Weill Medical College of Cornell University

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Malaria:

Endothelial Progenitor Cells and Malaria Pathogenesis. Golightly, Gyan. Despite its virulence, the pathophysiologic basis of P. falciparum disease and cerebral malaria are poorly understood. Sequestration of infected red blood cells (iRBCs) in the microvasculature is a major pathologic finding in P. falciparum infections. The repair of microvasculature damaged by infection may occur either by the proliferation or migration of local endothelial cells, or the recruitment of bone marrow-derived circulating endothelial progenitor cells (EPCs). We hypothesize that P. falciparum infection results in an imbalance between microvascular damage and repair. Cerebral malaria occurs when circulating EPCs are diminished and damaged endothelial cells cannot be replaced. To test this hypothesis, EPC levels and markers of bone marrow activation in P. falciparum-infected patients with different degrees of disease severity are being compared with normal uninfected controls. These studies are being performed in collaboration with the Noguchi Memorial Institute for Medical Research in Accra, Ghana.

• Desruisseaux MS, Machado FS, Weiss LM, Tanowitz HB, Golightly LM. Cerebral malaria, a vasculopathy. Am J Pathol 2010;176(3):1075-78.
• Gyan B, Quarm Goka B, Adjei GO, Tetteh JKA, Kusi KA, Aikins A, Dodoo D, Lesser ML, Sison CP, Das S, Howard ME, Milbank E, Fischer K, Rafii S, Jin D, Golightly LM. Cerebral malaria is associated with low levels of circulating endothelial progenitor cells in African children. Am J Trop Med Hyg 2009;80:541-46.

A Non-invasive Cell Phone Imaging Probe for Diagnosing Malaria. Bilenca, Golightly. A Non-invasive Cell Phone Imaging Probe for Diagnosing Malaria. Bilenca, Golightly. Cerebral malaria is a major cause of morbidity and mortality particularly in young children. There are currently no tests to determine which of those infected will develop the syndrome or recover. In collaboration with Dr. Alberto Bilenca at the University of the Negev in Israel, a cell phone imaging system that can non-invasively detect malaria parasites in the blood is being developed. The system uses a polarized laser to detect hemozoin crystals indicative of malaria parasite infection, as well as micro-obstructions in the circulatory system that result from the infection and have been postulated to be indicative of disease severity. Ultimately human testing of the device is planned in Ghana in collaboration with colleagues at the NMIMR. This project is part of a Bill and Melinda Gates Foundation Grand Challenges Explorations to Create Low-Cost Cell Phone-Based Applications for Priority Global Health Conditions.

Genetic variation in the human malaria parasite, Plasmodium falciparum. Kirkman. Malaria, a vector borne disease, causes great morbidity and mortality in tropical and subtropical regions of the world. Infection with the parasite leads to one to two million deaths and 300 to 500 million clinical cases per year. Crucial to the continuing burden of disease is the parasite�s ability to evade clearance in the host; both the ability to evade the host immune system by changing surface proteins inserted into the host red blood cell, a process termed antigenic variation, and the ability to develop drug resistance. Underlying both is the ability of this eukaryotic pathogen with a haploid genome for most of its lifecycle to generate and incorporate DNA mutations. We aim to study malaria DNA recombination and repair in the context of disease pathogenesis focusing on antigenic variation and the development of drug resistance.

Antigenic Variation: After invading a red blood cell the malaria parasite modifies its host cell in different ways including inserting parasite derived proteins into the surface of the parasitized red blood cell. These parasite proteins bind to receptors on host endothelial cells, a process termed cytoadherence and is one of the key pathogenic and virulence factors of P. falciparum infections. A surface protein termed Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) was identified as the protein responsible for cytoadherence. This protein is encoded by the large multi-copy gene family termed var. There is great diversity within this gene family and the mechanisms creating this diversity are a focus of our work. To better understand the generation of genetic diversity within this multi-copy gene family we are manipulating the parasite genome to determine how the parasite repairs damaged DNA.

Drug Resistance: We are studying the mechanisms by which a parasite becomes resistant to antimalarials by focusing on the ways in which the parasites acquire mutations in DNA. Using genetically modified parasites we are studying the ability of the parasite to generate point mutations and gene duplications that have been previously associated with drug resistance in the field. We are able to manipulate both copy number and specific sequence in order to further study the interplay of different aspects of pathways implicated in parasite drug resistance.

• Djimdé AA, Kirkman L, Kassambara L, Diallo M, Plowe CV, Wellems TE and Doumbo KO. Culture in vitro de souches locales de Plasmodium falciparum au Mali. Le Bulletin de la Soci�t� de pathologie exotique 2007;100:3-5.
• Frank M, Kirkman L, Constantini D, Sanyal S, Lavazec C, Templeton T and Deitsch K. Frequent recombination events generate diversity within the multi-copy variant antigen gene families of Plasmodium falciparum. International Journal of Parasitology 2008;38: 1099-1109.