Hookworm infection is the leading cause of malnutrition and anemia in the developing world. Nearly one billion individuals worldwide are infected with these bloodfeeding nematode parasites, which attach to the intestinal mucosa and ingest blood and tissue. Chronic hookworm disease is associated with severe anemia, malnutrition, and growth/cognitive delay. Hookworms survive for years attached to the intestinal mucosa, therefore it has long been theorized that the parasites must effectively dampen the host immune response in order to prolong survival. It has been shown both in humans and animal models that hookworm infection is associated with varying degrees of immunosuppression, manifested by impaired lymphocyte responses to both hookworm and heterologous antigens. However, to date, little is known about the specific evolutionary strategies utilized by hookworms to evade the host immune response during host tissue migration and subsequent development in order to establish or maintain an infection. We have identified an orthologue of the inflammatory mammalian cytokine macrophage migration inhibitory factor (MIF) from the human hookworm Ancylostoma ceylanicum. This novel protein, AceMIF, is present in soluble extracts and excretory/secretory (ES) proteins from adult hookworms, but its potential role in disease pathogenesis has not been defined. Preliminary data reveal that AceMIF binds the human MIF receptor (CD74), and possesses macrophage chemotaxis and tautomerase catalytic activity similar to that of human MIF. Unlike the human protein, AceMIF is resistant to the small molecule inhibitor of mammalian MIFs, ISO-1, establishing proof of concept for the design of pathogen specific inhibitors. We propose that AceMIF promotes parasite survival by effectively modulating the host immune response at the site of attachment within the host small intestine. The immunomodulatory role of AceMIF will be investigated using cell based in vitro assays to elucidate signal transduction events distal to CD74 receptor engagement. The kinetics of host MIF expression in vivo will be deduced through tissue-specific ELISA and immunohistochemical studies will define the spatial relationship of host and parasite MIF expression. The role of host MIF during hookworm infection will be investigated by inhibition with neutralizing antibodies and ISO-1 using a fully permissive animal model of A. ceylanicum. The role of hookworm MIF in the pathogenesis of anemia and growth delay will be characterized using animal vaccine trials aimed at neutralizing the activity of AceMIF in vivo and impairing the ability of adult worms to survive within the intestine. These studies will allow for the development of new methods aimed at controlling this important human pathogen. ? ? ?
| Cho, Yoonsang; Vermeire, Jon J; Merkel, Jane S et al. (2011) Drug repositioning and pharmacophore identification in the discovery of hookworm MIF inhibitors. Chem Biol 18:1089-101 |
