al. 2008

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To investigate how intracellular parasites manipulate their host cell environment at the molecular level, we undertook a quantitative proteomic study of cells following infection with the apicomplexan parasite Toxoplasma gondii. Using conventional two-dimensional electrophoresis, difference gel electrophoresis (DIGE), and mass spectrometry, we identified host proteins that were consistently modulated in expression following infection. We detected modification of protein expression in key metabolic pathways, including glycolysis, lipid and sterol metabolism, mitosis, apoptosis, and structural-protein expression, suggestive of global reprogramming of cell metabolism by the parasite. Many of the differentially expressed proteins had not been previously implicated in the response to the parasite, while others provide important corroborative protein evidence for previously proposed hypotheses of pathogen-cell interactions. Significantly, over one-third of all modulated proteins were mitochondrial, and this was further investigated by DIGE analysis of a mitochondrion-enriched preparation from infected cells. Comparison of our proteomic data with previous transcriptional studies suggested that a complex relationship exits between transcription and protein expression that may be partly explained by posttranslational modifications of proteins and revealed the importance of investigating protein changes when interpreting transcriptional data. To investigate this further, we used phosphatase treatment and DIGE to demonstrate changes in the phosphorylation states of several key proteins following infection. Overall, our findings indicate that the host cell proteome responds in a dramatic way to T. gondii invasion, in terms of both protein expression changes and protein modifications, and reveal a complex and intimate molecular relationship between host and parasite.The obligate intracellular protozoan Toxoplasma gondii has evolved an intimate relationship with its host that extends to the cellular and molecular levels (82, 83). The absolute requirement for invasion of an appropriate host cell in the replication of the parasite suggests that modification of host functions is central to pathogenesis. Intuitively, this subversion of the cell must be a complex process, since host cells are not inherently programmed to provide an environment conducive to pathogens. Host cells have evolved primary lines of defense as countermeasures to pathogen invasion, establishment, and replication. These include elaborate systems, such as the phagolysosomal fusion, reactive oxygen and nitrogen intermediates, the sequestration of nutrients, and even cell suicide (apoptosis), as defenses to limit pathogen growth. The implementation of these systems and the ability of successful pathogens to mitigate their effects are ultimately mediated by changes in both the levels and activities of key proteins. While some of these changes may be transcriptionally regulated and thus potentially revealed by microarray analysis, the true effectors are proteins,...

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Suicide prevention: disruption of apoptotic pathways by protozoan parasites

Cited by 79 publications

References 119 publications

Toxoplasma Rhoptry Protein 16 (ROP16) Subverts Host Function by Direct Tyrosine Phosphorylation of STAT6

Toxoplasma Rhoptry Protein 16 (ROP16) Subverts Host Function by Direct Tyrosine Phosphorylation of STAT6

Differential nitric oxide synthesis and host apoptotic events correlate with bleaching susceptibility in reef corals

Modulation of the Host Cell Proteome by the Intracellular Apicomplexan ParasiteToxoplasma gondii

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