Development of Fatal Intestinal Inflammation in MyD88 Deficient Mice Co-infected with Helminth and Bacterial Enteropathogens

Libo Su,Mei Zhang,Chienwen Su,Hai Ning Shi,Yujuan Qi,Meiqian Weng,Xichen Zhang,Christian R Engwerda

doi:10.1371/journal.pntd.0002987

Abstract

Infections with intestinal helminth and bacterial pathogens, such as enteropathogenic Escherichia coli, continue to be a major global health threat for children. To determine whether and how an intestinal helminth parasite, Heligomosomoides polygyrus, might impact the TLR signaling pathway during the response to a bacterial enteropathogen, MyD88 knockout and wild-type C57BL/6 mice were infected with H. polygyrus, the bacterial enteropathogen Citrobacter rodentium, or both. We found that MyD88 knockout mice co-infected with H. polygyrus and C. rodentium developed more severe intestinal inflammation and elevated mortality compared to the wild-type mice. The enhanced susceptibility to C. rodentium, intestinal injury and mortality of the co-infected MyD88 knockout mice were found to be associated with markedly reduced intestinal phagocyte recruitment, decreased expression of the chemoattractant KC, and a significant increase in bacterial translocation. Moreover, the increase in bacterial infection and disease severity were found to be correlated with a significant downregulation of antimicrobial peptide expression in the intestinal tissue in co-infected MyD88 knockout mice. Our results suggest that the MyD88 signaling pathway plays a critical role for host defense and survival during helminth and enteric bacterial co-infection.

Highlights

Infectious gastroenteritis leading to severe diarrhea is a major global health threat, in children
Helminth parasites are of particular interest in this context because of their ability to modulate host immune responses, and because their geographic distribution coincides with those parts of the world where infections caused by bacterial enteropathogens are most problematic
We found that coinfection with the helminth parasite significantly worsened Citrobacter-induced colitis in the MyD88-deficient mice, in association with increased mortality and compromised innate immune responses

Summary

Introduction

Infectious gastroenteritis leading to severe diarrhea is a major global health threat, in children. Bacteria such as enteropathogenic E. coli (EPEC) are important agents of this disease. The ability of the host to control such bacterial pathogens may be influenced by concurrent infections. Helminth infections, including those caused by soil-transmitted helminths, schistosomiasis and filariasis, form a major group of neglected tropical diseases that affect about one third of the world’s population [1]. It is well known that helminths induce Th2 polarization of helper T cells, our understanding of the exact mechanism by which these parasites modulate the host’s innate defense against concurrently infecting bacterial enteropathogens is incomplete

Methods

Results

Discussion

Conclusion