<i>Giardia</i> secretome highlights secreted tenascins as a key component of pathogenesis

Dubourg, Audrey; Xia, Dong; Winpenny, John P.; Naimi, Suha Al; Bouzid, Maha; Sexton, Darren W.; Wastling, Jonathan M.; Hunter, Paul R.; Tyler, Kevin M.

doi:10.1093/gigascience/giy003

Cited by 62 publications

(69 citation statements)

References 41 publications

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“…Consistent with this possibility, several of the identified proteins without transmembrane regions or palmitoylation sites are translational factors associated with the endoplasmic reticulum. Alternatively, biotin labeling as done in this study may label some secreted proteins since a number of the identified proteins overlap those found in studies of the secretome of G. lamblia (41,63).…”

Section: Discussionmentioning

confidence: 92%

Identification of Conserved Candidate Vaccine Antigens in the Surface Proteome of Giardia lamblia

et al. 2019

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Giardia lamblia, one of the most common protozoal infections of the human intestine, is an important worldwide cause of diarrheal disease, malabsorption, malnutrition, delayed cognitive development in children, and protracted postinfectious syndromes. Despite its medical importance, no human vaccine is available against giardiasis. A crude veterinary vaccine has been developed, and experimental vaccines based on expression of multiple variant-specific surface proteins have been reported, but poorly defined vaccine components and excessive antigen variability are problematic for pharmaceutical vaccine production. To expand the repertoire of antigen candidates for vaccines, we reasoned that surface proteins may provide an enriched source of such antigens since key host effectors, such as secretory IgA, can directly bind to such antigens in the intestinal lumen and interfere with epithelial attachment. Here, we have applied a proteomics approach to identify 23 novel surface antigens of G. lamblia that show Ͼ90% amino acid sequence identity between the two humanpathogenic genetic assemblages (A and B) of the parasite. Surface localization of a representative subset of these proteins was confirmed by immunostaining. Four selected proteins, uridine phosphorylase-like protein-1, protein 21.1 (GL50803_27925), ␣1-giardin, and ␣11-giardin, were subsequently produced in recombinant form and shown to be immunogenic in mice and G. lamblia-infected humans and confer protection against G. lamblia infection upon intranasal immunization in rodent models of giardiasis. These results demonstrate that identification of conserved surface antigens provides a powerful approach for overcoming a key rate-limiting step in the design and construction of an effective vaccine against giardiasis.

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Section: Discussionmentioning

confidence: 92%

Identification of Conserved Candidate Vaccine Antigens in the Surface Proteome of Giardia lamblia

et al. 2019

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“…Cathepsins-B from Giardia are known to play a role in host-parasite interaction. Several orthologs have been demonstrated to be excreted (Dubourg et al 2018) and digestion by cathepsins-B of host IL-8 (Cotton et al 2014) and of proteins involved in tight junction of host epithelial cells and several chemokines (Liu et al 2018) have been described. The phylogenetic tree of the cathepsin-B sequences from all 11 Giardia genomes consisted of 9 clades.…”

Section: Discussionmentioning

confidence: 99%

“…A recent finding suggests that the cathepsins from the variable clades indeed have an important function. It was shown that the orthologs from clade 7, GL50803.15564 and GL50581.2036 from genome WB and GS, respectively, have dN/dS values of >26, indicating very strong positive selection (Dubourg et al 2018). This strong selection is not expected when these genes do not have an important function.…”

Section: Discussionmentioning

confidence: 99%

“…Proteins excreted by the trophozoites are likely to play a role in host specificity and immunity. Several proteins from the WB and GSB isolates excreted in the absence of host cells were identified by proteomics (Dubourg et al 2018). The most abundant proteins in both isolates were variant-specific surface proteins (VSPs), cathepsins, high cysteine membrane proteins and tenacins.…”

Section: Introductionmentioning

confidence: 99%

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Whole genome sequencing of dog specific assemblages C and D of Giardia duodenalis from single and pooled cysts indicates host associated genes

Kooyman

Wagenaar

Zomer

2019

Preprint

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Giardia duodenalis (Syn. G. intestinalis or G. lamblia) infects over 280 million people each year and numerous animals. G. duodenalis can be subdivided into 8 assemblages with different host specificity. Unculturable assemblages have so far resisted genome sequencing efforts. In this study we isolated single and pooled cysts of assemblage C and D from dog faeces by FACS and sequenced them using multiple displacement amplification and Illumina paired end sequencing. The genomes of assemblages C and D were compared with genomes of assemblages A and B from humans and assemblage E from ruminants and pigs. The genomes obtained from the pooled cysts and from the single cysts were considered complete (>99% marker genes observed) and the allelic sequence heterozygosity (ASH) of assemblage C and D was 0.89% and 0.74%, respectively. Higher than for assemblage B (> 0.43%) and much higher than for assemblages A and E (<0.01%). The flavohemoglobin and 4Fe-4S binding domain family gene involved in O2 and NO detoxification were only present in assemblages A, B and E. Cathepsin-B orthologs were found in all genomes. Six clades of cathepsin-B orthologs contained one gene of each genome, while in three clades not all assemblages were represented. We conclude that whole genome sequencing from a single Giardia cyst results in complete draft genomes making the genomes of unculturable Giardia assemblages accessible. Observed differences between the genomes of assemblage C and D on one hand and the assemblages A, B and E on the other hand are possibly associated with host specificity.

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“…cause disease; they are not invasive and secrete no known toxins [12]. Recent research suggests that G. intestinalis can secrete a large number of immunomodulatory proteins, possibly regulating host immune responses [13][14][15][16]. However, the mechanisms on how interactions between the host and Giardia either lead to parasite clearance or to disease remain to be understood.Recent studies have shown the importance of different immune cells in giardiasis, where both innate and adaptive immunity seem to play significant roles [17][18][19].…”

mentioning

confidence: 99%

The Chymase Mouse Mast Cell Protease-4 Regulates Intestinal Cytokine Expression in Mature Adult Mice Infected with Giardia intestinalis

Peirasmaki

Svärd

et al. 2020

Cells

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Mast cells have been shown to affect the control of infections with the protozoan parasite Giardia intestinalis. Recently, we demonstrated that Giardia excretory-secretory proteins inhibited the activity of the connective tissue mast cell-specific protease chymase. To study the potential role of the chymase mouse mast cell protease (mMCP)-4 during infections with Giardia, mMCP-4 +/+ and mMCP-4 −/− littermate mice were gavage-infected with G. intestinalis trophozoites of the human assemblage B isolate GS. No significant changes in weight gain was observed in infected young (≈10 weeks old) mMCP-4 −/− and mMCP-4 +/+ littermate mice. In contrast, infections of mature adult mice (>18 weeks old) caused significant weight loss as compared to uninfected control mice. We detected a more rapid weight loss in mMCP-4 −/− mice as compared to littermate mMCP-4 +/+ mice. Submucosal mast cell and granulocyte counts in jejunum increased in the infected adult mMCP-4 −/− and mMCP-4 +/+ mice. This increase was correlated with an augmented intestinal trypsin-like and chymotrypsin-like activity, but the myeloperoxidase activity was constant. Infected mice showed a significantly lower intestinal neutrophil elastase (NE) activity, and in vitro, soluble Giardia proteins inhibited human recombinant NE. Serum levels of IL-6 were significantly increased eight and 13 days post infection (dpi), while intestinal IL-6 levels showed a trend to significant increase 8 dpi. Strikingly, the lack of mMCP-4 resulted in significantly less intestinal transcriptional upregulation of IL-6, TNF-α, IL-25, CXCL2, IL-2, IL-4, IL-5, and IL-10 in the Giardia-infected mature adult mice, suggesting that chymase may play a regulatory role in intestinal cytokine responses.Cells 2020, 9, 925 2 of 19 infections, including infections with G. intestinalis [9][10][11]. However, there is little insight into how Giardia spp. cause disease; they are not invasive and secrete no known toxins [12]. Recent research suggests that G. intestinalis can secrete a large number of immunomodulatory proteins, possibly regulating host immune responses [13][14][15][16]. However, the mechanisms on how interactions between the host and Giardia either lead to parasite clearance or to disease remain to be understood.Recent studies have shown the importance of different immune cells in giardiasis, where both innate and adaptive immunity seem to play significant roles [17][18][19]. Accumulated data suggest that there is a mixed Th1/Th2/Th17 response during giardiasis [19,20]. When G. intestinalis attach to the microvillus brush border of intestinal epithelial cells (IECs) there is a production of chemokines and cytokines that will attract immune cells to the intestinal submucosa [20][21][22]. However, the effects differ depending on model systems used. In cultured human IECs challenged by G. intestinalis trophozoites (assemblage B, isolate GS), several chemokines were highly up-regulated early-at 1.5 h after challenge [21]. In experimental infections of gerbils with the WB isolate (ATCC 50803)...

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Giardia secretome highlights secreted tenascins as a key component of pathogenesis

Cited by 62 publications

References 41 publications

Identification of Conserved Candidate Vaccine Antigens in the Surface Proteome of Giardia lamblia

Identification of Conserved Candidate Vaccine Antigens in the Surface Proteome of Giardia lamblia

Whole genome sequencing of dog specific assemblages C and D of Giardia duodenalis from single and pooled cysts indicates host associated genes

The Chymase Mouse Mast Cell Protease-4 Regulates Intestinal Cytokine Expression in Mature Adult Mice Infected with Giardia intestinalis

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