Golightly, Bilencia, Gyan
Despite its virulence, the pathophysiologic basis of P. falciparum disease and cerebral malaria is 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. 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. Ultimately, human testing of the device is planned in Ghana in collaboration with colleagues at the NMIMR. This project is part of Bill and Melinda Gates Foundation Grand Challenges Explorations to Create Low-Cost Cell Phone-Based Applications for Priority Global Health Conditions.
- 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.
Genetic variation and drug resistance of Plasmodium falciparum
Malaria, a vector borne disease, causes great morbidity and mortality in tropical and subtropical regions of the world. 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. To better understand the generation of genetic diversity within the multi-copy gene family, we are manipulating the parasite genome to determine how the parasite repairs damaged DNA. 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 pathways implicated in parasite drug resistance.
- Heinberg A, Kirkman, L. The molecular basis of anitfolate resistance in Plasmodium falciparum: looking beyond point mutations. Ann N Y Acad Sci. 2015;1342:10-18.
- Heinberg A, Siu E, Stern C, Lawrence EA, Ferdig MT, Deitsch KW, Kirkman L. Direct evidence for the adaptive role of copy number variation on antifolate susceptibility in Plasmodium falciparum. Mol Microbiol 2013; 88:702-12.
- Kirkman L, Deitsch KW. Antigenic variation and the generation of diversity in malaria parasites. Curr Opin Microbiol. 2012; 15(4):456-62.
- Kirkman LA, Deitsch KW. Recombination and Diversification of the Variant Antigen Encoding Genes in the Malaria Parasite Plasmodium falciparum. Microbiol Spectr 2014;2; doi: 10.1128/microbiolspec.
- Kirkman L, Lawrence B and Deitsch K. Malaria parasites utilize both homologous recombination and alternative end joining pathways to maintain genome integrity. Nucleic Acids Research. 2014; 42:370-9.
- Kümpornsin K, Modchang C, Heinberg A, Ekland EH, Jirawatcharadech P, Chobson P, Suwanakitti N, Chaotheing S, Wilairat P, Deitsch KW, Kamchonwongpaisan S, Fidock DA, Kirkman LA, Yuthavong Y, Chookajorn T. Origin of Robustness in Generating Drug-Resistant Malaria Parasites. Mol Biol Evol. 2014;31:1649-1660.
Babesiosis is a tickborne zoonotic disease found worldwide. This once relatively obscure disease has been gaining recognition in the New York region as "the local malaria". In a new initiative, we have started working with Babesia divergens in initial drug screening assays and are considering ways to further our studies using the local parasite, Babesia microti.