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

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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. Infections with intestinal helminths and enteric bacterial pathogens such as enteropathogenic Escherichia coli (EPEC) continue to be major global health problems, especially for children. The ability of the host to control bacterial enteropathogens may be influenced by host immune status and by concurrent infections. 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. In this study, we determined how intestinal helminth infection regulates host innate immunity against bacterial enteropathogens by using a murine co-infection model. This model involves co-infection with the intestinal nematode parasite Heligmosomoides polygyrus and the Gram-negative bacterial pathogen Citrobacter rodentium, the murine equivalent of EPEC. The infections were carried out in wild-type mice and in mice lacking MyD88, a protein required for signaling by the Toll-like receptors. We found that co-infection with the helminth parasite significantly worsened Citrobacter-induced colitis in the MyD88-deficient mice, in association with increased mortality and compromised innate immune responses. Our observations demonstrate an important role for MyD88-dependent and -independent signaling in host survival during helminth and enteric bacterial co-infection.

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