Host Cell Invasion by Toxoplasma gondii Is Temporally Regulated by the Host Microtubule Cytoskeleton

Sweeney, Kristin R.; Morrissette, Naomi S.; LaChapelle, Stephanie; Blader, Ira J.

doi:10.1128/ec.00079-10

Cited by 57 publications

(63 citation statements)

References 41 publications

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“…The role of host microtubules recruited by either parasite needs to be clarified, but it is known that host microtubules are important for T. gondii (RH) intracellular development. These cytoskeletal elements are exploited by Toxoplasma to facilitate its invasion into a host cell (89): it has been proposed that host microtubules selectively concentrated on one side of the moving junction may help stabilize the site of parasite invasion. After invasion, the PV is positioned at the center of the microtubular network in the host perinuclear region and remains surrounded by host microtubules throughout infection (32,57).…”

Section: Discussionmentioning

confidence: 99%

Neospora caninum Recruits Host Cell Structures to Its Parasitophorous Vacuole and Salvages Lipids from Organelles

et al. 2015

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Toxoplasma gondii and Neospora caninum, which cause the diseases toxoplasmosis and neosporosis, respectively, are two closely related apicomplexan parasites. They have similar heteroxenous life cycles and conserved genomes and share many metabolic features. Despite these similarities, T. gondii and N. caninum differ in their transmission strategies and zoonotic potential. Comparative analyses of the two parasites are important to identify the unique biological features that underlie the basis of host preference and pathogenicity. T. gondii and N. caninum are obligate intravacuolar parasites; in contrast to T. gondii, events that occur during N. caninum infection remain largely uncharacterized. We examined the capability of N. caninum (Liverpool isolate) to interact with host organelles and scavenge nutrients in comparison to that of T. gondii (RH strain). N. caninum reorganizes the host microtubular cytoskeleton and attracts endoplasmic reticulum (ER), mitochondria, lysosomes, multivesicular bodies, and Golgi vesicles to its vacuole though with some notable differences from T. gondii. For example, the host ER gathers around the N. caninum parasitophorous vacuole (PV) but does not physically associate with the vacuolar membrane; the host Golgi apparatus surrounds the N. caninum PV but does not fragment into ministacks. N. caninum relies on plasma lipoproteins and scavenges cholesterol from NPC1-containing endocytic organelles. This parasite salvages sphingolipids from host Golgi Rab14 vesicles that it sequesters into its vacuole. Our data highlight a remarkable degree of conservation in the intracellular infection program of N. caninum and T. gondii. The minor differences between the two parasites related to the recruitment and rearrangement of host organelles around their vacuoles likely reflect divergent evolutionary paths.

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Section: Discussionmentioning

confidence: 99%

Neospora caninum Recruits Host Cell Structures to Its Parasitophorous Vacuole and Salvages Lipids from Organelles

et al. 2015

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“…Fifty vacuoles were counted for each time point. Synchronized parasite invasion assays were performed with GFP ϩ parasites using a high potassium buffer as described (49). Sixty minutes after adding invasion buffer, the cells were fixed by adding formaldehyde (final concentration, 3%) directly to the wells.…”

Section: Methodsmentioning

confidence: 99%

Toxoplasma gondii Activates Hypoxia-inducible Factor (HIF) by Stabilizing the HIF-1α Subunit via Type I Activin-like Receptor Kinase Receptor Signaling

Wiley

Sweeney

Chan

et al. 2010

Journal of Biological Chemistry

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Toxoplasma gondii is an intracellular protozoan parasite that can cause devastating disease in fetuses and immune-compromised individuals. We previously reported that the ␣ subunit of the host cell transcription factor, hypoxia-inducible factor-1 (HIF-1), is up-regulated by infection and necessary for Toxoplasma growth. Under basal conditions, HIF-1␣ is constitutively expressed but rapidly targeted for proteasomal degradation after two proline residues are hydroxylated by a family of prolyl hydroxylases (PHDs). The PHDs are ␣-ketoglutarate-dependent dioxygenases that have low K m values for oxygen, making them important cellular oxygen sensors. Thus, when oxygen levels decrease, HIF-1␣ is not hydroxylated, and HIF-1 is activated. How Toxoplasma activates HIF-1 under normoxic conditions remains unknown. Here, we report that Toxoplasma infection increases HIF-1␣ stability by preventing HIF-1␣ prolyl hydroxylation. Infection significantly decreases PHD2 abundance, which is the key prolyl hydroxylase for regulating HIF-1␣. The effects of Toxoplasma on HIF-1␣ abundance and prolyl hydroxylase activity require activin-like receptor kinase signaling. Finally, parasite growth is severely diminished when signaling from this family of receptors is inhibited. Together, these data indicate that PHD2 is a key host cell factor for T. gondii growth and represent a novel mechanism by which a microbial pathogen subverts host cell signaling and transcription to establish its replicative niche.Toxoplasma gondii is an obligate intracellular protozoan parasite that can cause devastating disease in immune-compromised people and fetuses (1, 2). The ability for the parasite to cause disease is directly linked to its replication inside a parasitophorous vacuole within its host cell. From this vacuole, parasites scavenge nutrients from its host cell while causing reorganization of host organelles and cytoskeletal elements, preventing host cell apoptosis, and altering host gene expression (3-5). Therefore, Toxoplasma has developed mechanisms to manipulate host cell processes that permit it to grow. Identifying the parasite factors that cause these changes and the specific host pathways modulated by these factors is critical for developing new drugs to treat and prevent Toxoplasma infections and disease.Previously, our laboratory demonstrated that Toxoplasma activates the host cell transcription factor hypoxia-inducible factor-1 (HIF-1) 3 (6). HIF-1 is activated by a parasite-derived, secreted factor independent of direct contact between the parasite and host cell. This is in contrast to other Toxoplasma factors that control host cell signaling by virtue of their secretion into the host cell cytoplasm (7-10). Significantly, HIF-1 is important for parasite growth at both normoxic and physiological O 2 levels but dispensable for host cell replication at either O 2 levels (6).HIF-1 is a heterodimer composed of ␣ and ␤ subunits and is the master regulator of the cellular response to decreased O 2 availability (11). Although both subunits are co...

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“…Besides actin microfilaments, which are most concentrated just beneath the cell membrane, another constituent of the host cell cytoskeleton has been suggested to be involved in an interaction with invading apicomplexan parasites: the microtubule network. Indeed, occasional association of host microtubules with Toxoplasma MJ has been described and an early stabilizing role for parasite entry has been proposed: integrity of the host microtubule cytoskeleton appears to render invasion by Toxoplasma tachyzoites more efficient (but is not essential for it) (Sweeney et al, 2010).…”

Section: Anchoring Of the Mj On The Host Cell's Sidementioning

confidence: 99%

The moving junction of apicomplexan parasites: a key structure for invasion

Besteiro¹,

Dubremetz

Lebrun

2011

Cellular Microbiology

267

214

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SummaryMost Apicomplexa are obligate intracellular parasites and many are important pathogens of human and domestic animals. For a successful cell invasion, they rely on their own motility and on a firm anchorage to their host cell, depending on the secretion of proteins and the establishment of a structure called the moving junction (MJ). The MJ moves from the apical to the posterior end of the parasite, leading to the internalization of the parasite into a parasitophorous vacuole. Based on recent data obtained in Plasmodium and Toxoplasma, an emerging model emphasizes a cooperative role of secreted parasitic proteins in building the MJ and driving this crucial invasive process. More precisely, the parasite exports the microneme protein AMA1 to its own surface and the rhoptry neck RON2 protein as a receptor inserted into the host cell together with other RON partners. Ongoing and future research will certainly help refining the model by characterizing the molecular organization within the MJ and its interactions with both host and parasite cytoskeleton for anchoring of the complex.

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Host Cell Invasion by Toxoplasma gondii Is Temporally Regulated by the Host Microtubule Cytoskeleton

Cited by 57 publications

References 41 publications

Neospora caninum Recruits Host Cell Structures to Its Parasitophorous Vacuole and Salvages Lipids from Organelles

Neospora caninum Recruits Host Cell Structures to Its Parasitophorous Vacuole and Salvages Lipids from Organelles

Toxoplasma gondii Activates Hypoxia-inducible Factor (HIF) by Stabilizing the HIF-1α Subunit via Type I Activin-like Receptor Kinase Receptor Signaling

The moving junction of apicomplexan parasites: a key structure for invasion

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