Rapid invasion of host cells by Toxoplasma requires secretion of the MIC2-M2AP adhesive protein complex

Huynh, My Hang

doi:10.1093/emboj/cdg217

Cited by 221 publications

(254 citation statements)

References 43 publications

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“…We hypothesize that this increase in attachment strength is due to high affinity binding following the burst of microneme secretion releasing high levels of adhesins (MICs) onto the parasite surface (Huynh et al, 2003, Huynh & Carruthers, 2006.…”

Section: Mathematical Modelingmentioning

confidence: 99%

Kinetic modeling of Toxoplasma gondii invasion

Kafsack

Carruthers

Pineda

2007

Journal of Theoretical Biology

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The phylum Apicomplexa includes parasites responsible for global scourges such as malaria, cryptosporidiosis, and toxoplasmosis. Parasites in this phylum reproduce inside the cells of their hosts, making invasion of host cells an essential step of their life cycle. Characterizing the stages of host-cell invasion, has traditionally involved tedious microscopic observations of individual parasites over time. As an alternative, we introduce the use of compartment models for interpreting data collected from snapshots of synchronized populations of invading parasites. Parameters of the model are estimated via a maximum negative log-likelihood principle. Estimated parameter values and their 95% confidence intervals (95% CI), are consistent with reported observations of individual parasites. For RH-strain parasites, our model yields that: 1) penetration of the host cell plasma membrane takes 26 sec (95% CI: 22-30 sec), 2) parasites that ultimately invade, remained attached 3 times longer than parasites that eventually detach from the host cells, and 3) 25% (95% CI: 19-33%) of parasites invade while 75% (95% CI: 67-81%) eventually detach from their host cells without progressing to invasion. A key feature of the model is the incorporation of invastion stages that cannot be directly observed. This allows us to characterize the phenomenon, of parasite detachment from host cells. The properties of this phenomenon would be difficult to quantify without a mathematical model. We conclude that mathematical modeling provides a powerful new tool for characterizing the stages of host-cell invasion by intracellular parasites.

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Section: Mathematical Modelingmentioning

confidence: 99%

Kinetic modeling of Toxoplasma gondii invasion

Kafsack

Carruthers

Pineda

2007

Journal of Theoretical Biology

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“…In T. gondii, the TRAP homolog TgMIC2 forms a macromolecular hexamer complex with MIC2-associated protein (M2AP) [61]. Disruption of the gene encoding TgM2AP provided indirect evidence that TgMIC2 is crucial for host cell invasion [62]. The short cytoplasmic domains of TgMIC2 and TRAP are implicated in protein trafficking using a tyrosine-based motif [63,64].…”

Section: Trapmentioning

confidence: 99%

Molecular and functional aspects of parasite invasion

Soldati

Foth

Cowman

2004

Trends in Parasitology

109

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Apicomplexan parasites have evolved an efficient mechanism to gain entry into non-phagocytic cells, hence challenging their hosts by the establishment of infection in immuno-privileged tissues. Gliding motility is a prerequisite for the invasive stage of most apicomplexans, allowing them to migrate across tissues, and actively invade and egress host cells. In the late 1960s, detailed morphological studies revealed that motile apicomplexans share an elaborate architecture comprising a subpellicular cytoskeleton and apical organelles. Since 1993, the development of technologies for transient and stable transfection have provided powerful tools with which to identify gene products associated with these structures and organelles, as well as to understand their functions. In combination with access to several parasite genomes, it is now possible to compare and contrast the strategies and molecular machines that have been selectively designed by distinct life stages within a species, or by different apicomplexan species, to optimize infection

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“…Micronemes discharge diverse adhesive proteins that bind to host cells (reviewed in Carruthers, 2002;Dowse and Soldati, 2004) and redistribute towards the posterior pole of the parasite during invasion (Carruthers et al, 1999). Among these microneme proteins, the members of the thrombospondinrelated anonymous protein (TRAP) family, including TgMIC2 in T. gondii, are known to play an essential role in host cell invasion (Sultan et al, 1997;Yuda et al, 1999;Templeton et al, 2000;Huynh et al, 2003). In T. gondii, microneme proteins form complexes, such as TgMIC1/ MIC4/MIC6, TgMIC3/MIC8 and TgMIC2/M2AP Carruthers, 2002;Dowse and Soldati, 2004), which are composed of a transmembrane escorter protein (TgMIC6, TgMIC8 or TgMIC2) essential for the correct targeting of the complex to the micronemes, and soluble proteins, some of which exhibit host cell binding properties (TgMIC1, TgMIC4 and TgMIC3) (Fourmaux et al, 1996;Garcia-Reguet et al, 2000;Brecht et al, 2001).…”

Section: Introductionmentioning

confidence: 99%

Apicomplexan rhomboids have a potential role in microneme protein cleavage during host cell invasion

Dowse

Pascall

Brown

et al. 2005

International Journal for Parasitology

112

130

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Apicomplexan parasites secrete transmembrane (TM) adhesive proteins as part of the process leading to host cell attachment and invasion. These microneme proteins are cleaved in their TM domains by an unidentified protease termed microneme protein protease 1 (MPP1). The cleavage site sequence (IAYGG), mapped in the Toxoplasma gondii microneme proteins TgMIC2 and TgMIC6, is conserved in microneme proteins of other apicomplexans including Plasmodium species. We report here the characterisation of novel T. gondii proteins belonging to the rhomboid family of intramembrane-cleaving serine proteases. T. gondii possesses six genes encoding rhomboid-like proteins. Four are localised along the secretory pathway and therefore constitute possible candidates for MPP1 activity. Toxoplasma rhomboids TgROM1, TgROM2 and TgROM5 cleave the TM domain of Drosophila Spitz, an established substrate for rhomboids from several species, demonstrating that they are active proteases. In addition, TgROM2 cleaves chimeric proteins that contain the TM domains of TgMIC2 and TgMIC12. q

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Rapid invasion of host cells by Toxoplasma requires secretion of the MIC2-M2AP adhesive protein complex

Cited by 221 publications

References 43 publications

Kinetic modeling of Toxoplasma gondii invasion

Kinetic modeling of Toxoplasma gondii invasion

Molecular and functional aspects of parasite invasion

Apicomplexan rhomboids have a potential role in microneme protein cleavage during host cell invasion

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