Role of Eosinophils and Tumor Necrosis Factor Alpha in Interleukin-25-Mediated Protection from Amebic Colitis.

Zannatun Noor,William A Petri,Koji Watanabe,Erica L Buonomo,Stacey L Burgess,Mayuresh M Abhyankar,Carrie A Cowardin,Alan Sher

doi:10.1128/mbio.02329-16

Abstract

ABSTRACTThe parasite Entamoeba histolytica is a cause of diarrhea in infants in low-income countries. Previously, it was shown that tumor necrosis factor alpha (TNF-α) production was associated with increased risk of E. histolytica diarrhea in children. Interleukin-25 (IL-25) is a cytokine that is produced by intestinal epithelial cells that has a role in maintenance of gut barrier function and inhibition of TNF-α production. IL-25 expression was decreased in humans and in the mouse model of amebic colitis. Repletion of IL-25 blocked E. histolytica infection and barrier disruption in mice, increased gut eosinophils, and suppressed colonic TNF-α. Depletion of eosinophils with anti-Siglec-F antibody prevented IL-25-mediated protection. In contrast, depletion of TNF-α resulted in resistance to amebic infection. We concluded that IL-25 provides protection from amebiasis, which is dependent upon intestinal eosinophils and suppression of TNF-α.

Highlights

The parasite Entamoeba histolytica is a cause of diarrhea in infants in low-income countries
We demonstrate that the anti-inflammatory cytokine IL-25 is suppressed during E. histolytica infection in humans and in a mouse model of amebic colitis
IL-25 is suppressed during E. histolytica infection in humans and in the mouse model

Summary

Introduction

The parasite Entamoeba histolytica is a cause of diarrhea in infants in low-income countries. It was shown that tumor necrosis factor alpha (TNF-␣) production was associated with increased risk of E. histolytica diarrhea in children. We discovered that the intestinal epithelial cytokine IL-25 was suppressed during amebic colitis in humans and that protection could be restored in the mouse model by IL-25 administration. E. histolytica disrupts the mucosal barrier in a sequential process of adherence to intestinal epithelial cells by a parasite Gal/GalNAc lectin, followed by killing of the epithelial cells in a nibbling process termed amebic trogocytosis, leading to penetration of the epithelium and destruction of underlying tissue [6,7,8]. High TNF-␣ correlated with diarrhea and disease severity in children infected with E. histolytica, and blocking TNF-␣ with neutralizing monoclonal antibody (MAb) was shown to reduce inflammation and intestinal damage [16,17,18]. Reactive oxygen species and nitric oxide to kill E. histolytica; oxygen free radicals may be responsible for collateral tissue damage [15]

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Conclusion