Gliding motility in apicomplexan parasites

Heintzelman, Matthew B.

doi:10.1016/j.semcdb.2015.09.020

Cited by 81 publications

(86 citation statements)

References 138 publications

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“…Most apicomplexans replicate exclusively within host cells but also require motile extracellular forms for active transmission between host cells (2). Egress, extracellular migration, and invasion require gliding motility in Toxoplasma gondii , a substrate-based form of motility that is unique to members of the phylum Apicomplexa (3). To initiate motility, microneme vesicles release membrane-spanning adhesins onto the parasite’s apical surface, where they can bind to extracellular substrates (e.g., host cells, matrix) (4).…”

Section: Introductionmentioning

confidence: 99%

Plasma Membrane Association by N-Acylation Governs PKG Function in Toxoplasma gondii

Brown

Long

Sibley

2017

mBio

174

239

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Cyclic GMP (cGMP)-dependent protein kinase (protein kinase G [PKG]) is essential for microneme secretion, motility, invasion, and egress in apicomplexan parasites, However, the separate roles of two isoforms of the kinase that are expressed by some apicomplexans remain uncertain. Despite having identical regulatory and catalytic domains, PKGI is plasma membrane associated whereas PKGII is cytosolic in Toxoplasma gondii. To determine whether these isoforms are functionally distinct or redundant, we developed an auxin-inducible degron (AID) tagging system for conditional protein depletion in T. gondii. By combining AID regulation with genome editing strategies, we determined that PKGI is necessary and fully sufficient for PKG-dependent cellular processes. Conversely, PKGII is functionally insufficient and dispensable in the presence of PKGI. The difference in functionality mapped to the first 15 residues of PKGI, containing a myristoylated Gly residue at position 2 that is critical for membrane association and PKG function. Collectively, we have identified a novel requirement for cGMP signaling at the plasma membrane and developed a new system for examining essential proteins in T. gondii.

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Section: Introductionmentioning

confidence: 99%

Plasma Membrane Association by N-Acylation Governs PKG Function in Toxoplasma gondii

Brown

Long

Sibley

2017

mBio

174

239

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“…During mosquito probing for a blood meal, sporozoites flow out with the saliva and are deposited in the skin of the mammalian host [30, 37–40]. Sporozoites, powered by an actomyosin system, move rapidly through the dermis using a form of locomotion referred to as gliding motility [30, 41, 42]. Sporozoites then associate with blood vessels and enter the blood stream whereby they passively drift before invading hepatocytes [29, 30, 43–45].…”

Section: Introductionmentioning

confidence: 99%

Screening for potential prophylactics targeting sporozoite motility through the skin

Douglas

Reinig

Neale

et al. 2018

Malar J

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BackgroundAnti-malarial compounds have not yet been identified that target the first obligatory step of infection in humans: the migration of Plasmodium sporozoites in the host dermis. This movement is essential to find and invade a blood vessel in order to be passively transported to the liver. Here, an imaging screening pipeline was established to screen for compounds capable of inhibiting extracellular sporozoites.MethodsSporozoites expressing the green fluorescent protein were isolated from infected Anopheles mosquitoes, incubated with compounds from two libraries (MMV Malaria Box and a FDA-approved library) and imaged. Effects on in vitro motility or morphology were scored. In vivo efficacy of a candidate drug was investigated by treating mice ears with a gel prior to infectious mosquito bites. Motility was analysed by in vivo imaging and the progress of infection was monitored by daily blood smears.ResultsSeveral compounds had a pronounced effect on in vitro sporozoite gliding or morphology. Notably, monensin sodium potently affected sporozoite movement while gramicidin S resulted in rounding up of sporozoites. However, pre-treatment of mice with a topical gel containing gramicidin did not reduce sporozoite motility and infection.ConclusionsThis approach shows that it is possible to screen libraries for inhibitors of sporozoite motility and highlighted the paucity of compounds in currently available libraries that inhibit this initial step of a malaria infection. Screening of diverse libraries is suggested to identify more compounds that could serve as leads in developing ‘skin-based’ malaria prophylactics. Further, strategies need to be developed that will allow compounds to effectively penetrate the dermis and thereby prevent exit of sporozoites from the skin.Electronic supplementary materialThe online version of this article (10.1186/s12936-018-2469-0) contains supplementary material, which is available to authorized users.

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“…The motor is located in the space that separates the parasite plasma membrane (PPM) and a layer of flattened vesicles called inner-membrane complex (IMC) or alveoli (Gould et al., 2011). The motor comprises a single-headed unconventional myosin of the apicomplexan-specific XIV class, called MyoA, bound to the IMC, and dynamic filaments of actin located underneath the plasma membrane (Heintzelman, 2015). A number of structural proteins called gliding-associated proteins appear to tether MyoA to the IMC as well as hold the PPM and the IMC together (Boucher and Bosch, 2015).…”

Section: Introductionmentioning

confidence: 99%

Plasmodium Merozoite TRAP Family Protein Is Essential for Vacuole Membrane Disruption and Gamete Egress from Erythrocytes

Bargieri

Thiberge

Tay

et al. 2016

Cell Host & Microbe

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SummarySurface-associated TRAP (thrombospondin-related anonymous protein) family proteins are conserved across the phylum of apicomplexan parasites. TRAP proteins are thought to play an integral role in parasite motility and cell invasion by linking the extracellular environment with the parasite submembrane actomyosin motor. Blood stage forms of the malaria parasite Plasmodium express a TRAP family protein called merozoite-TRAP (MTRAP) that has been implicated in erythrocyte invasion. Using MTRAP-deficient mutants of the rodent-infecting P. berghei and human-infecting P. falciparum parasites, we show that MTRAP is dispensable for erythrocyte invasion. Instead, MTRAP is essential for gamete egress from erythrocytes, where it is necessary for the disruption of the gamete-containing parasitophorous vacuole membrane, and thus for parasite transmission to mosquitoes. This indicates that motor-binding TRAP family members function not just in parasite motility and cell invasion but also in membrane disruption and cell egress.

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Gliding motility in apicomplexan parasites

Cited by 81 publications

References 138 publications

Plasma Membrane Association by N-Acylation Governs PKG Function in Toxoplasma gondii

Plasma Membrane Association by N-Acylation Governs PKG Function in Toxoplasma gondii

Screening for potential prophylactics targeting sporozoite motility through the skin

Plasmodium Merozoite TRAP Family Protein Is Essential for Vacuole Membrane Disruption and Gamete Egress from Erythrocytes

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