Lectin-Carbohydrate Interactions in the Host-Parasite System

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DESCRIPTION (provided by applicant): Parasites are causative agents of some insect-borne infectious diseases such as malaria and filariasis. Insects respond to infection by parasites with both cellular and humoral immune responses. However, parasites have developed strategies to evade or suppress immune responses of their vectors. Insects must first recognize pathogens before they can mount an immune response, and recognition of nonself infective agents is mediated by pattern recognition receptors (PRRs). We have some understanding of the proteins that serve as PRRs in insects to stimulate immune responses to bacterial or fungal infection. However, very little is known about how insect immune systems recognize eukaryotic parasites and how these parasites evade the host immune system. We propose that parasites have variations in the molecular character of their surface, which determine selective binding of host proteins to parasites and the fate of parasites. The C-type lectins are a family of proteins with functions as PRRs in innate immunity. We have identified a group of C-type lectins (immulectins) from the tobacco hornworm Manduca sexta, which function as PRRs to stimulate immune responses. Immulectin-2 (IML-2) directly binds to nematodes Caenorhabditis elegans and Brugia malayi, and binding of IML-2 to C. elegans stimulates melanization of the worms. However, C-type lectins from mosquitoes have not been well characterized, particularly with regard to biochemical functions. Thus, we will use two systems, M. sexta - nematodes and the mosquito Armigeres subalbatus - filarial nematodes, to study interactions of IML-2 and Armigeres C-type lectins with microfilariae, and to study the roles of IML-2 and Armigeres lectins in melanotic encapsulation of microfilariae. The two specific aims are: 1) Investigate molecular interaction of an insect prototype C-type lectin, Manduca immulectin-2, with nematodes (B. malayi, B. pahangi, D. immitis, and C. elegans) as a guide to understanding potential lectin-parasite interactions that influence the outcome of pattern recognition and innate immune responses. 2) Investigate the ligand-binding specificity and affinity of nine selected Armigeres C-type lectins for microfilariae (B. malayi, B. pahangi, and D. immitis), and study functions of these lectins in melanotic encapsulation of microfilariae in Ar. subalbatus. Identify surface proteins or surface polysaccharides of C. elegans and B. malayi that can be recognized by Manduca immulectin-2 or Armigeres C-type lectins. PUBLIC HEALTH RELEVANCE Parasites are causative agents of some insect-borne infectious diseases such as malaria and filariasis. Insects respond to infection by parasites with both cellular and humoral immune responses. However, insects must first recognize pathogens before they can mount an immune response, and recognition of nonself infective agents is mediated by pattern recognition receptors (PRRs). We have some understanding of the proteins that serve as PRRs in insects to stimulate immune responses to bacterial or fungal infection. However, very little is known about how insect immune systems recognize non-fungal eukaryotic parasites: what are the pathogen-associated molecular patterns on such organisms and what PRRs bind to them? The C-type (calcium-dependent) lectins are a family of proteins with functions as PRRs in innate immune systems of vertebrates and invertebrates. This project is to investigate how selective binding of host proteins to parasites determines the fate of parasites using two systems, the tobacco hornworm Manduca sexta - nematodes and the mosquito Armigeres subalbatus - filarial nematodes.