Mosquito Heparan Sulfate and Its Potential Role in Malaria Infection and Transmission

Abstract

Heparan sulfate has been isolated for the first time from the mosquito Anopheles stephensi, a known vector for Plasmodium parasites, the causative agents of malaria. Chondroitin sulfate, but not dermatan sulfate or hyaluronan, was also present in the mosquito. The glycosaminoglycans were isolated, from salivary glands and midguts of the mosquito in quantities sufficient for disaccharide microanalysis. Both of these organs are invaded at different stages of the Plasmodium life cycle. Mosquito heparan sulfate was found to contain the critical trisulfated disaccharide sequence, 34)␤-D-GlcNS6S(1 3 4)-␣-L-IdoA2S(13, that is commonly found in human liver heparan sulfate, which serves as the receptor for apolipoprotein E and is also believed to be responsible for binding to the circumsporozoite protein found on the surface of the Plasmodium sporozoite. The heparan sulfate isolated from the whole mosquito binds to circumsporozoite protein, suggesting a role within the mosquito for infection and transmission of the Plasmodium parasite.Malaria infection is initiated with the bite of an infected anophelene mosquito, which injects Plasmodium sporozoites into the skin of the vertebrate host (Fig. 1A). Sporozoites migrate from the site of injection, enter the blood stream, and are carried to the liver, where they invade hepatocytes and develop into exoerythrocytic forms. Many lines of evidence suggest that clearance of sporozoites by the liver is mediated by the binding of the sporozoite major surface protein, the circumsporozoite protein (CSP), 2 to heparan sulfate proteoglycans in the liver (1, 2). Liver heparan sulfate is more highly sulfated than heparan sulfate from other organs (3-6) and frequently contains the fully biosynthetically modified, highly sulfated sequence: 34)-GlcNS6S(1 3 4)IdoA2S(13 (Fig. 2). Such fully modified sequences, while commonly found in the mast cell glycosaminoglycan, heparin, are infrequently found in heparan sulfate. Some heparan sulfates, such as those present in the liver, have a richer content of fully modified sequences in their high sulfate domains. These sequences have been shown to bind to apoE and facilitate the clearance of lipoprotein remnants from the blood by the liver (7,8). ApoE containing remnant lipoproteins inhibits Plasmodium sporozoite infectivity and decreases clearance of CSP from the blood circulation, suggesting that sporozoites bind to the same hepatic heparan sulfate proteoglycans as remnant lipoproteins (9). This hypothesis is further supported by the finding that CSP binds to the same decasaccharide structure that binds to apoE (10, 11).Less is known about the role of proteoglycans in the mosquito host, where the parasite encounters a variety of mosquito matrices as it develops (Fig. 1B). When the mosquito takes a blood meal from an infected vertebrate host, gametocytes present in the blood meal differentiate, and fertilization occurs. The zygote develops into an ookinete, which crosses the midgut wall, stops at the basal lamina of the midgut, and develops into an oo...

Plasmodium falciparum BAEBL Binds to Heparan Sulfate Proteoglycans on the Human Erythrocyte Surface

“…Thrombospondin-related anonymous protein on the surface of sporozoites may interact with HSPGs on hepatocytes (51,52). Additionally, the existence of HS in salivary glands and midguts of the mosquito has been reported (53). Because of the binding to circumsporozoite protein, this HS was suggested to mediate the transmission of the parasite.…”

Residue 82 of the Chikungunya Virus E2 Attachment Protein Modulates Viral Dissemination and Arthritis in Mice

“…Several mosquito species express the enzymes capable of synthesizing GAGs (62), but a thorough characterization of GAGs expressed by C6/36 cells has not been reported. Additionally, GAGs are present on the surfaces of midgut and salivary gland cells of certain mosquito species (62,63), but it is not clear whether these molecules contribute to CHIKV infection in the invertebrate host. In contrast to mammalian cells, substituting 181/25 E2 Arg82 with glycine enhances infection of C6/36 cells.…”

Baculovirus Envelope Protein ODV-E66 Is a Novel Chondroitinase with Distinct Substrate Specificity

“…CS proteoglycans have been detected in Drosophila ovaries, embryos, larvae, and adults (28,29) and Anopheles salivary glands, midguts, and ovaries (30). By histological analysis, the CS proteoglycans were found in the apical microvilli of the mosquito midgut (31).…”