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

Abstract

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.

Targeting innate immunity for neurodegenerative disorders of the central nervous system

“…However, it remains uncertain as to which mediated the autophagy response, arginine deprivation or polyamine production. Yet, this is consistent with other reports demonstrating that L-arginine and L-arginine deprivation act as a sensor for autophagy arguably through mTOR signaling (Ban et al 2004;Yao et al 2008;Savaraj et al 2010;Wu et al 2011;Hsueh et al 2012;Banik et al 2013;Angcajas et al 2014). However, making the association less clear, the longer chain polyamine spermidine also acts as an inducer of autophagy but may not occur through mTOR signaling (Eisenberg et al 2009;Morselli et al 2009Morselli et al , 2011, yet it has been demonstrated to increase longevity, restore memory in various models through autophagy, and is elevated in centenarians (Eisenberg et al 2009;Morselli et al 2009Morselli et al , 2011Madeo et al 2010;Marino et al 2011;Minois et al 2011;Gupta et al 2013;Minarini et al 2013).…”

Interactions ofGiardia sp.with the intestinal barrier: Epithelium, mucus, and microbiota

“…65 Decreased expression of genes related to cell proliferation has been observed following Giardia exposure to human colonic cell lines. 28,66 Furthermore, sodium-glucose transport proteins such as SGLT-1 appear to play a protective role in enterocyte apoptosis during the infection. Indeed, by enhancing epithelial SGLT-1 activity and therefore increasing glucose uptake, enterocytes try to protect against Giardia-induced apoptosis.…”

Giardia duodenalis Cathepsin B Proteases Degrade Intestinal Epithelial Interleukin-8 and Attenuate Interleukin-8-Induced Neutrophil Chemotaxis

“…Previous studies have demonstrated that mast cell hyperplasia occurs in the late stages of a Giardia infection or following parasite clearance (20,21) and that eosinophil accumulation may occur in vivo in an isolate-dependent manner (22). Furthermore, G. duodenalis parasite products have been shown to modulate dendritic cell responses to lipopolysaccharide (23,24), while separate studies have demonstrated that intestinal epithelial cells (IECs) exposed to Giardia trophozoites produce a unique chemokine profile (25). The need to investigate G. duodenalis's ability to modulate its host's proinflammatory responses is now apparent due to data collected from in vivo animal and human studies.…”