Abstract
The mucosal cytokine response of healthy humans to parasitic helminths has never been reported. We investigated the systemic and mucosal cytokine responses to hookworm infection in experimentally infected, previously hookworm naive individuals from non-endemic areas. We collected both peripheral blood and duodenal biopsies to assess the systemic immune response, as well as the response at the site of adult worm establishment. Our results show that experimental hookworm infection leads to a strong systemic and mucosal Th2 (IL-4, IL-5, IL-9 and IL-13) and regulatory (IL-10 and TGF-β) response, with some evidence of a Th1 (IFN-γ and IL-2) response. Despite upregulation after patency of both IL-15 and ALDH1A2, a known Th17-inducing combination in inflammatory diseases, we saw no evidence of a Th17 (IL-17) response. Moreover, we observed strong suppression of mucosal IL-23 and upregulation of IL-22 during established hookworm infection, suggesting a potential mechanism by which Th17 responses are suppressed, and highlighting the potential that hookworms and their secreted proteins offer as therapeutics for human inflammatory diseases.
Highlights
The hookworms Necator americanus and Ancylostoma duodenale infect an estimated 740 million people, mostly in tropical regions of the world, causing significant burden of disease [1]
We conducted a clinical trial where we obtained gut biopsies from people experimentally infected with hookworms and present here the first report of the immune response by healthy human gut tissue to a parasitic worm
We show that hookworms suppress the production of pro-inflammatory molecules and promote the expression of anti-inflammatory and wound healing molecules in the gut, providing a potential mechanism by which parasitic worms reside for long periods in their human hosts and suppress inflammation associated with auto-immune diseases
Summary
The hookworms Necator americanus and Ancylostoma duodenale infect an estimated 740 million people, mostly in tropical regions of the world, causing significant burden of disease [1]. Despite efforts to eliminate this disease from developing countries, experimentally-induced hookworm infection offers potential as an anti-inflammatory therapy for human autoimmune [3] and allergic [4,5] diseases. Despite their importance in regards to disease burden in resource poor countries (especially in children and women of child bearing years) and their potential as an anti-inflammatory therapy for use in industrialized countries, little is known about the mucosal immune responses of humans to hookworm, or any other gastrointestinal (g.i.) helminths parasites. IL-5 production correlates positively with resistance to reinfection after anthelmintic drug cure [8], and levels of IgE reactive against defined larval antigens are negatively associated with hookworm egg counts [9]
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