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Malaria Research Challenges
Rapid emergence of drug resistant infectious parasites represents an ever increasing global health burden. Malaria, caused by protozoa of the genus Plasmodia, is characterized as endemic in 101 countries and annually results in 300-500 million clinical cases with over 2 million deaths. Given the global scope of the disease, the need for improved understanding in the pathogenesis to develop strategies to fight malaria is self evident. The National Institute for Allergy and Infections Disease (NIAID) has acknowledged that “the magnitude of the malaria problem and the existing barriers to controlling infection require a multitude of approaches”. The SB2 group at CFDRC is actively contributing to the malaria fight in three active areas: antimalarial development, characterization of host-pathogen response, and mitigating the neurotoxic effects of existing antimalarials.
Sustainable Development of Antimalarial Lead Compounds Using Natural Product Extracts
Continual emergence of drug resistant malaria poses a continual threat to global health, and the primary motivator for innovation in the development of sustainable drug discovery efforts. However, despite strong efforts, the introduction of new chemical entities into the malaria drug pipeline is essentially non-existent, with recent drug discovery efforts focusing mainly on derivatives of pre-existing drugs (quinolines, artemisinins, and antifolates). The primary objective of this line of research is to enable the development of a long-term, sustainable drug discovery efforts designed to continually generate lead compounds for antimalarial discovery. CFDRC’s primary contribution is the development of an advanced data management and analysis tools suite to automate the determination of optimal lead compounds from experimental data.
Understanding Host-Pathogen Interaction: Role of Hemozoin Immunomodulation
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Hemozoin Action on phagocytic cells |
During the intraerythrocytic phase of the malaria parasite life cycle, the parasite consumes the infected erythrocyte’s hemoglobin to obtain requisite amino acids for maturation. Ironically, proteolysis of hemoglobin produces high levels of free heme, which can prove extremely toxic to the parasites. To balance the metabolic need for amino acids against the toxic effects of free heme, malaria parasites have developed a detoxification scheme which involves the formation of an insoluble heme aggregate known in malarial infections as hemozoin. Once the RBC’s hemoglobin has been consumed, the parasites rupture from the red blood cell (RBC) and release the accumulated hemozoin into the host’s vasculature. Monocytes that phagocytose native hemozoin exhibit a marked decrease in the production of ROS, along with other impaired functions including: re-phagocytosis, killing of ingested bacteria, fungi or tumor cells, and response to interferon gamma stimulation. While all of these activities show how Hz can play an immunomodulatory role in malaria, the cellular level details responsible for these observations are still unclear. The primary involvement of CFDRC in this effort is the development of computational methods that enable the analysis of microarray and proteomic data in the context of a pathway model using an advanced clustering analysis.
Mefloquine Neurotoxicity
Mefloquine is a potent blood schizontocide, effective against drug-resistant Plasmodium falciparum, maintaining high concentrations in the blood sustained periods. However, Mefloquine (MFQ) is known to cause adverse neurological or psychiatric effects (ataxia and mood changes) in up to 25% of individuals at the prophylactic dose and 70% of individuals at treatment doses, offsetting MFQ’s many positive prophylactic aspects. Currently, there is no predictive clinical test capable of determining a priori the susceptibility of an individual to MFQ-induced neurotoxicity. Recent research strongly indicates that the neurotoxic effects can be attributed to specific single nucleotide polymorphisms (SNPs). Identification of a critical set of SNPs capable of predicting an individual’s level of susceptibility could form the basis of a genetic test, enabling physicians to rapidly identify at-risk persons prior to administering prophylaxis. However, trial and error methods for SNP identification are resource (time and cost) expensive and error prone. Our objective in this effort is to use advanced pathway modeling techniques combined with genomic and proteomic data to develop a genetic screen to identify individuals susceptible to mefloquine neurotoxicity. |
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