Hepatic Kupffer cells: The portal that permits infection of hepatocytes by malarial sporozoites?

Malaria was endemic to every continent except Antarctica at the beginning of the 20th century. By midcentury, although malaria was mostly eradicated from North America and Europe, 1.6 billion people were still exposed, and 2.5 million deaths occurred annually. Today, at the beginning of the 21st century, an estimated 1.5 to 2 billion people reside in areas where malaria continues to be transmitted giving rise to between 300 and 500 million cases with an estimated 1 to 2 million deaths each year. Malaria in humans is caused by 4 distinct species of protozoan parasites within the genus Plasmodium. The organisms and the disease(s) they cause are genetically, biologically, ecologically, and pathologically complex making it difficult to control the disease, particularly in its subtropical and tropical haunts. Along with new money, new control strategies, new drugs, new tools such as vaccines, and knowledge from the newly deciphered genome of Plasmodium falciparum, a more thorough understanding of the biology of the parasite and interactions with its hosts is necessary to effectively thwart the survival strategies inherent to Plasmodium. Despite 120 years of fundamental research since their discovery, many aspects of the biology of malaria parasites remain cloaked. In this issue of HEPATOLOGY the article by Pradel and Frevert sheds light on one of these unknown facets of fundamental malaria biology. The developmental biology of Plasmodium cycles between an invertebrate (mosquito) host and a vertebrate (mammals, birds, and reptiles) host where both sexual and asexual forms develop and replicate. Female Anopheles mosquitoes transmit malaria parasites to humans when they “bite” to take a blood meal. An elongated slightly-curved needle-like invasive form known as a sporozoite is passed in the saliva as the mosquito probes for a capillary. Experiments first conducted during and shortly after World War II showed that within minutes after mosquitoes deposit their parasite-laden spit in the dermis, the sporozoites enter the blood, circulate for up to 30 minutes,1 and during that short time find and infect hepatocytes.2,3 The targeting of the hepatic tissue is specific and efficient since the inoculation of one sporozoite is capable of initiating a malaria infection. Once in a liver cell, a sporozoite becomes rounded, grows, and differentiates into a schizont where nuclear division produces tens of thousands of merozoites. It is these minute (1-2 mm), oval invasive forms that rupture from the infected hepatocyte to enter the blood circulation and rapidly infect red blood cells to begin the erythrocytic phase or blood cycle of a malaria infection. In a persistent, pernicious cycle the parasites grow in parasitized red blood cells, produce new merozoites that rupture from the hemoglobin-depleted erythrocyte, and invade new ones to continue the infection. It is in the blood cycle where all the clinical symptoms and disease of malaria are manifested. The liver stage or exoerythrocytic cycle lasting 6 to 15 days is clinically silent. The circle of development that malaria parasites go through to survive is on the way to completion when a few of the newly invaded merozoites that have differentiated into male and female forms known as gametocytes are ingested by a feeding mosquito. The male and female gametocytes undergo fertilization (fusion) with each other in the midgut of the mosquito to form a zygote that transforms into another invasive stage termed an ookinete. The ookinete penetrates the epithelia of the midgut and lodges between the epithelial cells and the basal lamina basement membrane of the midgut. Here the ookinete becomes an oocyst that replicates its nucleus thousands of times to form sporozoites. When the oocyst ruptures the sporozoites migrate through hemocoel and invade into the salivary glands where they await the opportunity to transmit malaria to another human host when the mosquito takes another helping of blood. Gaining full knowledge of the precise biological and molecular details of how each of these invasive stages interacts with specific host tissues, ookinetes with mosquito epithelia, merozoites with red blood cells, and sporozoites with salivary glands and liver, is fundamental to devising new methods effective at blocking malaria infection and transmission. The study of Pradel and Frevert focuses on precisely how, once sporozoites hone in on the sinusoidal architecture of the liver, they are able to infect hepatocytes. While 53 years ago it was first discovered that mammalian malaria parasites infect and developmentally mature in hepatocytic cells of the liver,2,3 it was only during the past decade that a possible molecular basis for the homing of sporozoites specifically to the liver was determined.4,5 A protein that covers the surface of the sporozoite, the circumsporozoite protein (CSP),6 was found to bind to heparan sulphate glycosylaminoglycans (GAGs) expressed specifically on the surface of hepatocytes.7,8 In sections of liver tissue the CSP bound to the basolateral hepatocyte surfaces exposed in the space of Disse of the hepatic sinusoid architecture separating the sinusoidal endothelial lining from the hepatic cells.9 Later it was also found that TRAP,10,11 a sporozoite organellar protein inducibly translocated to the sporozoite surface,12 also binds to hepatocytes via the GAGs.13 Based on these findings it is widely thought that multivalent interactions between CSP and TRAP Abbreviations: CSP, circumsporozoite protein; GAG, glycosylaminoglycan; EEF, exoerythrocytic forms. From the Centers for Disease Control and Prevention, Division of Parasitic Diseases, Atlanta, GA. Received March 19, 2001; accepted March 21, 2001. Address reprint requests to: John W. Barnwell, Ph.D, M.P.H. , Division of Parasitic Diseases, F-13, Bldg. 22B, National Center for Infectious Disease, Centers for Disease Control and Prevention, 4770 Buford Highway, Cahmblee, GA 30341. E-mail: barnwell@rmy.emory. edu; fax: 770-488-4253. Copyright © 2001 by the American Association for the Study of Liver Diseases. 0270-9139/01/3305-0040$35.00/0 doi:10.1053/jhep.2001. 24740