Anecdotal reports of malaria infections in South Asia indicate that the classical symptoms of P. falciparum and P. vivax malaria are rapidly changing. Malaria parasite populations that have the capacity to rapidly alter their genetic makeup, to avoid drugs or to avoid host immune responses, may contribute to this change in pathogenesis. Since all of the aspects that contribute to the pathogenesis of malaria infection cannot be addressed in a single project, we have chosen to focus on host mechanisms that remove infected erythrocytes from peripheral circulation and the parasites'ability to sequester in specific tissues in order to avoid the spleen. Project 3 is divided into two specific aims for understanding malaria pathogenesis.
The first aim will study cytoadhesion and acquired immunity during pregnancy associated malaria, particularly in the context of varying genetic plasticity.
The second aim will indirectly measure splenic function by observing deformability of cells in peripheral circulation and correlating this with the clinical severity of malaria infection. The P. falciparum erythrocyte membrane 1 (PfEMPI) proteins, encoded by the var gene family, play a key role in parasite cytoadherance and evading host clearance of infected erythrocytes. The best understood paradigm of pathogenesis is pregnancy associated malaria. This syndrome is a major cause of poor mother/child health and is associated with placental sequestration of P. falciparum infected erythrocytes (lEs) by a single PfEMPI variant. We will study acquired immunity to pregnancy malaria, the antigenic diversity of adhesion blocking epitopes in East and West India, and the evolution of polymorphism in parasite populations that differ in mutagenic potential by the ARMD phenotype. The Rathod lab has developed a microfiuidic assay to indirectly observe splenic filtration by observing the minimum cylindrical diameter of erythrocytes in peripheral circulation. The minimum cylindrical diameter (MCD) is a parameter which describes the smallest sized tube which an erythrocyte may successfully pass through without lysing or becoming trapped. The MCD is particularly useful for describing the probability of a cell becoming trapped as it passes through a filter. If the spleen is essentially a filter for erythrocytes in peripheral circulation, then splenic filtration is thought to define the MCD profile of cells in circulation. Data from a preliminary study in Malawi indicates that MCD profiles vary between individuals and may correlate with severity of malaria infection. This project will use microfluidic devices to indirectly observe splenic filtration by the MCD profile of individuals and the presentation of malaria infection.
Overall, Project 3 is linked to the general theme of this grant through the investigation of whether malaria parasites harbor specific phenotypes which make them more pathogenic. Specifically, aims of this project will address whether the ARMD phenotype affects the parasites'ability to alter their repertoire of var genes (through studies on cytoadherence and antigenic recognition) or to deform an invaded erythrocyte (through studies measuring MCD). This project will require identification of ARMD parasites as performed in Project 2. In addition, recruitment of patients will occur concurrently with Projects 1 and 5.
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