Entamoeba histolytica-secreted cysteine proteases induce IL-8 production in human mast cells via a PAR2-independent mechanism

Abstract

Entamoeba histolytica is an extracellular tissue parasite causing colitis and occasional liver abscess in humans. E. histolytica-derived secretory products (SPs) contain large amounts of cysteine proteases (CPs), one of the important amoebic virulence factors. Although tissue-residing mast cells play an important role in the mucosal inflammatory response to this pathogen, it is not known whether the SPs induce mast cell activation. In this study, when human mast cells (HMC-1 cells) were stimulated with SPs collected from pathogenic wild-type amoebae, interleukin IL-8 mRNA expression and production were significantly increased compared with cells incubated with medium alone. Inhibition of CP activity in the SPs with heat or the CP inhibitor E64 resulted in significant reduction of IL-8 production. Moreover, SPs obtained from inhibitors of cysteine protease (ICP)-overexpressing amoebae with low CP activity showed weaker stimulatory effects on IL-8 production than the wild-type control. Preincubation of HMC-1 cells with antibodies to human protease-activated receptor 2 (PAR2) did not affect the SP-induced IL-8 production. These results suggest that cysteine proteases in E. histolytica-derived secretory products stimulate mast cells to produce IL-8 via a PAR2-independent mechanism, which contributes to IL-8-mediated tissue inflammatory responses during the early phase of human amoebiasis.

Diet regulates liver autophagy differentially in murine acute Trypanosoma cruzi infection

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An amebic protein disulfide isomerase (PDI) complements the yeast PDI1 mutation but is unable to support cell viability under ER or thermal stress

“…Many of these domains comprise the canonical tetrapeptide CxxC as the active site motif, while some others have a derivative sequence, in which one cysteine was substituted by a selenocysteine, serine, or threonine residue [3]. So far studied, almost all eukaryotic cells contain a PDI family with a diverse domain structure and function, for instance, 21 for human and five in yeast cells [4,5].The pathobiology of the protozoan parasite Entamoeba histolytica, the causative agent of human amebiasis, depends on direct cell contact and secretion of virulence factors [6][7][8]. Although the native conformation of some of the latter is stabilized by disulfide bondsAbbreviations 5-FOA, 5-fluoroorotic acid; ER, endoplasmic reticulum; G-418, geneticin; PDI, protein disulfide isomerase; SD, synthetic dextrose; UPR, unfolded protein response; YPD, yeast extract/peptone/dextrose.…”

Entamoeba histolytica: Host parasite interactions at the colonic epithelium

“…Alternatively, Eh cysteine proteases can increase the expression of IL-8 however, this occurs independent of the protease-activated receptor 2 (PAR2). 32 Cysteine proteases have emerged as critical virulence factors in Eh pathogenesis. This stems mainly from observations that attenuation of protease activity with E64 or silencing of EhCP5, the predominant CP that is secreted, leads to reduced gut inflammation, damage to the barrier and Eh that are unable to form liver abscess.…”