Molecular negotiations at the host-parasite interface

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Parasitism is the commonest life-style for animals, yet hosts resist almost all parasite species; each host has a set of relatively specific parasites. Host defense systems provide inhospitable conditions for the vast majority of parasite species. The molecular negotiations between parasite and host that enable parasite success underlie a fundamental aspect of life: how to prevent parasitism to conserve nutritional resources (on the part of the host) and how to evade host defenses to reproduce (on the part of the parasite). The molecules deployed in this negotiation are poorly understood; our research aims to develop a better understanding of how parasites overcome host defenses and usurp host resources. We used genomic/proteomic approaches to identify proteins secreted by a filarial parasitic nematode, Brugia malayi, and showed that the main drug for filariasis, ivermectin, blocks protein secretion by the parasite. We will continue work on the molecular basis of the host-parasite interface using several methods. These include intensive studies on how parasite secreted proteins affect host immune responses at the cellular level, based on a deeper understanding of the secretomes of nematodes. We will also investigate interactions between parasites and their hosts based on the release of metabolites which modulate immune responses. Finally, we will resolve how ivermectin persistently sterilizes adult parasites (it does not kill them). Our hypothesis is that the drug inhibits the ingestion of iron bound to host proteins by paralyzing the pharynx. Most nutrients needed by filarial nematodes are obtained via absorption, but iron is tightly bound to host proteins and requires ingestion. Production of microfilariae requires a constant supply of heme, and the irreversible nature of the ivermectin-receptor interaction means that recovery from drug exposure depends on renewal of parasite receptors in target tissues. As host- parasite interactions represent prime drivers of evolution, understanding the interface on a molecular level has deep implications for basic animal biology.