IL-1β Suppresses Innate IL-25 and IL-33 Production and Maintains Helminth Chronicity

Abstract

Approximately 2 billion people currently suffer from intestinal helminth infections, which are typically chronic in nature and result in growth retardation, vitamin A deficiency, anemia and poor cognitive function. Such chronicity results from co-evolution between helminths and their mammalian hosts; however, the molecular mechanisms by which these organisms avert immune rejection are not clear. We have found that the natural murine helminth, Heligmosomoides polygyrus bakeri (Hp) elicits the secretion of IL-1β in vivo and in vitro and that this cytokine is critical for shaping a mucosal environment suited to helminth chronicity. Indeed in mice deficient for IL-1β (IL-1β^−/−), or treated with the soluble IL-1βR antagonist, Anakinra, helminth infection results in enhanced type 2 immunity and accelerated parasite expulsion. IL-1β acts to decrease production of IL-25 and IL-33 at early time points following infection and parasite rejection was determined to require IL-25. Taken together, these data indicate that Hp promotes the release of host-derived IL-1β that suppresses the release of innate cytokines, resulting in suboptimal type 2 immunity and allowing pathogen chronicity. Parasitic soil-transmitted helminths (STH) live, feed and mate within the intestine of their mammalian hosts. Infection is caused by ingestion of eggs and larvae or by active penetration of the skin by larvae from contaminated soil in poverty stricken areas lacking adequate sanitation. Infection with soil-transmitted helminths results in a wide range of symptoms including intestinal complications (diarrhea, abdominal pain), anemia, general malaise and nutritional deficiencies that negatively impact on working and learning capacities and impair physical growth. The host typically raises a strong type 2 immune response against the invading helminth; however, the majority of helminthes have developed the capacity to escape effective immunity and can remain chronically within the intestine for years. We explored the mechanisms responsible for helminth chronicity using a murine model of Heligmosomoides polygyrus bakeri (Hp) infection. We found that Hp is able to induce IL-1β secretion in the intestine and that this cytokine acts to suppress the production of the innate cytokines IL-25 and IL-33. Furthermore, we show that parasite rejection requires IL-25 indicating that suboptimal production of this cytokine in the presence of IL-1β is responsible for the ability of IL-1β to promote parasite chronicity. Our study provides new insights into the mechanisms used by helminths to establish chronic infections, and reveals a novel role for IL-1β in protective immunity.