Characterization of Membrane Permeability Alterations in Plasmodium-Infected Erythrocytes: Insight into Novel Mechanisms for Malaria Chemotherapy

Current malaria research is geared toward identifying novel targets for malaria chemotherapy because of the growing resistance of Plasmodium falciparum to existing drug options (Trager et. al., 1997). Potential targets not yet explored are the new permeability pathways induced by Plasmodium on host erythrocytes. These pathways confer increased permeability to inorganic ions including chloride, sodium, and calcium (Adovelande et al. 1993, Brand et al. 2003, Garcia et al. 1996, Lang et al. 2003), as well as organic solutes such as sorbitol (Tanneur et al. 2005), lactic acid, and hemoglobin-derived amino acids (Duranton et al. 2004). Evidence suggests that the primary function of these pathways is to allow for abundant access to nutrients and vitamins essential for parasite growth (Brand et al. 2003, Duranton et al. 2004), while facilitating elimination of metabolic waste products (Duranton et al. 2004). Due to the apparent dependence of Plasmodium survival on these transport pathways (Brand et al. 2003), targeting the pathways could be a potent method for inhibiting the blood stage life cycle of Plasmodium and, in turn, arresting disease progression. However, the precise nature of the new permeability pathways induced by Plasmodium on host erythrocytes is ill-defined. That is, it is not clear whether the pathways are endogenous membrane proteins activated by Plasmodium or, alternatively, if they are xenoproteins encoded by Plasmodium and shuttled to the host cell membrane. Classification of these membrane channels is essential before pharmacological antagonists can be developed. Additionally, it is unclear how Plasmodium prevents premature cell death of erythrocytes, which is one of the expected consequences of parasite-induced new permeability pathways. Specifically, osmolyte influx via these pathways leads to a breakdown of plasma membrane asymmetry (Brand et al. 2003), which in normal erythrocytes triggers apoptosis (Lang et al. 2003). Obviously, it is crucial to understand the mechanisms by which Plasmodium avoids programmed cell death if we are to formulate ways to initiate parasite destruction. One possibility is that Plasmodium activates osmolyte pathways that allow for nutrient influx, while simultaneously inhibiting efflux pathways normally stimulated during apoptosis that allow for a decrease in erythrocyte volume. Research aimed at assessing this possibility is severely lacking.