Abstract
Parasite infection can lead to alterations in the permeability of host plasma membranes. Presented here is the first demonstration that this phenomenon occurs in Plasmodium-infected liver cells. Using the whole-cell patch-clamp technique, volume-regulated anion channel (VRAC) activity was characterized in Huh-7 cells (a human hepatoma cell line) before and after infection with Plasmodium berghei. Consistent with the presence of VRACs, hypotonic bath solution induced large ion currents in Huh-7 cells that rectified outwardly, reversed close to the equilibrium potential for Cl- and were inhibited by tamoxifen, clomiphene, mefloquine and 5-nitro-2, 3-(phenylpropylamino)-benzoic acid (NPPB), with IC50 values of 4 ± 1, 4 ± 2, 2 ± 1 and 52 ± 12 μM respectively. In isotonic conditions, initial current recordings measured in uninfected and immature (24 h post invasion) parasite-infected Huh-7 cells were similar (with conductances of 14 ± 3 versus 19 ± 5 pS/pF). However, in mature (48–72 h post invasion) parasite-infected Huh-7 cells there was a sevenfold increase in currents (with a conductance of 98 ± 16 pS/pF). The elevated currents observed in the latter are consistent with VRAC-like activity and the possible reasons for their activation are discussed.
Highlights
Malaria causes nearly one million human deaths worldwide, annually, and is associated with morbidity in a further 250 million individuals
Using the whole-cell patch-clamp technique, volume-regulated anion channel (VRAC) activity was characterized in Huh-7 cells before and after infection with Plasmodium berghei
This need has been heightened by a disturbing recent report that malarial parasites in Western Cambodia are resistant to artemisinins (Noedl et al, 2008), the most effective antimalarial drug class currently available (Krishna et al, 2008)
Summary
Malaria causes nearly one million human deaths worldwide, annually, and is associated with morbidity in a further 250 million individuals (refer to http://www.who.int/ malaria/wmr2008). There is currently a critical need for novel antimalarial interventions (CunhaRodrigues et al, 2006), if the disease is to be effectively managed in coming years. This need has been heightened by a disturbing recent report that malarial parasites in Western Cambodia are resistant to artemisinins (Noedl et al, 2008), the most effective antimalarial drug class currently available (Krishna et al, 2008). Two asexual reproductive phases take place within the parasite’s vertebrate host in liver and red blood cells. The liver stages of malarial parasites, clinically silent, are an attractive target for antimalarial vaccines and prophylactic drugs (Prudencio et al, 2006), especially as intervening here will prevent symptomatic malaria
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