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We currently study two tropical infectious diseases, malaria and leptospirosis, through at UCSD in the field in the Peruvian Amazon.

Malaria:

Our malaria studies focus on molecular, cellular and biochemical mechanisms by which the malaria parasite (the ookinete) stage invades the mosquito midgut; the long-term goal is to develop strategies of blocking malaria transmission from humans to mosquitoes. Malaria is among the three most important causes of gloal morbidity and mortality, affecting hundreds of millions of people in Africa, Asia, and South America yearly, and leading to millions of deaths annually. Drug resistance to standard anti-malarial drugs is increasing and no deployable malaria vaccine has been produced. There is major emphasis in governmental and private funding agencies on malaria research to address this major ongoing public health threat.

The genome of the lethal human malaria parasite, Plasmodium falciparum has been sequenced, as well as that of the major mosquito vector, Anopheles gambiae. In addition, other Plasmodium genomes of parasites used to study animal models of malaria have been sequenced, including our collaboration with the Sanger Centre in Cambridge, U.K. to sequence the genome of the avian malaria parasite, Plasmodium gallinaceum, which is a major model for detailed mechanistic studies of malaria transmission to mosquitoes. We also have ongoing proteomics projects in collaboration with John Yates, Ph.D. and colleagues of the Scripps Research Institute to define the ookinete proteome. These projects in genomics and proteomics are at the cutting edge of the field, and are timely resources and an amazing scientific environment for highly motivated students interested in exploring the cutting edge of a field of global importance.

The overall theme of our studies in malaria transmission is that by understanding the molecular and cellular mechanisms by which the ookinete invades the mosquito midgut, novel approaches to developing strategies of preventing malaria transmission can be developed. Over the past 8 years, we have focused on the ookinete-secreted chitinase, which allows the ookinete to penetrate the first physical barrier to parasite invasion, the chitin-containing peritrophic matrix surrounding the blood meal. Antibodies to recombinant, enzymatically active Plasmodium chitinase block parasite infectivity for the mosquito when added to an infectious blood meal. Deleting the extreme carboxy-terminus of the P. falciparum chitinase prevents ookinete secretion of the protein, and hence blocks the parasite's ability to invade the mosquito midgut. This was a formal proof that the Plasmodium We have also identified a number of other ookinete-secreted proteins, antibodies to which block ookinete invasion of the mosquito midgut, including a secreted integrin-like protein and the ookinete surface molecular CTRP (Circumsporozoite and thrombospondin-related anonymous protein-related protein). We have also shown that a recombinant, insect-cell-produced, single chain antibody derived from a hybridoma producing a chitinase-neutralizing monoclonal antibody, blocks ookinete infectivity for the mosquito. Our studies depend heavily on detailed studies of parasite-mosquito interactions; hence we have an insectary facility on the UCSD campus in which Anopheles and Aedes aegypti mosquitoes are raised for malaria transmission experiments.

Our studies also have a strong focus on cell biology, in particular, defining mechanisms by which ookinete-secreted proteins are packaged into their membrane-bound secretory organelles, micronemes. Using immuno-electron microscopy and confocal microscopy, we have demonstrated, for the first time, a novel pathway of secretion in ookinetes that is relevant to the entire class of Apicomplexan parasites. Current studies focus on delineating mechanisms of organellar biogenesis, with a variety of proteins under study.

Leptospirosis:

Leptospirosis is a zoonotic disease caused by spirochetes of the genus Leptospira, which are transmitted from infected mammals (wild and domestic) to humans via infected urine. Our studies range from epidemiology and ecology to immunology to molecular pathogenesis. One of the major questions we are addressing is why some patients with leptospirosis develop only inapparent infection or mild febrile disease, while others develop fulminant jaundice, renal failure, hemorrhage, meningitis and.or myocarditis/heart failure. We have recently successfully developed a small animal model which is allowing us to study molecular and cellular mechanisms of the pathogenesis of severe leptospirosis. In our field site in the Peruvian Amazon region of Iquitos, we have found leptospirosis to cause far more infection and morbidity than the other presumed causes of febrile illness such as malaria or dengue. Our studies in Iquitos include human and mammalian ecology studies.

Keywords: Parasitology, Bacterial pathogenesis, Leptospirosis, Spirochete, Genomics, Proteomics, Malaria Tropical Medicine, Field work

Track(s):
Microbiology/Immunology