Phone: (212) 570-3119
The primary goal of the Laboratory of Molecular Parasitology, headed by Sara Lustiman, Ph.D., is the prevention of parasitic diseases, specifically Onchocerciasis, also knows as "river blindness", Lymphatic Filariasis, also known as Elephantiasis, and Malaria. The Laboratory, however, is also focused on understanding the biology of Onchocerca Volvulus, Brugia Malayi, and Plasmodium Falciparum, the causative agents of these diseases, respectively. Information gained by studying the basic biology and host-parasite interactions may be used to identify key pathways essential for parasite development, survival and/or propogation that could be then targeted by novel drugs or vaccines.
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 causing elephantiasis are transmitted by mosquitos 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 the infective stages of O. volvulus, and studies eight of them as vaccine candidates. In experimental vaccines, no one protein kills all parasites, but each has reduced their survival by 35 to 65 percent. Future research will optimize the production of these proteins, refining their chemical structure so an effective vaccine can be produced. As many of the O. volvulus protective proteins are also found in other parasitic nematodes, the information gained from these studies could potentially support the efforts of developing a vaccine against 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 the incoming infection, by studying the immunomodulatory properties of distinct parasite proteins. Particularly, we are studying a molecule named Ov-ASP-1, that belongs to the activation associated secreted protein (ASP) family of nematode proteins and, more distantly, to the vespid venom allergen antigen. Ov-ASP-1 was found to have interesting immunological properties, which could be applied more broadly as biologics to benefit human health. Recombinant Ov-ASP-1 can stimulate both antibody and Th1 responses that exceed those generated against the antigens in the presence of alum or MPL+TDM adjuvants. Moreover, rOv-ASP-1 improved the immune efficacy, including lgG1 and lgG2a isotype responses, of commercial inactivated vaccines when used as a single vaccine or in a combination of three vaccines with reduced doses. In vitro, rOv-ASP-1 was able to not only induce the secretion of IFN-y from naive PBMC but also to enhance IFN-y recall responses to tetanus toxoid and HCV core antigens of normal helathy donor and of chronic hepatitis C virus infected patients PBMC's respectively. The recall response appeared to be dependent on contact between CD56+ and CD56- fractions of the PBMC's. This research has possible applications for prophylactic or therapeutic treatments of allergy, infectious diseases and/or tumors.
The laboratory is using functional genomic approaches to identify and study novel drug targets. One of these focuses is on protease inhibitors that have essential functions during embryogenesis and/or molting. We also use a common nematode, Caenorhabditis elegans, found in the soil, as a model system to study the functions of these common nematode proteins during their development. In addition, we study the 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. We expect through these studies to identify a selct number of Wolbachia genes and their interacting partners in B.malayi that are involved in the symbiotic relationship, and thus 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. The parasite employs several ligand-receptor interactions for invasion of red blood cells. Dr. Lustigman and her colleagues in Brazil study invasion under "real-life conditions" using malaria parasites that are isolated from infected individuals living in endemic areas of Brazil Amazon and red blood cells that carry blood group antigens prevalent in the endemic population. The focus is on invasion via the glycophorin B receptor and/or other receptors that are preferably used by these parasites. Once the molecular action of these ligands and receptors has been charted, molecular candidates can be selected for developmet as potential drug vaccine targets to inhibit invasion and prevent malaria.