Abstract
Intestinal invasion by the protozoan parasite Entamoeba histolytica is characterized by remodelling of the extracellular matrix (ECM). The parasite cysteine proteinase A5 (CP-A5) is thought to cooperate with human matrix metalloproteinases (MMPs) involved in ECM degradation. Here, we investigate the role CP-A5 plays in the regulation of MMPs upon mucosal invasion. We use human colon explants to determine whether CP-A5 activates human MMPs. Inhibition of the MMPs' proteolytic activities abolishes remodelling of the fibrillar collagen structure and prevents trophozoite invasion of the mucosa. In the presence of trophozoites, MMPs-1 and -3 are overexpressed and are associated with fibrillar collagen remodelling. In vitro, CP-A5 performs the catalytic cleavage needed to activate pro-MMP-3, which in turn activates pro-MMP-1. Ex vivo, incubation with recombinant CP-A5 was enough to rescue CP-A5-defective trophozoites. Our results suggest that MMP-3 and/or CP-A5 inhibitors may be of value in further studies aiming to treat intestinal amoebiasis.
Highlights
Intestinal invasion by the protozoan parasite Entamoeba histolytica is characterized by remodelling of the extracellular matrix (ECM)
We propose that the cysteine proteinase A5 (CP-A5) has the following two functions during intestinal invasion: (i) the indirectly triggering of matrix metalloproteinases (MMPs) production and release through inflammatory cytokine induction, and (ii) directly catalytic cleavage of pro-MMP-3 and conversion into active MMP-3
We demonstrated that proMMP-1, pro-MMP-3, the [MMP-1:tissue endogenous inhibitors of MMPs (TIMPs)-1] and [MMP-3:TIMP1] complexes, and WT-r-CP-A5 were not able to cleave the FS-6 substrate; any increase in fluorescence was specific for activated MMPs
Summary
Intestinal invasion by the protozoan parasite Entamoeba histolytica is characterized by remodelling of the extracellular matrix (ECM). The cysteine proteinase A5 (CP-A5) interacts directly with integrins at the surface of human colon epithelial cells and induces the secretion of pro-inflammatory cytokines We propose that the CP-A5 has the following two functions during intestinal invasion: (i) the indirectly triggering of MMP production and release through inflammatory cytokine induction, and (ii) directly catalytic cleavage of pro-MMP-3 and conversion into active MMP-3. Together, these processes are involved in the ECM remodelling required for tissue invasion
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