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During Sporozoite Invasion* J.P Plasmodium sporozoite-host cell interactions during sporozoite invasion* J.P. Vanderberg & M.J. Stewart In vitro and in vivo studies were performed to clarify the nature of some interactions between Plasmodium berghei sporozoites and rodent host cells. Videomicroscopic observations were made on in vitro inter- actions between sporozoites and cultured host cells (rodent peritoneal macrophages, W138 human lung fibroblasts, and HepG2 human hepatoma cells). The results showed a diversity of dynamic interactions and sporozoite activities, including active sporozoite penetration, often followed by sporozoite escape, killing of invaded macrophages, phagocytosis ofsporozoites by macrophages, and elaboration ofa weblike structure by the sporozoite, following its escape from cells. Other studies were performed to examine host cell inflammatory responses to challenge sporozoites in the livers of rats that had been previously immunized with radiation-attenuated sporozoites. The results showed a variety of focal inflammatory infiltrates in the livers ofthe challenged animals. The relevance ofthese observations to the problems ofsporozoite invasion into naive and immunized animals is discussed. Introduction eral of these factors act together against the pre- A Plasmodium sporozoite that reaches the circulatory erythrocytic stages of the parasite. system ofits mammalian host must distinguish among The purpose ofthis paper is to review some of the a succession of host cells if it is to be successful in ways in which sporozoites interact with mammalian ending up as a pre-erythrocytic schizont (PES). First, host cells, and to present some new data describing the sporozoite, while flowing rapidly through the interactions between the parasite and host cells circulation, must stop in the liver and become firmly in vitro and in vivo. attached to one of the two types of cells lining the lumen of the hepatic sinusoid: Kupffer cells or endo- Sporozoite interactions with hepatic thelial cells. Then, it must pass through one of these sinusoidal cells cells into the space of Disse and recognize and invade its final destination, the hepatocyte. It is impressive to Sporozolte binding within the hepatic sinusoid: consider that the very same sporozoite must be pro- Kupffer cells vs. endothelial cells grammed to recognize and invade at least two distinct types of host liver cells. We will show that sporozoites Sporozoites flowing through the blood of a mamma- are aggressive in their ability to penetrate these cells. lian host rapidly penetrate the liver, many of them During this journey, the sporozoite must run a apparently in a single passage (1). In a well-adapted gauntlet of host defence cells before it can impact host-parasite system, the large majority of sporo- upon its final destination within the liver. Some sporo- zoites successfully invade the liver, few appear to be zoites are successful in reaching and invading hep- strained out and sequestered in other capillary beds of atocytes; others are intercepted during their travels the body. The evidence for this includes the fact that through the body, or are destroyed within the liver only several sporozoites are needed to induce an as they are developing into PES. To develop better infection in well-adapted simian malaria systems and strategies to intercept or destroy the parasite during that as many as 95% of the P. berghei sporozoites any of these stages, it behoves malariologists to under- injected into their natural tree rat host may develop stand how the parasite interacts with host cells and into PES (2). This strongly implies a liver-specific how host defence mechanisms function against the mechanism for sporozoite entrapment. It is important parasite in nonimmunized and immunized hosts. to recognize that cells within the blood have no direct Sporozoite-induced immunity is a multifactorial contact with hepatocytes. Blood flowing through the phenomenon; protective immunity occurs when sev- liver sinusoids has contact only with the cells that line the sinusoids. An important unanswered question relating to * From the Department of Medical and Molecular Parasitology, sporozoite biology is whether a sporozoite, rapidly New York University School of Medicine, 550 First Avenue, New flowing through a liver sinusoid, interacts with the York, NY tO016, USA. Correspondence to Dr. J.P. Vanderberg. liver via a sporozoite ligand-liver receptor interaction 74 Bulletin of the World Health Organization, 68 (Suppl.): 74-79 (1990) Plasmodlum sporozolte-host cell interactions and remains there, or whether a nonspecific sinusoidal static carcinoma cells, which move through endo- trapping mechanism filters out sporozoites as they thelial fenestrae to invade the liver parenchyma (11). pass. In either event, the attachment would require The early anatomists recognized that endothelial strong binding between the sporozoite and a cell cells lining blood vessels of the liver are structurally lining the liver sinusoid to prevent the sporozoite different from those lining blood vessels in other parts from being swept away in the sinusoidal blood flow. of the body, and that the liver cells are permeable to There are only two candidates for this: Kupffer cells blood components that could not penetrate else- and endothelial cells. where. It is now recognized that these cells contain a number of receptors designed to remove components Posible role of host plasma proteins in medating destined for the liver, and that the two classes of cells recognition. Though the circumsporozoite (CS) pro- lining the sinusoid have different types of receptors. tein covering the sporozoite is a prime candidate for For instance, endotoxin is taken up almost entirely by a ligand that could recognize a sinusoid-lining cell, Kupffer cells (12), whereas the endothelial cells have a blood plasma proteins binding to sporozoites could high specificity for acetylated low-density lipoprotein also play a role in mediating this putative recognition. (13), transferrin (14), bound albumin (12) and heparin A serum glycoprotein binds to P. berghei and (12). P. knowlesi sporozoites and appears to enhance sporozoite binding to macrophages in vitro (3, 4). Dynamk Interacffons betwen sporozoltes and Furthermore, incubation of sporozoites in serum macrophages In vitro prior to injecting them intravenously into their mam- In view of the possible role of liver macrophages in malian hosts has been shown to greatly enhance their mediating infection by sporozoites (as described infectivity (reviewed in (3)). above), in intercepting and killing some sporozoites attempting to invade the liver, and in possibly func- Posaibie roie of the Kupfer ceii. The suggestion that tioning as antigen-presenting cells during the induc- sporozoites are phagocytosed by Kupffer cells prior to tion ofthe immune response, many workers have been infection of hepatocytes has long been entertained interested in studying sporozoite-macrophage inter- (5, 6). This concept is attractive from an evolutionary actions in vitro. standpoint because sporozoites of reptilian and avian These studies have involved incubating sporozo- malarias invade and then develop in reticuloendo- ites with target host cells under given conditions for a thelial cells, including macrophages. The proposal has given period of time, after which the slide is fixed, recently been revived (7, 8). These workers have ar- stained, and viewed through a microscope. Unfortu- gued that there is a nonspecific initial interaction nately, this approach results in a frozen picture of the between sporozoites and Kupffer cells, followed by interaction at an arbitrary point in time. Our own active Kupffer cell phagocytosis of the sporozoite. recent studies, using videomicroscopy, have shown Our own data have shown, instead, active and aggres- that there is a diversity of dynamic interactions be- sive penetration of macrophages by sporozoites tween sporozoites and host cells that is not recog- in vitro (see below). A relevant question is whether the nizable on fixed slides. We used Plasmodium berghei rapidly moving sporozoites attach to Kupffer cells by sporozoites obtained from the salivary glands of in- nonspecific mechanisms, or whether this attachment fected Anopheles stephensi mosquitos, and pipetted is enhanced by CS protein or by opsonization of the drops of a sporozoite suspension on coverslips con- circulating sporozoite by plasma proteins. taining monolayers of peritoneal macrophages from mice (Swiss-Webster) and rats (Norway brown). The medium consisted of Minimal Essential Medium Po"sibe role of the sinusoidal-finIng endothelial cell. (MEM) with 3% bovine serum albumin and all pre- Because ofthe speed with which sporozoites can leave parations were maintained at 37°C. Observations the blood to invade hepatocytes, we suggested a rapid were made by phase-contrast microscopy, using a and direct passage through the endothelial cells (9). video camera and a video cassette recorder to record Others have argued that this is impossible because of observations. the small diameters of the fenestrae that pass through results demonstrated the wide these cells (8). However, our demonstration of rapid, Our following active invasion by sporozoites through cells (including range of sporozoite-macrophage interactions: liver endothelial cells) in vitro indicates that sporo- A. No interaction. The most common observation zoites could actively squeeze through these contrac- was that actively gliding sporozoites would come in tile, microfilament-enveloped,
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