title: Giardia duodenalis arginine deiminase modulates the phenotype and cytokine secretion of human dendritic cells by depletion of arginine and formation of ammonia.
abstract: Depletion 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 IL-12p40 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.
authors.affiliation: Department of Parasitology/Mycology/Intracellular Pathogens, FG 16, Robert Koch Institute, Berlin, Germany.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Banik
authors.forename: Pablo
authors.initials: P
authors.lastname: Renner Viveros
authors.forename: Frank
authors.initials: F
authors.lastname: Seeber
authors.forename: Christian
authors.initials: C
authors.lastname: Klotz
authors.forename: Ralf
authors.initials: R
authors.lastname: Ignatius
authors.forename: Toni
authors.initials: T
authors.lastname: Aebischer
mesh_terms: D000641:Ammonia / Q000378:metabolism*; D015703:Antigens, CD / Q000276:immunology; D001120:Arginine / Q000378:metabolism*; D051940:B7-2 Antigen / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology / Q000469:parasitology*; D016829:Giardia lamblia / Q000201:enzymology* / Q000276:immunology / Q000472:pathogenicity; D006801:Humans; D006867:Hydrolases / Q000235:genetics / Q000378:metabolism*; D007136:Immunoglobulins / Q000276:immunology; D016753:Interleukin-10 / Q000276:immunology; D053762:Interleukin-12 Subunit p40 / Q000276:immunology; D008070:Lipopolysaccharides / Q000276:immunology; D008562:Membrane Glycoproteins / Q000276:immunology; D010641:Phenotype; D010766:Phosphorylation; D019893:Ribosomal Protein S6 Kinases / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology; D014508:Urea / Q000378:metabolism; D000097802:CD83 Antigen
chemical_list: D000641:Ammonia; D015703:Antigens, CD; D001120:Arginine; D051940:B7-2 Antigen; D006867:Hydrolases; D007136:Immunoglobulins; D016753:Interleukin-10; D053762:Interleukin-12 Subunit p40; D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins; D019893:Ribosomal Protein S6 Kinases; D058570:TOR Serine-Threonine Kinases; D014409:Tumor Necrosis Factor-alpha; D014508:Urea; D000097802:CD83 Antigen; C497964:CD86 protein, human; C508609:IL10 protein, human; C546842:MTOR protein, human; C019723:arginine deiminase