Introduction

Research in our laboratory encompasses two broad disciplines. Our primary interest has been the pathogenesis of parasitic helminth infections. The majority of this work involves laboratory investigations aimed at characterizing the pathogenesis of hookworm infection, a leading cause of anemia and malnutrition in developing countries. Over the past decade, we have studied how adult hookworms, bloodfeeding nematode parasites, evade host defenses in order to feed successfully while attached to the intestinal mucosa. A number of novel hookworm proteins secreted at the site of attachment have been isolated and/or cloned, including anticoagulants, platelet inhibitors, immunomodulatory compounds (including a homologue of human cytokine macrophage migration inhibitory factor), and tissue degrading proteases. Using a model of infection with the human and animal hookworm Ancylostoma ceylanicum, it has also been demonstrated that immunization with single recombinant antigens confers partial protection against anemia and/or growth delay. This discovery further establishes the proof of concept for development of a vaccine that may impact the health of hundreds of millions of people worldwide. In addition to our work on hookworm pathogenesis, we have recently established field based immunoepidemiologic studies aimed at characterizing host immune responses to hookworm infection in endemic countries in Latin America, Asia, and Africa. These studies have been supported by the National Institutes of Health, The Burroughs Wellcome Fund, and The March of Dimes Birth Defects Foundation.

A second focus of our laboratory research is aimed at characterizing the anti-thrombotic mechanisms of hematophagous invertebrates, studies which have been carried out in conjunction with collaborators working in a variety of biological systems. To date, we have characterized novel anticoagulants and platelet inhibitors from hookworms, schistosomes, tsetse flies, and Ixodes ticks. These collaborative studies may ultimately lead to the identification of novel targets for preventing diseases caused or transmitted by bloodfeeding parasites, including hookworm anemia, schistosomiasis, sleeping sickness (African trypanosomiasis), and tick-borne infections. In addition, these parasite antithrombotics may also represent potential therapeutic agents for “first world” diseases associated with thrombosis, including heart disease, cancer, and stroke. This work has been supported through grants from the American Heart Association, and the Charles Hood Foundation. Preclinical development of lead compounds has also been supported by the NIH Small Business program in collaboration with L2 Diagnostics, Inc., a New Haven biotechnology company.

The long range goal of our research program is to advance the field of helminthology by identifying novel parasite virulence factors and characterizing host immune responses. In addition, we believe that anti-thrombotics isolated from hematophagous invertebrates hold great promise as therapeutic agents for the treatment and/or prevention of a variety of cardiovascular conditions.