STRUCTURAL STUDIES OF HUMAN HOOKWORM VACCINE CANDIDATES

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Human hookworm disease is a devastating disease and a major source of blood-loss and iron-deficiency anemia in the developing world. Human hookworm infection affects about one billion people, many of them children, leading to stunted physical growth, mental underdevelopment and reduced quality of life. This disease is caused by parasitic nematodes with a complex life cycle which includes a free-living stage. Hookworms are the most pathogenic soil-transmitted helminthes. Hookworms are also masters of disguise that upon infection produce antigens that facilitate the evasion and suppression of the host¿s immune system. Immune suppression by hookworms leads to easier infection by other diseases, including malaria, tuberculosis, and HIV/AIDS. Conventional methods of hookworm control and eradication have largely failed and there is a need to develop new therapeutics to combat this devastating disease. There are on-going efforts to develop new tools to control hookworm infection, including a hookworm vaccine development program (The Human Hookworm Vaccine Initiative, HHVI). The HHVI identified candidate vaccine antigens from the infective L3 as well as from the adult stage. We are in the process of crystallizing and solving the structures of some of these vaccine candidates. Beamline access will facilitate our ongoing structural studies of novel hookworm vaccines and drug targets. Our second study is the 3-dimensional X-ray structural studies of membrane proteins involved in cell death. There are no known 3-dimensional structures of holins / anti-holins or other similar membrane proteins. Experiments are underway in our laboratory and that of our collaborators that may generate some of these structures. Our objective is to solve the structures of Cid A, Cid B, Lrg A and Lrg B from S. aureus and B. anthracis. Our third study is the mechanisms of drug detoxification by BChE.