Immunomodulation by hookworm infection
Human hookworm infection is a leading cause of iron-deficiency anemia and malnutrition in the tropical developing world with an estimated 600 million cases. Hookworm infection is unique among human helminthiases because there is no evidence of age- or exposure-related immunity, with adults typically harboring the highest parasite burdens. This observation leads to hypothesize that exposure to adult hookworms, or their secreted products, might induce immunosuppression. Studies over the last decade have revealed that adult hookworms release a battery of pharmacologically active agents into host tissues, some of them with immunomodulatory properties. Tissue inhibitors of metalloproteinases (TIMPs) are proteinase inhibitors critical in the control of metalloproteinases (MMPs). Expression of TIMPs, aside from its role in proteinase equilibrium, has been shown to possess immunoregulatory functions. A hookworm TIMP (AcTIMP) has been identified in the hookworms Ancylostoma caninum and A. ceylanicum. AcTIMP is among the most abundant proteins released by the adult parasite (40 ng/hour). We hypothesize that AcTIMP is taken up by mucosal dendritic cells that produce tolerogenic signals to induce expansion of CD4+T cells subsets with a regulatory function. We intend to study the effect of AcTIMP on DC and CD4+ T cell function, investigate how the parasite molecule affects the physiology of the DC to initiate a tolerogenic response, and determine whether there are domains on the AcTIMP molecule that are pivotal to the immunomodulatory effect.