The Pathogenic Cascade of Acanthamoeba Keratitis
Clarke, Daniel William
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Acanthamoeba keratitis is a blinding infection of the cornea caused by the ubiquitous, free-living amoeba, Acanthamoeba. The pathogenic cascade of Acanthamoeba keratitis is a sequential process that begins with adherence of trophozoites to the corneal epithelium and culminates in the destruction of the corneal epithelium and the dissolution of the corneal stroma. This work examined the pathophysiology and immunobiology of Acanthamoeba keratitis. First, we explored possible mechanisms to explain why A. castellanii remains restricted to the cornea and rarely produces intraocular infections. One hypothesis proposed that trophozoites cannot penetrate Descemet's membrane and the corneal endothelium to enter the anterior chamber. However, amoebae utilized a mannose-induced serine protease to penetrate Descemet's membrane within 24 hr of in vitro culture. The second hypothesis proposed that the trophozoites can enter the anterior chamber; however, the aqueous humor contains factors that either induce encystment or kill the amoebae. Injection of amoebae into the anterior chamber induced a robust neutrophil infiltrate, which was associated with complete clearance by day 15 post anterior chamber injection. This indicates that neutrophils of the innate immune apparatus are important in preventing Acanthamoeba keratitis from progressing to become an intraocular infection. Previous reports have shown that intracorneal instillation of sterile latex beads results in resistance to Acanthamoeba keratitis and mitigation of corneal inflammation. This study examined the mechanisms that could be responsible for the latex bead protective effect. Latex bead treatment induced a significant increase in the infiltration of macrophages into the corneas that peaked at day 4 of infection. Additionally, depletion of conjunctival macrophages with the macrophagicidal drug, clodronate, eliminated the latex bead protective effect, providing further evidence that macrophages are crucial in resistance to Acanthamoeba keratitis. With the exception of mucosal IgA antibody, the adaptive immune apparatus is not typically effective against Acanthamoeba keratitis. The results presented here provide evidence that neutrophils and macrophages of the innate immune response are crucial in resistance to Acanthamoeba keratitis. Collectively, these results suggest that recruitment and/or activation of the innate immune apparatus may lead to resolution of disease in Acanthamoeba keratitis patients.