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

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, →4)β-d-GlcNS6S(1 → 4)-α-l-IdoA2S(1→, 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. 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, →4)β-d-GlcNS6S(1 → 4)-α-l-IdoA2S(1→, 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), 2The abbreviations used are:CSPcircumsporozoite proteinapoEapolipoprotein EGlcN2-deoxy-2 aminoglucopyranoseIdoAidopyranosyluronic acidSsulfateCHAPS3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonic acidΔUA4-deoxy-α-l-threo-hexenepyranosyluronic acidSPRsurface plasmon resonanceHPLChigh performance liquid chromatography;ΔDi2-acetamido-2-deoxy-3-O-(β-d-gluco-4-enopyranosyluronic acid)-d-galactose(glucose). to heparan sulfate proteoglycans in the liver (1Frevert U. Sinnis P. Cerami C. Shreffler W. Takacs B. Nussenzweig V. J. Exp. Med. 1993; 177: 1287-1298Crossref PubMed Scopus (277) Google Scholar, 2Pinzon-Ortiz C. Friedman J. Esko J. Sinnis P. J. Biol. Chem. 2001; 276: 26784-26791Abstract Full Text Full Text PDF PubMed Scopus (110) Google Scholar). Liver heparan sulfate is more highly sulfated than heparan sulfate from other organs (3Lyon M. Dakin J.A. Gallagher J.T. J. Biol. Chem. 1994; 269: 11208-11215Abstract Full Text PDF PubMed Google Scholar, 4Hernáiz M.J. Yang H.O. Gunay N.S. Linhardt R.J. Carbohydr. Polym. 2002; 48: 153-160Crossref Scopus (7) Google Scholar, 5Vongchan P. Warda M. Toyoda H. Toida T. Marks R.M. Linhardt R.J. Biochim. Biophys. Acta. 2005; 1721: 1-8Crossref PubMed Scopus (63) Google Scholar, 6Warda M. Toida T. Zhang F. Sun P. Munoz E. Linhardt R.J. Glycoconj. J. 2006; 23: 553-561Crossref Scopus (66) Google Scholar) and frequently contains the fully biosynthetically modified, highly sulfated sequence: →4)-GlcNS6S(1 → 4)IdoA2S(1→ (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 (7Dong J. Peters-Libeu C.A. Weisgraber K.H. Segelke B.W. Rupp B. Capila I. Hernáiz M.J. LeBrun L.A. Linhardt R.J. Biochemistry. 2001; 40: 2826-2834Crossref PubMed Scopus (88) Google Scholar, 8Peters-Libeu C. Lund-Katz S. Phillips M. Wehrli S. Hernáiz M.J. Capila I. Linhardt R.J. Raffai R. Newhouse Y.M. Zhou M.F. Weisgraber K.H. J. Biol. Chem. 2001; 276: 39138-39142Abstract Full Text Full Text PDF PubMed Scopus (84) Google Scholar). 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 (9Sinnis P. Willnow T.E. Briones M.R.S. Herz J. Nussenzweig V. J. Exp. Med. 1996; 184: 945-954Crossref PubMed Scopus (84) Google Scholar). This hypothesis is further supported by the finding that CSP binds to the same decasaccharide structure that binds to apoE (10Rathore D. McCutchan T.F. Hernáiz M.J. LeBrun L.A. Lang S.C. Linhardt R.J. Biochemistry. 2001; 40: 11518-11524Crossref PubMed Scopus (61) Google Scholar, 11Rathore D. Hrstka S.C.L. Sacci J.B. de la Vega P. Linhardt R.J. Kumar S. McCutchan T.F. J. Biol. Chem. 2003; 278: 40905-40910Abstract Full Text Full Text PDF PubMed Scopus (43) Google Scholar).FIGURE 2Structure of heparan sulfate glycosaminoglycans. A, unsulfated disaccharide sequence prominent in heparan sulfate. B, fully sulfated disaccharide sequence prominent in heparin. C, structural variants of glucuronic acid containing disaccharide sequences found in heparan sulfate and heparin (X = SO–3, H). D, structural variants of iduronic acid containing disaccharide sequences found in heparan sulfate and heparin (X = SO–3,H; Z = SO–3, COCH3, H). E, proposed apoE and CSP binding domain.View Large Image Figure ViewerDownload Hi-res image Download (PPT) circumsporozoite protein apolipoprotein E 2-deoxy-2 aminoglucopyranose idopyranosyluronic acid sulfate 3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonic acid 4-deoxy-α-l-threo-hexenepyranosyluronic acid surface plasmon resonance high performance liquid chromatography; 2-acetamido-2-deoxy-3-O-(β-d-gluco-4-enopyranosyluronic acid)-d-galactose(glucose). 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 oocyst. There is evidence that ookinetes recognize and adhere to specific sugars on the luminal side of the midgut (12Zieler H. Nawrocki J.P. Shahabuddin M. J. Exp. Biol. 1999; 202: 485-495Crossref PubMed Google Scholar, 13Siden-Kiamos I. Louis C. Insect Biochem. Mol. Biol. 2004; 34: 679-685Crossref PubMed Scopus (23) Google Scholar) and that recognition of the basal lamina by the migrating ookinete is a factor in its differentiation into an oocyst (14Arrighi R.B.G. Hurd H. Int. J. Parasitol. 2002; 32: 91-98Crossref PubMed Scopus (41) Google Scholar). Sporozoites develop in oocysts, emerge into the hemolymph, and invade salivary glands, where they wait for the mosquito to take another blood meal. Previous studies have shown that salivary gland recognition and invasion are probably receptor-mediated processes (15Brennan J.D.G. Kent M. Dhar R. Fujioka H. Kumar N. Proc. Natl. Acad. Sci. U. S. A. 2000; 97: 13859-13864Crossref PubMed Scopus (73) Google Scholar, 16Mo Myung J. Marshall P. Sinnis P. Mol. Biochem. Parasitol. 2004; 133: 53-591Crossref PubMed Scopus (55) Google Scholar, 17Korochkina S. Barreau C. Pradel G. Jeffery E. Li J. Natarajan R. Shabanowitz J. Hunt D. Frevert U. Vernick K.D. Cell Microbiol. 2006; 8: 163-175Crossref PubMed Scopus (71) Google Scholar) and can be blocked by lectins (18Barreau C. Touray M. Pimenta P.F. Miller L.H. Vernick K.D. Exp. Parasitol. 1995; 81: 332-343Crossref PubMed Scopus (67) Google Scholar), suggesting that carbohydrates are involved. We have previously shown that CSP binds specifically to salivary glands and not to other mosquito organs (19Sidjanski S.P. Vanderberg J.P. Sinnis P. Mol. Biochem. Parasitol. 1997; 90: 33-41Crossref PubMed Scopus (83) Google Scholar), raising the possibility that heparan sulfate proteoglycans are involved in target cell recognition in the mosquito just as they are in the vertebrate host. Although the glycosaminoglycans in Drosophila melanogaster have been studied, there is currently no information on either the presence or the structure of glycosaminoglycans in the mosquito or any other insects of medical importance. The recent sequencing of the mosquito genome (20Holt R.A. Subramanian G.M. Halpern A. Sutton G.G. Charlab R. Nusskern D.R. Wincker P. Clark A.G. Ribeiro J.M. Wides R. Salzberg S.L. B. M. V. P. H. de V. D. V. J. C. R. D. M. S. A. M. A. V. A. A. I. C.A. M. A. P. R. S.L. J. C. E. A. I. A. J.A. S. Miller J. C. E. C. R. H. J. R. Sun J. D. P. M.F. B. A. J. M. M. A. Zhang H. S. S.C. I. M. A. Louis C. F. R.J. H.O. S. M.J. E. P. J. S.L. 2002; PubMed Scopus Google Scholar) as as of the salivary gland and Ribeiro J.M. Insect Biochem. Mol. Biol. 2003; PubMed Scopus Google Scholar) the presence of the protein and the heparan sulfate Biochem. 2002; PubMed Scopus Google Scholar), suggesting that heparan sulfate proteoglycans are present in Anopheles was for the in to its a vector of human P.F. J. Med. PubMed Scopus Google Scholar), it is used in the to it can the of human and the glycosaminoglycans present in mosquito disaccharide H. A. J. Biol. Chem. 2000; Scholar) and their to liver heparan sulfate and their binding to E was from The were from in C. was from heparin heparin and heparin were from and and heparan sulfate, from were from Heparan sulfate from liver was as previously M.J. Yang H.O. Gunay N.S. Linhardt R.J. Carbohydr. Polym. 2002; 48: 153-160Crossref Scopus (7) Google Scholar). CSP was in E. with The contains the P. CSP sequence from the that the and have been and were to the to facilitate The protein used in was by Takacs M.F. J. PubMed Scopus Google Scholar). heparan sulfate were from and heparan sulfate from sulfate were from and were from and was from were from The was from and were from was from and were from other used were of a a from a for the and a with a and a were on a and were on a at in A. were as previously P. Scholar). was with that been to for on an to the mosquito on and of also used A. that a blood meal. were on in and to were in and organs were into and on were at for to the was and the organs were at were in as in and at of midguts and salivary glands were a were and for were in of and of salivary glands were in of of for Mosquito for disaccharide were first to was with and the was with and The was with a containing with for at of and of were the was and was to the was by at for at was to the and for at and the was by at for at The was in of and the was H. A. J. Biol. Chem. 2000; Scholar). was to with and used as the for disaccharide microanalysis. was and of an containing and were to a of the and at for of was by high performance liquid heparan sulfate and were and the was on an which been with containing The with in the same were with and in of in of heparin containing and of an containing heparin heparin heparin and heparin were to a of The was at for and an was the high performance liquid H. A. J. Biol. Chem. 2000; Scholar). of from Heparan and Chondroitin from heparan sulfate and sulfate were by a with and specific was at a of a at The used were as A, B, C, D, The was as A, A, A, A, A, with and for The of and were at and of and was at the same to the a The a in a at and a The was H. A. J. Biol. Chem. 2000; Scholar). 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PubMed Scopus Google Scholar) that of heparan sulfate was was used for and were with and for at a of CSP was at a of The were with The was The surface was the same of was a of and of the CSP and and of heparan sulfate was studied, an with an time of and time of injection, the surface was with The was by the in time and the cell was from the The were with studies on salivary glands, from A. that they sulfate and heparan sulfate. The of sulfate in the mosquito, to be than that in the whole of D. melanogaster H. A. J. Biol. Chem. 2000; Scholar). on these of A. and from these were glands, and with were in to and into a for The to and of is in The of or organs was by either the by the of or by on a and for glands and midguts to and of the for or of A. on the of insects by from of the of either midguts or of salivary The of was by the by to a content of from of the of either midguts or of salivary The of was by the by to a content of and of not on the of insects by from of the of either midguts or of salivary The of was by the by to a content of not in a The whole and these isolated organs were by a previously for with D. melanogaster H. A. J. Biol. Chem. 2000; Scholar) to glycosaminoglycans. mosquito was found to contain of sulfate and of heparan sulfate and We used that a blood meal to the blood in the Insect Biochem. Mol. Biol. 2003; PubMed Scopus (63) Google Scholar), which in the of the cell by (15Brennan J.D.G. Kent M. Dhar R. Fujioka H. Kumar N. Proc. Natl. Acad. Sci. U. S. A. 2000; 97: 13859-13864Crossref PubMed Scopus (73) Google Scholar). of whole that it it that the blood meal to the sulfate and heparan sulfate in the for the sulfate and heparan sulfate content of blood with and found no in disaccharide the not from sulfate of of of of or A. salivary and not melanogaster of a is not The of a is H. A. J. Biol. Chem. 2000; Scholar). in a from heparan sulfate of or A. not salivary and melanogaster not H. A. J. Biol. Chem. 2000; 5Vongchan P. Warda M. Toyoda H. Toida T. Marks R.M. Linhardt R.J. Biochim. Biophys. Acta. 2005; 1721: 1-8Crossref PubMed Scopus (63) Google in a a disaccharide of whole and mosquito of glycosaminoglycans with The disaccharide was by high performance liquid H. A. J. Biol. Chem. 2000; Scholar, A. Toyoda H. T. Sci. 8: Scopus Google Scholar) (Fig. and 2). The whole insects and organs → and → of the were not no of or trisulfated be The glycosaminoglycans from no acid or dermatan sulfate. The presence of was a that can and A. Toyoda H. 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J.M. J. Linhardt R.J. J. Sci. 81: Full Text PDF PubMed Scopus Google Scholar) The of the presence of heparin in from to were and used to of heparan sulfate for CSP binding of were to the of the heparan sulfate and the of and sulfate The of the mosquito heparan sulfate with CSP was and with on the of CSP with heparin and heparan sulfate (10Rathore D. McCutchan T.F. Hernáiz M.J. LeBrun L.A. Lang S.C. Linhardt R.J. Biochemistry. 2001; 40: 11518-11524Crossref PubMed Scopus (61) Google Scholar, 11Rathore D. Hrstka S.C.L. Sacci J.B. de la Vega P. Linhardt R.J. Kumar S. McCutchan T.F. J. Biol. Chem. 2003; 278: 40905-40910Abstract Full Text Full Text PDF PubMed Scopus (43) Google Scholar). The to a with for The for mosquito heparan sulfate binding to CSP are shown in to was to the binding to CSP of mosquito heparan sulfate with that of heparin and other heparan with a than other with liver heparan sulfate binding with the Mosquito heparan sulfate a CSP binding with heparan sulfate. is that the heparan sulfate from while the different binding from the from The of mosquito heparan sulfate was by its and by a for a with at binding to liver in a The proteoglycans sulfate and heparan sulfate, as as the heparin R.J. J. Med. Chem. 2003; PubMed Scopus Google Scholar), have been in a variety of from (3Lyon M. Dakin J.A. Gallagher J.T. J. Biol. Chem. 1994; 269: 11208-11215Abstract Full Text PDF PubMed Google Scholar, 4Hernáiz M.J. Yang H.O. Gunay N.S. Linhardt R.J. Carbohydr. Polym. 2002; 48: 153-160Crossref Scopus (7) Google Scholar, 5Vongchan P. Warda M. Toyoda H. Toida T. Marks R.M. Linhardt R.J. Biochim. Biophys. 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The role of CSP in sporozoites to their target organs in the and mosquito to mosquito salivary glands have heparan sulfate it is to that found in the vertebrate This for the first that contain heparan sulfate and sulfate These the possibility that Plasmodium sporozoites heparan sulfate proteoglycans in the mosquito and to to their target they also be of to other which heparan sulfate proteoglycans T. Esko Linhardt R.J. Marks R.M. Med. 1997; PubMed Scopus Google Scholar), is to by and the heparan sulfate in the mosquito to to the salivary of the salivary gland Ribeiro J.M. Insect Biochem. Mol. Biol. 2003; PubMed Scopus Google Scholar) has shown that is of the in mosquito salivary glands, the of The the sequence of mosquito heparan sulfate are not as as those found in the mosquito contains of the found in human heparan sulfate. The mosquito contain the critical trisulfated disaccharide sequence, which binds to apoE in the liver (7Dong J. Peters-Libeu C.A. Weisgraber K.H. Segelke B.W. Rupp B. Capila I. Hernáiz M.J. LeBrun L.A. Linhardt R.J. Biochemistry. 2001; 40: 2826-2834Crossref PubMed Scopus (88) Google Scholar, 8Peters-Libeu C. Lund-Katz S. Phillips M. Wehrli S. Hernáiz M.J. Capila I. Linhardt R.J. Raffai R. Newhouse Y.M. Zhou M.F. Weisgraber K.H. J. Biol. Chem. 2001; 276: 39138-39142Abstract Full Text Full Text PDF PubMed Scopus (84) Google Scholar) and which sporozoites to specifically to hepatocytes (9Sinnis P. Willnow T.E. Briones M.R.S. Herz J. Nussenzweig V. J. Exp. Med. 1996; 184: 945-954Crossref PubMed Scopus (84) Google Scholar). There are also high sulfate in the mosquito heparan sulfate that with the decasaccharide site for CSP (10Rathore D. McCutchan T.F. Hernáiz M.J. LeBrun L.A. Lang S.C. Linhardt R.J. Biochemistry. 2001; 40: 11518-11524Crossref PubMed Scopus (61) Google Scholar). is that found no in the or of heparan sulfate in salivary glands and Plasmodium sporozoites develop in on the mosquito midgut wall, it is that they not bind to the midgut from the oocyst but in the that they can salivary glands, to which they bind and We at but finding that the midgut contains a of sulfate with the salivary gland the binding of sporozoites to these This hypothesis is supported by the that CSP also binds to sulfate P. Esko Sinnis P. J. Biol. Chem. 1997; Full Text Full Text PDF PubMed Scopus Google Scholar), and are currently of CSP have different binding for Previous studies have shown that heparin and liver heparan sulfate bind CSP (10Rathore D. McCutchan T.F. Hernáiz M.J. LeBrun L.A. Lang S.C. Linhardt R.J. Biochemistry. 2001; 40: 11518-11524Crossref PubMed Scopus (61) Google Scholar, 11Rathore D. Hrstka S.C.L. Sacci J.B. de la Vega P. Linhardt R.J. Kumar S. McCutchan T.F. J. Biol. Chem. 2003; 278: 40905-40910Abstract Full Text Full Text PDF PubMed Scopus (43) Google Scholar). used to the CSP and heparan sulfate from whole with its mosquito heparan sulfate binds to CSP but with and different of mosquito heparan sulfate is from infected by the parasite it is to the role of the binding whole mosquito heparan sulfate and liver heparan sulfate in infection and be to the CSP and glycosaminoglycans isolated from mosquito it has been to sufficient of heparan sulfate for studies from mosquito studies to and of glycosaminoglycans and from mosquito salivary glands and midgut are currently in have heparan sulfate and sulfate from Anopheles the major surface protein of the Plasmodium the of the parasite that is by anophelene binds to mosquito heparan sulfate. These suggest that the have mosquito and glycosaminoglycans facilitate transmission of the sporozoite from the mosquito to the host.