The Critical Role of the Cytoskeleton in the Pathogenesis of Giardia

Nosala, Christopher; Dawson, Scott C.

doi:10.1007/s40588-015-0026-y

Cited by 35 publications

(30 citation statements)

References 64 publications

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“…Given the lack of GARP domains in the mammalian host and their putative role in regulating elements of the physiological stress response, these transcription factors are worthy candidates for further investigation as chemotherapeutic targets. GARP proteins are implicated in twocomponent signaling in plants (82), and we previously elucidated structural homologues of two-component signaling proteins in G. duodenalis, including an MtrR repressor, since localized in the trophozoite nucleus (85), that may be involved in oxidative stress signaling (39). The transcript encoding the MtrR homologue is downregulated under Mtz stress, further supporting the notion that the response to Mtz exposure, at least under anaerobic conditions, opposes the oxidative stress response.…”

Section: Discussionmentioning

confidence: 62%

Divergent Transcriptional Responses to Physiological and Xenobiotic Stress in Giardia duodenalis

Ansell

McConville

Baker

et al. 2016

Antimicrob Agents Chemother

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dUnderstanding how parasites respond to stress can help to identify essential biological processes. Giardia duodenalis is a parasitic protist that infects the human gastrointestinal tract and causes 200 to 300 million cases of diarrhea annually. Metronidazole, a major antigiardial drug, is thought to cause oxidative damage within the infective trophozoite form. However, treatment efficacy is suboptimal, due partly to metronidazole-resistant infections. To elucidate conserved and stress-specific responses, we calibrated sublethal metronidazole, hydrogen peroxide, and thermal stresses to exert approximately equal pressure on trophozoite growth and compared transcriptional responses after 24 h of exposure. We identified 252 genes that were differentially transcribed in response to all three stressors, including glycolytic and DNA repair enzymes, a mitogen-activated protein (MAP) kinase, high-cysteine membrane proteins, flavin adenine dinucleotide (FAD) synthetase, and histone modification enzymes. Transcriptional responses appeared to diverge according to physiological or xenobiotic stress. Downregulation of the antioxidant system and ␣-giardins was observed only under metronidazole-induced stress, whereas upregulation of GARP-like transcription factors and their subordinate genes was observed in response to hydrogen peroxide and thermal stressors. Limited evidence was found in support of stress-specific response elements upstream of differentially transcribed genes; however, antisense derepression and differential regulation of RNA interference machinery suggest multiple epigenetic mechanisms of transcriptional control. Giardia duodenalis (synonyms, Giardia lamblia and Giardia intestinalis) is a parasitic protist of the vertebrate gastrointestinal tract and the most common parasite of humans (1). The vegetative life cycle stage (trophozoite) infects around 1 billion people and causes 200 to 300 million cases of diarrheal disease (giardiasis) each year (1). Infection with G. duodenalis is also associated with the development of chronic diseases such as irritable bowel syndrome, chronic fatigue, and diabetes (2). At present, only two major drug classes are available to treat giardiasis: nitroimidazoles, primarily metronidazole (Mtz), and benzimidazoles, such as albendazole (3,4). Resistance to Mtz is documented in treatment-resistant clinical isolates (5-8), and resistant lines can be generated in vitro (reviewed in reference 9).The mechanism of action of Mtz is relatively poorly understood. This compound is thought to diffuse into G. duodenalis trophozoites as an inactive prodrug, whereupon it is enzymatically reduced (activated), yielding reactive intermediates. Mtz intermediates are thought to kill trophozoites by oxidizing proteins, lipids, and DNA (10, 11); however, the relative importance of damage to different biomolecules for Mtz-induced cytotoxicity is contested (10, 12). Resistance to Mtz involves changes in enzyme expression which limit drug activation. Nitroreductase-1, thioredoxin reductase, and pyruvat...

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Section: Discussionmentioning

confidence: 62%

Divergent Transcriptional Responses to Physiological and Xenobiotic Stress in Giardia duodenalis

Ansell

McConville

Baker

et al. 2016

Antimicrob Agents Chemother

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“…intestinalis is not known to possess classical virulence factors, such as 264 enterotoxins, but several genes are important for colonization of the host and thus for 265 pathogenesis. These include genes for motility 10 , the adhesive disc for attachment 9 , 266 secreted cysteine proteases that can degrade host defensive factors 12,13 , and cysteine-rich surface protein like the VSPs 51 and the HCMPs 48 that undergo antigenic variation. The 268 cytoskeletal protein repertoire in G. muris is very similar to G. intestinalis apart from 269 several fragmented alpha-tubulins (3 complete genes with homologs in G. intestinalis and 270 9 incomplete gene fragments).…”

Section: Virulence Factors In Giardia 263mentioning

confidence: 99%

The compact genome ofGiardia murisreveals important steps in the evolution of intestinal protozoan parasites

Jiménez-González

Einarsson

et al. 2019

Preprint

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AbstractDiplomonad parasites of the genus Giardia have adapted to colonizing different hosts, most notably the intestinal tract of mammals. The human-pathogenic Giardia species, Giardia intestinalis, has been extensively studied at the genome and gene expression level, but no such information is available for other Giardia species. Comparative data would be particularly valuable for Giardia muris, which colonizes mice and is commonly used as a prototypic in vivo model for investigating host responses to intestinal parasitic infection. Here we report the draft-genome of G. muris. We discovered a highly streamlined genome, amongst the most densely encoded ever described for a nuclear eukaryotic genome. G. muris and G. intestinalis share many known or predicted virulence factors, including cysteine proteases and a large repertoire of cysteine-rich surface proteins involved in antigenic variation. Different to G. intestinalis, G. muris maintains tandem arrays of pseudogenized surface antigens at the telomeres, whereas intact surface antigens are present centrally in the chromosomes. The two classes of surface antigens engage in genetic exchange. Reconstruction of metabolic pathways from the G. muris genome suggest significant metabolic differences to G. intestinalis. Additionally, G. muris encodes proteins that might be used to modulate the prokaryotic microbiota. The responsible genes have been introduced in the Giardia genus via lateral gene transfer from prokaryotic sources. Our findings point to important evolutionary steps in the Giardia genus as it adapted to different hosts and it provides a powerful foundation for mechanistic exploration of host-pathogen interaction in the G. muris – mouse pathosystem.Author summaryThe Giardia genus comprises eukaryotic single-celled parasites that infect many animals. The Giardia intestinalis species complex, which can colonize and cause diarrheal disease in humans and different animal hosts has been extensively explored at the genomic and cell biologic levels. Other Giardia species, such as the mouse parasite Giardia muris, have remained uncharacterized at the genomic level, hampering our understanding of in vivo host-pathogen interactions and the impact of host dependence on the evolution of the Giardia genus. We discovered that the G. muris genome encodes many of the same virulence factors as G. intestinalis. The G. muris genome has undergone genome contraction, potentially in response to a more defined infective niche in the murine host. We describe differences in metabolic and microbiome modulatory gene repertoire, mediated mainly by lateral gene transfer, that could be important for understanding infective success across the Giardia genus. Our findings provide new insights for the use of G. muris as a powerful model for exploring host-pathogen interactions in giardiasis.

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“…The trophozoite’s interphase cytoskeleton comprises many microtubule structures including the ventral disc, four pairs of bisymmetrical flagella, the median body, and the funis (2). The ventral disc mediates attachment within the host gut and is essential for in vivo colonization because unattached trophozoites are swept away via peristalsis and shed in the feces where they cannot survive harsh environmental conditions (3). Recent studies indicate that Giardia can attach to a variety of surfaces regardless of surface treatment (PEG, Teflon) (4).…”

Section: Introductionmentioning

confidence: 99%

The ventral disc is a flexible microtubule organelle that depends on domed ultrastructure for functional attachment ofGiardia lamblia

Dawson

Nosala

2017

Preprint

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The parasite Giardia lamblia interacts with its host by directly attaching the lumen of the small intestine. Attachment is mediated by a cytoskeletal structure termed the ventral disc and proceeds in four distinct stages: skimming, seal formation, cell body contacts, and bare area contacts. The precise mechanism of disc-mediated attachment is unclear and attachment models rely heavily on whether or not the ventral disc is a dynamic structure. We sought to investigate the second stage of attachment in which a seal is formed beneath the ventral disc. Three-dimensional, live imaging of Giardia expressing specific ventral disc markers to the lateral crest, ventral groove, and disc body indicate dynamic movement in all of these regions. We observe seal formation by the lateral crest and determine that movement of the ventral groove region aids lateral crest seal formation. We also report the discovery of a new protein that is necessary for ventral disc formation and functional attachment (DAP_7268). Lastly, we observed that attachment largely depends on ventral disc ultrastructure as flattened discs display hindered attachment proficiency whether or not they retain the ability to form a seal. We propose a synthesized mechanism for attachment that includes flagellar hydrodynamic flow to help generate suction as well as disc conformational dynamics to aid in both hydrodynamic flow and the maintenance of negative pressure.

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The Critical Role of the Cytoskeleton in the Pathogenesis of Giardia

Cited by 35 publications

References 64 publications

Divergent Transcriptional Responses to Physiological and Xenobiotic Stress in Giardia duodenalis

Divergent Transcriptional Responses to Physiological and Xenobiotic Stress in Giardia duodenalis

The compact genome ofGiardia murisreveals important steps in the evolution of intestinal protozoan parasites

The ventral disc is a flexible microtubule organelle that depends on domed ultrastructure for functional attachment ofGiardia lamblia

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