The Laboratory of Molecular Parasitology looks for new ways to treat and prevent debilitating parasitic diseases that undermine the health, energy and productivity of people in developing countries. The research concentrates on the parasitic worms that cause river blindness or elephantiasis, and the parasite responsible for a deadly type of malaria.
River Blindness and Elephantiasis
River blindness afflicts over 37 million people, primarily in Africa, and is the second most common cause of infectious blindness. It is spread by a biting black fly that hosts the parasite, Onchocerca volvulus, in an early phase of its five-stage life cycle. Adult worms live in humans in subcutaneous tissues for up to 15 years and produce millions of minute worms called microfilaria. These burrow under the skin and cause debilitating, severe itching, and when they invade the eyes, they produce lesions that can lead to blindness. The filarial nematodes (Wuchereria bancrofti, Brugia timori and B. malayi) causing elephantiasis are transmitted by infected mosquito and infect 120 million people in developing countries. These parasites can live for 5 years or more and reside in the lymphatic system.
The laboratory has identified many proteins that may be essential to the development of O. volvulus, and studies eight of them as vaccine candidates. In experimental vaccines, no one protein kills every parasite, but they have reduced their numbers by 35 to 65 percent. Future research will optimize the ability of these proteins to induce protection so an effective vaccine can be produced. As many of the O. volvulus protective proteins are also found in other nematodes, a vaccine against river blindness could potentially work against the filariae parasites that cause elephantiasis and hookworms - and thus benefit billions of people around the world prone to these parasitic infections.
The laboratory also studies the ability of O. volvulus to influence the immune system and reduce its ability to fight infection by studying the immunomodulatory properties of distinct parasite proteins. In particularly, we are focused on a naturally occurring secreted protein from O. volvulus (rOv-ASP-1) with intrinsic immunostimulatory properties that it is a powerful immunostimulatory adjuvant; it promotes a balanced Th1/Th2 antibody response and cellular responses to several soluble vaccine candidate antigens, and commercial inactivated viral vaccines, including trivalent-inactivated flu vaccines.Our long-term objective is to develop this highly effective and safe protein adjuvant in a simple aqueous formulation of vaccines that also requires a much lower dose of antigen. By enhancing vaccine efficacy in this way, we can effectively increase the number of vaccine doses available that can be administered to humans to boost their immune response. This research has implications for the preventive treatment of various infectious diseases.
New Drug Therapies
The laboratory is engaged in a collaborative research effort to discover new drug therapies for the treatment of river blindness. The goal is to identify a novel, potent macrofilaricidal drug candidate that is capable of killing adult worms. In addition, the lab is studying proteins that are possibly involved in the endosymbiotic relationship between the filarial worms and the endosymbiotic bacterium of the genus Wolbachia that they harbor. These endobacteria are essential, as elimination of the endosymbiont leads to arrested larval development and the sterilization of the adult female parasite. It is expected that by identifying a select number of Wolbachia genes and their interacting partners in B. malayi involved in the symbiotic relationship, it will be possible to also identify processes within B. malayi and Wolbachia that may be sensitive to interference with new drugs.
The laboratory's malaria research targets P. falciparum at the stage when it penetrates a red blood cell, then multiplies and breaks out to infect new cells. Dr. Lustigman and her colleagues study parasite ligands, the molecules that bind P. falciparum to red blood cell receptors so it can enter them. The parasite employs several ligand-receptor interactions for invasion. To validate whether the parasite uses different pathways to invade red blood cells also under real-life conditions, the invasion of malaria parasites that are isolated from infected individuals living in endemic areas of South America is studied. We found that parasites from these regions have unique invasion profiles. Once the molecular action of these ligands and receptors has been charted, molecular candidates can be selected for development as potential drug or vaccine targets to inhibit invasion and prevent malaria.
- Melnikow E, Xu S, Liu J, Li L, Oksov Y, Ghedin E, Unnasch TR and Lustigman S (2011). Interaction of a Wolbachia WSP-like Protein with a Nuclear-encoded Protein of Brugia malayi. International Journal for Parasitology 41(10):1053-61.
Wang J, Tricoche N, Du L, Hunter M, Zhan B, Goud G, Didier ES, Liu J, Lu L, Marx PA, Jiang S and S Lustigman (2012). The Adjuvanticity of an O. volvulus-Derived rOv-ASP-1 Protein in Mice Using Sequential Vaccinations and in Non-Human Primates. PLoS One 7(5):e37019.
- Lopez-Perez M, Villasis E, Machado RL, Póvoa MM, Vinetz JM, Blair S, Gamboa D and Lustigman S (2012). Plasmodium falciparum Field Isolates from South America Use an Atypical Red Blood Cell Invasion Pathway Associated with Invasion Ligand Polymorphisms. PLoS One 7(10):e47913.