Sturm A, Amino R, van de Sand C, Regen T, Retzlaff S, Rennenberg A, Krueger A, Pollok JM, Menard R, Heussler VT. Manipulation of host hepatocytes by the malaria parasite for delivery into liver sinusoids. Science 2006;313:1287-1290. (Reprinted by permission)
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The merozoite stage of the malaria parasite that infects erythrocytes and causes the symptoms of the disease is initially formed inside host hepatocytes. However, the mechanism by which hepatic merozoites reach blood vessels (sinusoids) in the liver and escape the host immune system before invading erythrocytes remains unknown. Here, we show that parasites induce the death and the detachment of their host hepatocytes, followed by the budding of parasite-filled vesicles (merosomes) into the sinusoid lumen. Parasites simultaneously inhibit the exposure of phosphatidylserine on the outer leaflet of host plasma membranes, which act as “eat me” signals to phagocytes. Thus, the hepatocyte-derived merosomes appear to ensure both the migration of parasites into the bloodstream and their protection from host immunity.
Malaria (Plasmodium spp.) annually kills more than 2 million children and is the deadliest parasitic disease of humans. Malaria develops in 2 stages, an early liver phase followed by a blood stage that initiates the pathophysiology of malaria. The malaria parasite (sporozoite) from mosquito saliva travels from the liver sinusoid into hepatocytes as few as 2 minutes after entering the peripheral blood. Each sporozoite traverses several hepatocytes before developing into thousands of merozoites, which enter the blood stream 2 to 16 days after the mosquito bite.1 Each merozoite can then invade and replicate inside a red blood cell.
Yet, how does the malaria parasite replicate and differentiate inside hepatocytes then re-enter the bloodstream, all while evading immune detection and postponing host cell death? Sturm et al. makes a significant contribution toward answering this question. A crucial challenge for the stealthy sporozoite, once it has differentiated into merozoites in its host hepatocyte, is to reach the hepatic sinusoids. Hepatic sinusoids are accessible to hepatocytes via endothelial fenestrations, which are pores of approximately 100 nm diameter that allow direct access of hepatocyte microvilli to the sinusoidal lumen without intervening basal lamina or extracellular matrix. Hepatocytes can project their microvilli through these pores.2 In both infected HepG2 cells and liver sections from mice infected with P. berghei, Sturm et al. observed hepatocytes and merosomes, which are packages of merozo ites surrounded by a hepatocyte-derived membrane, become detached from neighboring cells 46 hours after infection. These findings were complemented by real-time intravital imaging studies showing merosome release into the sinusoid. The low-resolution movies suggest that merosomes extrude through a small opening in the sinusoid, which may be a fenestration. The merosome probably cloaks merozoites from recognition by dendritic cells.
Generally, hepatocyte infection triggers apoptosis, which involves caspase up-regulation and leads to phagocytosis. However, Plasmodium infection of the liver is silent in that few cells die and no immune response is detected. Hepatocyte growth factor (HGF) signaling via the MET receptor protects Plasmodium-infected cells from apoptosis.3 Sturm et al. found that Plasmodium forestalls host hepatocyte death until it departs. They also showed the subsequent host hepatocyte cell death is unusual in that hepatocyte DNA is not fragmented and cysteine proteases other than caspases are involved. Furthermore, phosphatidylserine residues, which are the usual recognition signal for phagocytes to engulf an apoptotic cell, are absent from infected hepatocytes. The parasite achieves this by absorbing calcium that would otherwise enter the cytoplasm from intracellular stores and cause phosphatidylserine expression on the cell surface.
Understanding the liver stage of the malaria parasite life cycle is important because hepatocyte infection is obligatory and involves fewer parasites than any other life-cycle stage. Thus, this stage is a potential target for preventative intervention that might defeat the parasite before pathophysiology can be initiated at the replicative blood stage. These discoveries also suggest that similar mechanisms of immune evasion might occur in other intracellular infections and provide fresh insights into hepatocyte cell biology.