Host Mechanic Download
Kelley Deppert
The brothers also appeared in the sitcom Sabrina the Teenage Witch in an episode called "Driving Mr. Goodman" which aired on May 3, 2002. Sabrina calls them on a magical car radio for car advice.[22] In the same year they appeared in the PBS Kids show Arthur episode called "Pick a Car, Any Car" which aired on November 25, 2002. Arthur calls them with a question about the family car, which would have been hauled away by the local mechanic without their help. The answer turns out to be a baby rattle lodged in the car's tailpipe.[23] In 2008, the brothers starred in their own PBS animated series Click and Clack's As the Wrench Turns, playing fictionalized versions of themselves.[24] They also hosted an episode of the PBS show NOVA entitled "The Car of the Future".[25] Ray did radio and TV ads for eBay Motors in 2022 and voiced the Father of the Bride in the animated short film The Ten Commandments of Banquet Serving in 2023.[26]
The capacity to migrate is fundamental to multicellular and single-celled life. Apicomplexan parasites, an ancient protozoan clade that includes malaria parasites (Plasmodium) and Toxoplasma, achieve remarkable speeds of directional cell movement. This rapidity is achieved via a divergent actomyosin motor system, housed within a narrow compartment that lies underneath the length of the parasite plasma membrane. How this motor functions at a mechanistic level during motility and host cell invasion is a matter of debate. Here, we integrate old and new insights toward refining the current model for the function of this motor with the aim of revitalizing interest in the mechanics of how these deadly pathogens move.
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Currently, the most widely accepted model for a how a subcortical actomyosin motor might function in apicomplexan cell motility envisages a complex of proteins, called the glideosome, anchoring the divergent apicomplexan class XIV myosin to the outer IMC membrane, linked to the surface via actin filaments, bridging proteins and secreted surface proteins. Force from the motor drives actin filaments and linked adhesins rearward, creating a traction force that drives the parasite forward or into the host cell (Soldati et al., 2004). The model is based on several molecular and microscopy-based studies localizing key glideosome components to the IMC and immunoprecipitating partner proteins to provide a linkage between the zoite and the extracellular environment (Buscaglia et al., 2003; Jewett and Sibley, 2003; Gaskins et al., 2004; Jones et al., 2006; Frénal et al., 2010; Fig. 2 a). Although a great deal of recent work has extended our understanding of the constituent molecular components of the glideosome and related structures (Alexander et al., 2005; Frénal et al., 2010; Riglar et al., 2011; Srinivasan et al., 2011; Weiss et al., 2015), the model is still incomplete in its ability to fully explain the mechanics of how zoites move on substrates or enter cells. Some of this deficit arises from limitations in the ability of immunoprecipitation, as a technique, to determine precise motor topology. Similarly, several recent studies that have viably knocked out key proteins associated with glideosome function, previously thought of as essential to the motor model, challenge our ability to completely understand how each protein is involved (Andenmatten et al., 2013; Egarter et al., 2014; Kehrer et al., 2016). Some residual motility from such mutants can certainly be explained by a redundancy in the expression of paralogs, as is the case for Toxoplasma apical membrane antigen 1 (AMA1) (Lamarque et al., 2014), or by prolonged protein stability over successive generations, as might be the situation with Toxoplasma actin (Drewry and Sibley, 2015). However, many of the nuances of each mutant phenotype and ongoing debates about the essential or nonessential role each factor might play (reviewed extensively by Meissner et al. [2013]) remain unresolved. For example, such explanations still require the definition of mechanisms that can trigger paralogue gene expression or the ability of proteins to remain stable over generations and across parasite systems (i.e., not just in Toxoplasma). Irrespective of these key debates, which we do not attempt to address here, it is our opinion that robust resolution for a detailed molecular basis of gliding motility is still left wanting.
For more than 100 years, parasitologists have observed apicomplexan gliding motility (Schewiakoff, 1894; Crawley, 1902; Freyvogel, 1966; Vanderberg, 1974), with the first movies of host-cell invasion taken more than 50 years ago (Hirai et al., 1966; Bannister et al., 1975; Dvorak et al., 1975). These original, premolecular descriptions, together with their detailed illustration by electron microscopy (Ladda et al., 1969; Bannister et al., 1975; Aikawa et al., 1977, 1978; Stewart et al., 1986) have played a key role in informing how we understand apicomplexan motility.
At the same time that actin inhibitors were shaping our understanding of gliding, invasion studies with Toxoplasma and Plasmodium parasites (Ryning and Remington, 1978; Miller et al., 1979; Dobrowolski and Sibley, 1996) consolidated the view that a subcortical linear motor was also responsible for driving host cell entry (Bannister et al., 1975; Dvorak et al., 1975; Pinder et al., 1998). These works proposed that invasion proceeded via distinct steps, from loose to intimate attachment between zoite and host cell, followed by subsequent apical reorientation and then invasion. Most strikingly, it appeared that the parasite was active in driving this process, as illustrated by Plasmodium merozoites that were seen to literally pull the target erythrocyte when attempting invasion (Dvorak et al., 1975). This process was also found to be sensitive to cytochalasin (Miller et al., 1979), providing further support for a parasite-centric process. Parasite actin-dependent invasion was then described for Toxoplasma (Nguyen and Stadtsbaeder, 1979; Morisaki et al., 1995), with tachyzoites arresting on cytochalasin treatment when attempting to invade cytochalasin-resistant fibroblasts (Dobrowolski and Sibley, 1996). These findings helped to define apicomplexan host-cell entry as being distinct from the induced phagocytic-dependent entry mechanism that characterizes invasion strategies of other intracellular pathogens (Sibley, 2004).
These findings together suggest that to understand gliding motility and invasion, we will need to integrate the currently separate concepts of retrograde flow across the zoite surface, actomyosin motor force potential, and the engagement of motor force by surface-bound adhesins. It appears from these results that linked adhesins play a central anchoring role in gliding, effectively slowing the (retrograde-dependent) flow of adhesion sites. This anchoring, when linked to the motor, maximizes traction forces, causing the net forward motion of the zoite. For invasion, links between the host and parasite membranes/cytoskeletons (through the tight junction) could then provide force transmission to a motile traction point (rather than to fixed adhesion site) that scans the zoite surface.
As technological advances continue, they can be used to address unresolved questions concerning the mechanics of apicomplexan cell motility and host-cell invasion. Potential future research directions could include the following.
Above all, the insights gained to date point to the need for a more integrative and less reductionist approach to understanding the motile and invasive mechanics among the Apicomplexa. The journey will be long, and we should resist the temptation to arrive too early, only to find that our understanding has taken us, unlike the parasites, in the wrong direction.
Motile apicomplexan zoite cells designed for invasion and motility. (a) Schematic of an apicomplexan zoite cell (here a merozoite) showing key cellular structures and apical complex, characteristic of motile zoites. (b and c) Electron micrographs of a P. knowlesi merozoite (b) and a Toxoplasma tachyzoite (c). Apicomplexan zoites are generally polarized and elongated, with either a crescent or oval shape. Each has a distinctive apical complex, which consists of secretory organelles called micronemes, rhoptries, and dense granules. Micronemes (oval or pear-shaped organelles) secrete their contents at the anterior tip of motile zoites during motility/invasion. Rhoptries (club-shaped organelles) fuse and release their contents concomitantly with host-cell invasion (Carruthers and Tomley, 2008; Counihan et al., 2013; Hanssen et al., 2013). Dense granules (a mixed grouping of secretory vesicles) are released via fusion with the plasma membrane before or after invasion (also called exonemes; Yeoh et al., 2007). Insets highlight the triple-layered appearance of the parasite pellicle at higher magnification (double-membraned IMC, lying under the PPM). The myosin motor is thought to lie between the outer (o) IMC membrane and the PPM. APR, apical polar (tubulin-rich) rings; Dg, dense granules; Go, Golgi apparatus; i, inner membrane of the IMC; Mn, micronemes; Mt, subpellicular microtubules; Nu, nucleus; Rh, rhoptries. Bars, 200 nm. Micrograph images courtesy of L.H. Bannister (Kings College London, London, England, UK) and D. Ferguson (University of Oxford, Oxford, England, UK).
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