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Induction of virulence factors in Giardia duodenalis independent of host attachment.

ABSTRACT: Giardia duodenalis is responsible for the majority of parasitic gastroenteritis in humans worldwide. Host-parasite interaction models in vitro provide insights into disease and virulence and help us to understand pathogenesis. Using HT-29 intestinal epithelial cells (IEC) as a model we have demonstrated that initial sensitisation by host secretions reduces proclivity for trophozoite attachment, while inducing virulence factors. Host soluble factors triggered up-regulation of membrane and secreted proteins, including Tenascins, Cathepsin-B precursor, cystatin, and numerous Variant-specific Surface Proteins (VSPs). By comparison, host-cell attached trophozoites up-regulated intracellular pathways for ubiquitination, reactive oxygen species (ROS) detoxification and production of pyridoxal phosphate (PLP). We reason that these results demonstrate early pathogenesis in Giardia involves two independent host-parasite interactions. Motile trophozoites respond to soluble secreted signals, which deter attachment and induce expression of virulence factors. Trophozoites attached to host cells, in contrast, respond by up-regulating intracellular pathways involved in clearance of ROS, thus anticipating the host defence response.

SUBMITTER: Emery SJ

PROVIDER: S-EPMC4751611 | biostudies-literature | 2016 Feb

REPOSITORIES: biostudies-literature

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Induction of virulence factors in Giardia duodenalis independent of host attachment.

Emery Samantha J SJ Mirzaei Mehdi M Vuong Daniel D Pascovici Dana D Chick Joel M JM Lacey Ernest E Haynes Paul A PA

Scientific reports 20160212

Giardia duodenalis is responsible for the majority of parasitic gastroenteritis in humans worldwide. Host-parasite interaction models in vitro provide insights into disease and virulence and help us to understand pathogenesis. Using HT-29 intestinal epithelial cells (IEC) as a model we have demonstrated that initial sensitisation by host secretions reduces proclivity for trophozoite attachment, while inducing virulence factors. Host soluble factors triggered up-regulation of membrane and secrete ...[more]

PMID: 26867958

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Project description:BackgroundThe aim of this study was to assess potential associations between Giardia duodenalis infection in dogs, as determined by three diagnostic tests, and dog's group of origin, fecal consistency, age, sex, neuter status, and co-infections with other gastrointestinal parasites.MethodsFecal samples from 1291 dogs from four groups (household, shelter, hunting and clinical dogs) were tested with qPCR, rapid enzyme immunochromatographic assay (IDEXX SNAP® Giardia), and direct immunofluorescence (DFA, Merifluor) for presence of G. duodenalis. Moreover, fecal samples were tested with centrifugation sedimentation flotation (CSF) coproscopical analysis for presence of gastrointestinal parasites. Associations were expressed as odds ratios (ORs).ResultsSeveral significant associations were found, of which a few were consistent for all three tests and Giardia positivity in general (positive with at least one of these tests). Dogs older than one year were significantly less likely to test positive for Giardia than younger dogs. Group-housed dogs, especially hunting dogs, were significantly more likely to test positive for Giardia compared to household and clinical dogs. A consistently significant association with Trichuris appeared to be driven by the high prevalence in hunting dogs. Although there was no significant association between loose stool and Giardia infection in the overall population, household dogs were significantly more likely to test Giardia-positive when having loose stool. Overall, Giardia-positive dogs with loose stool shed significantly more cysts, both determined semi-quantitatively with CSF and quantitatively by qPCR, than positive dogs with no loose stool. When other gastrointestinal parasites were present, significantly fewer cysts were detected with CSF, but this was not confirmed with qPCR.ConclusionGiardia is the most common gastrointestinal parasite in Dutch dogs, except for hunting dogs, in which Trichuris and strongyle-type eggs (hookworms) prevailed. Giardia infection was not significantly associated with loose stool, except for household dogs. Young dogs and group-housed dogs were significantly more often Giardia-positive. These associations were consistent across diagnostic tests. Young dogs, clinical dogs and dogs with loose stool shed Giardia cysts in the highest numbers. If another gastrointestinal parasite was present lower numbers of cysts were observed by microscope (CSF), but not with a molecular method (qPCR).

Project description:Purpose of reviewHere, we review recent progress made on the genetic characterization of Giardia duodenalis assemblages and their relationship with virulence. We also discuss the implications of virulence factors in the pathogenesis of giardiasis, and advances in the development of vaccines and drugs based on knowledge of virulence markers.Recent findingsThe use of transcriptomic and proteomic technologies as well as whole genome sequencing (WGS) from single cysts has allowed the assembly of the draft genome sequences for assemblages C and D of G. duodenalis. These findings, along with the published genomes for assemblages A, B, and E, have allowed comparative genomic investigations. In addition, the use of these methodologies for the characterization of the secretomes of trophozoite-epithelial cell interactions for assemblages A/B has led to the identification of virulence markers including energy metabolism enzymes, proteinases, high-cysteine membrane proteins (HCMPs), and variant surface proteins (VSPs). Recently, some drugs and vaccines, targeting virulence factors have been developed, offering possible alternatives to current treatment and prevention options against giardiasis.SummaryAmong the nine recognized species of Giardia, G. duodenalis stands out because of its broad spectrum of hosts and its socio-economic importance. This species comprises eight genetic assemblages (A to H), of which A and B are zoonotic, and the other assemblages have narrow host specificities. Assemblages A and B may be considered as the most virulent ones, but the existence of asymptomatic carriers and considerable genetic variability within and among these assemblages hampers the definition of common virulence factors. The attachment of Giardia trophozoites to epithelial cells and structural cytoskeleton components of the adhesive disk, such as giardins or tubulins, is proposed to play key roles, but toxins have not yet been precisely defined. However, recent transcriptomic and proteomic analyses of the secretomes of trophozoites representing assemblages A and B and interacting with particular epithelial cell lines have defined a series of virulence factors, including glycolytic (e.g., enolase) and arginolytic (e.g., arginine deiminase) enzymes, cysteine proteases (e.g., giardipain-1) and VSPs (e.g., VSP9B10A). Other factors, such as HCMPs and tenascins, have been consistently found to be excreted/secreted, but their role(s) in the pathogenesis of giardiasis has not yet been elucidated. Interestingly, recent investigations of single cysts representing assemblages C and D using advanced sequencing and informatic methods have suggested that the transcription/expression profiles of virulence factors vary both within and between assemblages, thus assemblage-specific molecules might allow adaptation to the microenvironment within the host. Importantly, some drugs active against cysteine-rich proteins of Giardia, including giardipain-1, VSPs and arginine deiminase, have been shown to be targeted by cysteine-modifying compounds as disulfiram, L-canavanin and allicin. On the other hand, VSPs are presently considered as key vaccine candidates because they induce protection against Giardia in rodents and dogs. Overall, this review reveals that much more work is needed to identify, characterize, and understand the roles of virulence factors in Giardia and to assess their validity as drug and vaccine targets. Clear, advanced omics and informatic tools should assist in this future endeavor, with a focus on targeting virulence factors that are common and/or unique to distinct assemblages to develop new and effective interventions against Giardia.

Dataset Information

Induction of virulence factors in Giardia duodenalis independent of host attachment.

Publications

Induction of virulence factors in Giardia duodenalis independent of host attachment.

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