Abstract
Acanthamoeba infections are characterized by an intense localized innate immune response associated with an influx of macrophages. Acanthamoeba protease production is known to affect virulence. Herein, the ability of Acanthamoeba trophozoite proteases, of either the laboratory Neff strain or a recently isolated clinical strain, to stimulate IL-12 and IL-6 and to activate protease-activated receptors, PAR1 and PAR2 expressed on murine macrophages, was investigated. Using selected protease inhibitors, leupeptin and E64, we showed that Acanthamoeba proteases can stimulate IL-12 and IL-6 by murine macrophages. Subsequently, using specific antagonists to inhibit PAR1 , and bone marrow-derived macrophages from PAR2 gene-deficient mice, we demonstrate that PAR1 , but not PAR2 contributes to macrophage IL-12 production in response to Acanthamoeba. In contrast, Acanthamoeba-induced IL-6 production is PAR1 and PAR2 independent. This study shows for the first time the involvement of PARs, expressed on macrophages, in the response to Acanthamoeba trophozoites and might provide useful insight into Acanthamoeba infections and their future treatments.
Highlights
Acanthamoeba castellanii is a facultative parasitic free-living amoeba known to be the agent of a serious, painful and potentially blinding keratitis, named Acanthamoeba keratitis (AK), as well as usually fatal encephalitis, named granulomatous amoebic encephalitis (GAE)
This study shows for the first time the involvement of Protease-activated receptors (PARs), expressed on macrophages, in the response to Acanthamoeba trophozoites and might provide useful insight into Acanthamoeba infections and their future treatments
IL-12 production by macrophages was induced by co-culture with both Neff and clinical isolate trophozoites in the absence of protease inhibitors
Summary
Acanthamoeba castellanii is a facultative parasitic free-living amoeba known to be the agent of a serious, painful and potentially blinding keratitis, named Acanthamoeba keratitis (AK), as well as usually fatal encephalitis, named granulomatous amoebic encephalitis (GAE). Among the 20 identified Acanthamoeba genotypes, A. castellanii T4 is the most common genotype in the environment and the most often associated with AK and non-AK infections as it is frequently isolated from the site of infections[2]. This has been attributed to its wide distribution in nature as well as in indoor environments, identified virulence factors, and its relative resistance to drugs and disinfectants[2]. The potential role of proteases released by Acanthamoeba, and their interaction with PARs expressed by macrophages have not until now been reported
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