Structural Basis of Novel Hookworm Vaccines

点击翻译按钮获取中文摘要

DESCRIPTION (provided by applicant): Human hookworm infection is a devastating disease which affects millions of the world's poorest people. This disease is caused by parasitic nematodes, that co-evolved with their hosts, consequently, these parasites are experts at surviving in hostile microenvironments where they feed on host tissues and evade host immune responses. There is a desperate need for alternative therapies that ameliorate the health status of infected people, prevent the infection of new patients, in order to alleviate the economic, and social burdens of these diseases. A viable approach is to develop novel vaccines that target critical stages in the complex life-cycles of the nematode parasite. A Gates-foundation sponsored vaccine initiative, the Human Hookworm Vaccine Initiative (HHVI) has identified vaccine candidates. HHVI vaccine candidates include Na-ASP-2 and Na-ASP-1, 2 members of the Ancylostoma secreted protein (ASP) family. Both are derived from infective L3 larval stage of Necatur americanus (Na), the predominant human hookworm parasite. The ASPs are a family of nematode proteins that are characterized by the presence of at least 1 pathogenesis related-1(PR-1) domain. The functions of the PR-1 domain are unclear as are molecular and structural basis for immune modulating activity of the ASPs. These need to be clarified in order to design better ASP based vaccines. Thus, a self-contained research project that takes a structure based approach to elucidate the function and mechanisms of action the ASPs is proposed. As part of these studies, the first structure of an ASP, the single PR-1 domain Na-ASP-2 has been solved to 1.56 Angstroms (protein data bank code 1U53). In addition, a 2 PR-1 domain ASP (Na-ASP-1) has been crystallized with data up to 2.7 Angstroms.