Abstract
Plasmodium undergoes one round of multiplication in the liver prior to invading erythrocytes and initiating the symptomatic blood phase of the malaria infection. Productive hepatocyte infection by sporozoites leads to the generation of thousands of merozoites capable of erythrocyte invasion. Merozoites are released from infected hepatocytes as merosomes, packets of hundreds of parasites surrounded by host cell membrane. Intravital microscopy of green fluorescent protein–expressing P. yoelii parasites showed that the majority of merosomes exit the liver intact, adapt a relatively uniform size of 12–18 μm, and contain 100–200 merozoites. Merosomes survived the subsequent passage through the right heart undamaged and accumulated in the lungs. Merosomes were absent from blood harvested from the left ventricle and from tail vein blood, indicating that the lungs effectively cleared the blood from all large parasite aggregates. Accordingly, merosomes were not detectable in major organs such as brain, kidney, and spleen. The failure of annexin V to label merosomes collected from hepatic effluent indicates that phosphatidylserine is not exposed on the surface of the merosome membrane suggesting the infected hepatocyte did not undergo apoptosis prior to merosome release. Merosomal merozoites continued to express green fluorescent protein and did not incorporate propidium iodide or YO-PRO-1 indicating parasite viability and an intact merosome membrane. Evidence of merosomal merozoite infectivity was provided by hepatic effluent containing merosomes being significantly more infective than blood with an identical low-level parasitemia. Ex vivo analysis showed that merosomes eventually disintegrate inside pulmonary capillaries, thus liberating merozoites into the bloodstream. We conclude that merosome packaging protects hepatic merozoites from phagocytic attack by sinusoidal Kupffer cells, and that release into the lung microvasculature enhances the chance of successful erythrocyte invasion. We believe this previously unknown part of the plasmodial life cycle ensures an effective transition from the liver to the blood phase of the malaria infection.
Highlights
Two billion people, more than one third of the world’s population, live at risk for malaria and about 1 billion are infected
The malaria parasite Plasmodium undergoes one large round of multiplication in the liver before beginning the blood phase of the life cycle, the phase that causes the typical episodes of fever and chills
Using intravital microscopy and fluorescent parasites, we studied the mode and dynamics of parasite release from the liver, a critical stage in the malaria life cycle
Summary
More than one third of the world’s population, live at risk for malaria and about 1 billion are infected. Acute danger of phagocytic elimination is presented in the form of Kupffer cells [8], the resident phagocytes of the liver that comprise by far the largest population of tissue macrophages of the body [9]. Kupffer cells are predominantly located at sinusoidal bifurcations, largely within and often spanning the sinusoidal lumen [9,10,11], thereby presenting significant obstacles for non-self particulate material. This strategic position of Kupffer cells makes it difficult for free merozoites to exit the liver without being trapped by these surveillance cells of the innate immune system
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