Arginine deiminase has multiple regulatory roles in the biology of<i>Giardia lamblia</i>

Touz, Marı́a C.; Rópolo, Andrea S.; Rivero, María Romina; Vranych, Cecilia V.; Conrad, John T.; Svärd, Staffan G.; Nash, Theodore E.

doi:10.1242/jcs.026963

Cited by 86 publications

(89 citation statements)

References 46 publications

(53 reference statements)

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“…1). However, we could not confirm a previously described higher-molecular-mass 85-kDa form of native G. duodenalis ADI (24). To achieve arginine depletion by recombinant ADI in a standard 24-h DC stimulation assay enabling us to study the consequences of arginine depletion on DC, we calculated that 4 g of active recombinant ADI (corresponding to 0.027 U and representing the equivalent of the enzymatic activity of two to three trophozoites per DC present in the assay) will convert all of the free arginine present in 43 min (culture volume of 1 ml RPMI containing 1.15 mM arginine), 10-fold less enzyme will achieve this in approximately 7 h, and 100-fold less enzyme would need nearly 72 h, assuming constant activity over time.…”

Section: Definition Of Experimental Conditions For Arginine Depletioncontrasting

confidence: 96%

Giardia duodenalis Arginine Deiminase Modulates the Phenotype and Cytokine Secretion of Human Dendritic Cells by Depletion of Arginine and Formation of Ammonia

et al. 2013

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bDepletion of arginine is a recognized strategy that pathogens use to evade immune effector mechanisms. Depletion depends on microbial enzymes such as arginases, which are considered virulence factors. The effect is mostly interpreted as being a consequence of successful competition with host enzymes for the substrate. However, both arginases and arginine deiminases (ADI) have been associated with pathogen virulence. Both deplete arginine, but their reaction products differ. An ADI has been implicated in the virulence of Giardia duodenalis, an intestinal parasite that infects humans and animals, causing significant morbidity. Dendritic cells (DC) play a critical role in host defense and also in a murine G. duodenalis infection model. The functional properties of these innate immune cells depend on the milieu in which they are activated. Here, the dependence of the response of these cells on arginine was studied by using Giardia ADI and lipopolysaccharide-stimulated human monocyte-derived DC. Arginine depletion by ADI significantly increased tumor necrosis factor alpha and decreased interleukin-10 (IL-10) and IL12p40 secretion. It also reduced the upregulation of surface CD83 and CD86 molecules, which are involved in cell-cell interactions. Arginine depletion also reduced the phosphorylation of S6 kinase in DC, suggesting the involvement of the mammalian target of rapamycin signaling pathway. The changes were due to arginine depletion and the formation of reaction products, in particular, ammonium ions. Comparison of NH 4 ؉ and urea revealed distinct immunomodulatory activities of these products of deiminases and arginases, respectively. The data suggest that a better understanding of the role of arginine-depleting pathogen enzymes for immune evasion will have to take enzyme class and reaction products into consideration.

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Section: Definition Of Experimental Conditions For Arginine Depletioncontrasting

confidence: 96%

Giardia duodenalis Arginine Deiminase Modulates the Phenotype and Cytokine Secretion of Human Dendritic Cells by Depletion of Arginine and Formation of Ammonia

et al. 2013

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“…There is some agreement between the microarray and the SAGE data (2): 5 of 12 identified genes are listed as downregulated. Interestingly, among those is ORF 112103, coding for arginine deiminase (17,33), an important factor in host-parasite interaction, which was reported to translocate to nuclei and inhibit CWP2 expression (41). Its relatively strong downregulation at 45 min and 3 h p.i.…”

Section: Resultsmentioning

confidence: 99%

The Transcriptional Response to Encystation Stimuli in Giardia lamblia Is Restricted to a Small Set of Genes

Morf

Spycher

Rehrauer³

et al. 2010

Eukaryot Cell

111

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The protozoan parasite Giardia lamblia undergoes stage differentiation in the small intestine of the host to an environmentally resistant and infectious cyst. Encystation involves the secretion of an extracellular matrix comprised of cyst wall proteins (CWPs) and a ␤(1-3)-GalNAc homopolymer. Upon the induction of encystation, genes coding for CWPs are switched on, and mRNAs coding for a Myb transcription factor and enzymes involved in cyst wall glycan synthesis are upregulated. Encystation in vitro is triggered by several protocols, which call for changes in bile concentrations or availability of lipids, and elevated pH. However, the conditions for induction are not standardized and we predicted significant protocol-specific side effects. This makes reliable identification of encystation factors difficult. Here, we exploited the possibility of inducing encystation with two different protocols, which we show to be equally effective, for a comparative mRNA profile analysis. The standard encystation protocol induced a bipartite transcriptional response with surprisingly minor involvement of stress genes. A comparative analysis revealed a core set of only 18 encystation genes and showed that a majority of genes was indeed upregulated as a side effect of inducing conditions. We also established a Myb binding sequence as a signature motif in encystation promoters, suggesting coordinated regulation of these factors.The differentiation of Giardia lamblia cells to cysts is a key step in the simple life cycle of this ubiquitous intestinal parasite. Induced trophozoites, the flagellated, motile, and attachment-competent stage, exit the cell cycle at the G 2 -M transition (1) and begin to synthesize the components of an extracellular matrix, the cyst wall (CW). Synthesis and export of the cyst wall proteins (CWPs) to specialized organelles, termed encystation-specific vesicles (ESVs), is completed between 8 and 10 h postinduction (p.i.). After proteolytic cleavage of the CWP2 C terminus, the CWPs are sorted into two fractions which are deposited sequentially and polymerize on the surface of the cyst (18). The first layer of the CW, which eventually completely encloses the parasite (19,24), is secreted in the last minutes of differentiation simultaneously with nuclear division and morphological transformation of the cell (cyst formation). In vitro, the entire encystation process typically takes 20 to 24 h in our hands and can be induced by modifying medium components and/or the concentrations of bile, fatty acids (cholesterol), or lactic acid (3,10,15,22). Because the condition(s) which induce encystation in vivo are not known, all factors and components mentioned above are implicated since their concentrations vary in the small intestine, as does the pH, which increases from ϳ6 in the duodenum to 7.5 to 8.0 in the distal ileum. Although all available data indicate that differentiation is induced by one or several environmental signals, the mechanism(s) for reception and transduction have not been characterized. Upregulation...

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“…The strongest immune responses to Giardia in humans are probably directed toward the variant-specific surface proteins (VSPs). Only 1 specific type, out of around 250, is expressed at any time point (37). Using semiconserved peptides from VSPs or recombinant Giardia trophozoites expressing all of the available VSPs could possibly have elicited stronger responses in Giardia-exposed individuals but could also have caused much larger variability, depending on which VSPs were expressed during Giardia infection.…”

Section: Discussionmentioning

confidence: 99%

Human Memory CD4 ⁺ T Cell Immune Responses against Giardia lamblia

Saghaug

Sørnes

Peirasmaki

et al. 2016

Clin Vaccine Immunol

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؉ EM T cells, as well as that of cells simultaneously producing both IL-17A and TNF-␣, to be significantly elevated in the Giardia-exposed individuals after 24 h of antigen stimulation. In supernatants of PBMCs stimulated with Giardia antigens for 6 days, we found inflammation-associated cytokines, including 1L-17A, as well as CD4 ؉ T cell activation and proliferation, to be significantly elevated in the Giardia-exposed individuals. We conclude that symptomatic Giardia infection in humans induces a CD4 ؉ EM T cell response of which IL-17A production seems to be an important component.

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Arginine deiminase has multiple regulatory roles in the biology ofGiardia lamblia

Cited by 86 publications

References 46 publications

Giardia duodenalis Arginine Deiminase Modulates the Phenotype and Cytokine Secretion of Human Dendritic Cells by Depletion of Arginine and Formation of Ammonia

Giardia duodenalis Arginine Deiminase Modulates the Phenotype and Cytokine Secretion of Human Dendritic Cells by Depletion of Arginine and Formation of Ammonia

The Transcriptional Response to Encystation Stimuli in Giardia lamblia Is Restricted to a Small Set of Genes

Human Memory CD4 ⁺ T Cell Immune Responses against Giardia lamblia

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Arginine deiminase has multiple regulatory roles in the biology ofGiardia lamblia

Cited by 86 publications

References 46 publications

Giardia duodenalis Arginine Deiminase Modulates the Phenotype and Cytokine Secretion of Human Dendritic Cells by Depletion of Arginine and Formation of Ammonia

Giardia duodenalis Arginine Deiminase Modulates the Phenotype and Cytokine Secretion of Human Dendritic Cells by Depletion of Arginine and Formation of Ammonia

The Transcriptional Response to Encystation Stimuli in Giardia lamblia Is Restricted to a Small Set of Genes

Human Memory CD4 + T Cell Immune Responses against Giardia lamblia

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Product

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Human Memory CD4 ⁺ T Cell Immune Responses against Giardia lamblia