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Title: IL-10 IS CRITICAL FOR RESISTANCE AND SURVIVAL DURING GASTROINTESTINAL HELMINTH INFECTION

Author
item SCHOPF, LISA - USDA, ARS, ANRI, IDRL
item HOFFMANN, KARL - NIH BETHESDA MD
item CHEEVER, ALLEN - BIOMED RES ROCKVILLE MD
item Urban, Joseph
item WYNN, THOMAS - NIH BETHESDA MD

Submitted to: Journal of Immunology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 1/15/2002
Publication Date: 3/1/2002
Citation: Schopf, L.R., Hoffmann, K.E., Cheever, A.W., Urban Jr, J.F., Wynn, T.A. 2002. Il-10 is critical for resistance and survival during gastrointestinal helminth infection. Journal of Immunology. 168:2383-2392 (2002)

Interpretive Summary: The rodent gastrointestinal whipworm parasite Trichuris muris provides an interesting and useful model for studying resistance and the expression of disease in both swine and humans infected with other species of Trichuris. The current study shows that there is a need for a balanced immune response to expel the worms and to minimize the extent of disease in the tissues that are infected with the worm. It was found that regardless of the number of infecting worms, adding antibiotics to the water of infected animals could reduce the level of disease. This indicated that tissue destruction and high mortality following infection with whipworm was indirectly related to the worm infection but directly related to secondary bacterial infection. The interest in this finding comes from the fact that similar results were observed in pigs infected with swine whipworm Trichuris suis and it suggests that antibiotic therapy may also be useful in treating humans infected with the human whipworm Trichuris trichiura. The impact of this study comes from the observation that a local immune response must be appropriate to the infectious agents that are present at the site of the response. Local production of immune response molecules that inherently work to inhibit attach by infectious agents can also have deleterious effects on surrounding tissues if they are over produced at the site leading to an imbalance in the nature of the immune response. This information will lead to better strategies for control the expression of disease in humans and livestock.

Technical Abstract: Resistance to many intestinal nematodes is dependent on the induction of polarized type 2 cytokine responses, whereas, type 1 responses can exacerbate these infections. The contributions of IL-4 and IL-13 to the development of resistance have been well described for a variety of intestinal parasites however; the role of IL-10 has not been previously investigated. In this study, we infected IL-10, IL-10/IL-4, IL-10/IL-12, IL-4, and IL-12-deficient mice with Trichuris muris to determine whether IL-10 contributes to the development of immunity. Interestingly, T. muris-infected IL-10, IL-4, and IL-10/IL-4-deficient mice failed to expel the parasite and animals deficient in IL-10 displayed marked morbidity and mortality. In contrast, double IL-10/IL-12-deficient mice were completely resistant and mounted a highly polarized type-2 cytokine response, demonstrating that the increased susceptibility of IL-10- deficient mice was dependent on IL-12. Further study suggested that the susceptibility of IL-10 and IL-10/IL-4-deficient mice was likely attributable to a marked increase in IFN-gamma and TNF-alpha production in those animals. The mortality observed in T. muris-infected IL-10 and IL-10/4-deficient mice correlated with increased inflammation, loss of Paneth cells and mucus in the cecum. Interestingly, survival was enhanced in T. muris-infected IL-10/4-deficient mice if a broad-spectrum antibiotic was administered, suggesting that an outgrowth of opportunistic bacteria was contributing to the high degree of morbidity and mortality. Overall, these studies reveal a critical role for IL-10 in the polarization of Th2 responses, development of resistance during T. muris infection, and maintenance of barrier function in the colon.