Transcriptional Responses of Parasite and Host during Intestinal Colonization and Invasion by Entamoeba histolytica
Amebiasis is a parasitic disease caused by a protozoan parasite Entamoeba histolytica. The most common manifestations of E. histolytica infection are dysentery and liver abscesses. E. histolytica usually resides in the large intestine, and can persist there for months or years and cause an asymptomatic intestinal infection. However, clinical amebiasis occurs when the parasite penetrates the colon wall, causing ulcerative colitis, or disseminates into other organs, most commonly the liver, leading to abscess formation. Current therapy for amebiasis relies on metronidazole, which was first introduced in 1959. Potential resistance of E. histolytica to metronidazole is an increasing concern and clinical failures have been linked to other metronidazole-resistant protozoa. Standard treatment with metronidazole requires three doses per day for 10 days and is accompanied by frequent side effects. In addition, metronidazole has no effect on intraluminal carriage, so follow-up treatment with a second, luminal active drug such as paromomycin is recommended to prevent prolonged carriage and excretion. Therefore, a shorter, less toxic, and more effective therapy is needed.
Our research on Entamoeba histolytica includes understanding how specific host factors influence the transcriptional program of E. histolytica and protease activity related to intestinal invasion. In collaboration with Sharon Reed of University of California, San Diego, we are studying the role of cysteine proteases in amebiasis.
In parallel, we pioneered the development of a high throughput assay for screening potential drugs against Entamoeba in culture. Utilizing this automated screening methodology we recently identified auranofin, an FDA-approved oral drug, as 10 times more effective in culture than metronidazole, the current drug of choice for amebiasis. Auranofin has been in clinical use to treat rheumatoid arthritis since 1985. Our studies indicated that auranofin targets the E. histolytica thioredoxin reductase. Oral auranofin at low dose significantly decreased the number of parasites and also host inflammation in a mouse model of colitis and a hamster model of amebic liver abscess. A similar dose of metronidazole had no effect. These findings suggest that thioredoxin reductase is a valid drug target in E. histolytica, which can be inhibited with a “repurposed” FDA approved drug, auranofin. Based on these results, the US FDA has given Orphan-Drug status to auranofin for treatment of amebiasis. A Phase II clinical trial of auranofin for human amebiasis is currently being planned by Dr. Reed.