A Small Molecule Glycosaminoglycan Mimetic Blocks Invasion of the Mosquito Midgut

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Malaria transmission-blocking (T-B) interventions are essential for malaria elimination. Small molecules that inhibit the Plasmodium ookinete-to-oocyst transition in the midgut of Anopheles mosquitoes, thereby blocking sporogony, represent one approach to achieving this goal. Chondroitin sulfate glycosaminoglycans (CS-GAGs) on the Anopheles gambiae midgut surface are putative ligands for Plasmodium falciparum ookinetes. We hypothesized that our synthetic polysulfonated polymer, VS1, acting as a decoy molecular mimetic of midgut CS-GAGs confers malaria T-B activity. In our study, VS1 repeatedly reduced midgut oocyst development by as much as 99% (P<0.0001) in mosquitoes fed with P. falciparum and Plasmodium berghei. Through direct-binding assays, we observed that VS1 bound to two critical ookinete micronemal proteins, each containing at least one von Willebrand factor A (vWA) domain: (i) circumsporozoite protein and thrombospondin-related anonymous protein-related protein (CTRP) and (ii) vWA domain-related protein (WARP). By immunofluorescence microscopy, we observed that VS1 stains permeabilized P. falciparum and P. berghei ookinetes but does not stain P. berghei CTRP knockouts or transgenic parasites lacking the vWA domains of CTRP while retaining the thrombospondin repeat region. We produced structural homology models of the first vWA domain of CTRP and identified, as expected, putative GAG-binding sites on CTRP that align closely with those predicted for the human vWA A1 domain and the Toxoplasma gondii MIC2 adhesin. Importantly, the models also identified patches of electropositive residues that may extend CTRP's GAG-binding motif and thus potentiate VS1 binding. Our molecule binds to a critical, conserved ookinete protein, CTRP, and exhibits potent malaria T-B activity. This study lays the framework for a high-throughput screen of existing libraries of safe compounds to identify those with potent T-B activity. We envision that such compounds when used as partner drugs with current antimalarial regimens and with RTS,S vaccine delivery could prevent the transmission of drug-resistant and vaccine-breakthrough strains.

Vyšlo v časopise: A Small Molecule Glycosaminoglycan Mimetic Blocks Invasion of the Mosquito Midgut. PLoS Pathog 9(11): e32767. doi:10.1371/journal.ppat.1003757
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1003757

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Zdroje

1. AlonsoPL, BrownG, Arevalo-HerreraM, BinkaF, ChitnisC, et al. (2011) A research agenda to underpin malaria eradication. PLoS Med 8(1): e1000406.

2. malERA Consultative Group on Drugs (2011) A research agenda for malaria eradication: Drugs. PLoS Med 8(1): e1000402.

3. DinglasanRR, Jacobs-LorenaM (2005) Insight into a conserved lifestyle: Protein-carbohydrate adhesion strategies of vector-borne pathogens. Infect Immun 73(12): 7797–7807.

4. DinglasanRR, KalumeDE, KanzokSM, GhoshAK, MuratovaO, et al. (2007) Disruption of Plasmodium falciparum development by antibodies against a conserved mosquito midgut antigen. Proc Natl Acad Sci USA 104(33): 13461–13466.

5. DinglasanRR, AlagananA, GhoshAK, SaitoA, van KuppeveltTH, et al. (2007) Plasmodium falciparum ookinetes require mosquito midgut chondroitin sulfate proteoglycans for cell invasion. Proc Natl Acad Sci USA 104(40): 15882–15887.

6. AngrisanoF, TanY, SturmA, McFaddenGI, BaumJ (2012) Malaria parasite colonisation of the mosquito midgut -⁠ placing the Plasmodium ookinete centre stage. Int J Parasitol 42(6): 519–527.

7. DelvesM, PlouffeD, ScheurerC, MeisterS, WittlinS, et al. (2012) The activities of current antimalarial drugs on the life cycle stages of Plasmodium: A comparative study with human and rodent parasites. PLoS Med 9(2): e1001169.

8. TrotteinF, TrigliaT, CowmanAF (1995) Molecular cloning of a gene from Plasmodium falciparum that codes for a protein sharing motifs found in adhesive molecules from mammals and plasmodia. Mol Biochem Parasitol 74(2): 129–141.

9. DessensJT, BeetsmaAL, DimopoulosG, WengelnikK, CrisantiA, et al. (1999) CTRP is essential for mosquito infection by malaria ookinetes. EMBO J 18(22): 6221–6227.

10. LiFW, TempletonTJ, PopovV, ComerJE, TsuboiT, et al. (2004) Plasmodium ookinete-secreted proteins secreted through a common micronemal pathway are targets of blocking malaria transmission. J Biol Chem 279(25): 26635–26644.

11. TempletonTJ, KaslowDC, FidockDA (2000) Developmental arrest of the human malaria parasite Plasmodium falciparum within the mosquito midgut via CTRP gene disruption. Mol Microbiol 36(1): 1–9.

12. YudaM, SawaiT, ChinzeiY (1999) Structure and expression of an adhesive protein-like molecule of mosquito invasive-stage malarial parasite. J Exp Med 189(12): 1947–1952.

13. YudaM, SakaidaH, ChinzeiY (1999) Targeted disruption of the Plasmodium berghei CTRP gene reveals its essential role in malaria infection of the vector mosquito. J Exp Med 190(11): 1711–1715.

14. YudaM, YanoK, TsuboiT, ToriiM, ChinzeiY (2001) Von willebrand factor A domain-related protein, a novel microneme protein of the malaria ookinete highly conserved throughout Plasmodium parasites. Mol Biochem Parasitol 116(1): 65–72.

15. RamakrishnanC, DessensJT, ArmsonR, PintoSB, TalmanAM, et al. (2011) Vital functions of the malarial ookinete protein, CTRP, reside in the A domains. Int J Parasitol 41(10): 1029–1039.

16. SinnisP, CoppiA, ToidaT, ToyodaH, Kinoshita-ToyodaA, et al. (2007) Mosquito heparan sulfate and its potential role in malaria infection and transmission. J Biol Chem 282(35): 25376–25384.

17. TsuboiT, TakeoS, IrikoH, JinL, TsuchimochiM, et al. (2008) Wheat germ cell-free system-based production of malaria proteins for discovery of novel vaccine candidates. Infect Immun 76(4): 1702–1708.

18. ArnoldK, BordoliL, KoppJ, SchwedeT (2006) The SWISS-MODEL workspace: A web-based environment for protein structure homology modelling. Bioinformatics 22(2): 195–201.

19. SchwedeT, KoppJ, GuexN, PeitschM (2003) SWISS-MODEL: An automated protein homology-modeling server. Nucleic Acids Res 31(13): 3381–3385.

20. KieferF, ArnoldK, KuenzliM, BordoliL, SchwedeT (2009) The SWISS-MODEL repository and associated resources. Nucleic Acids Res 37: D387–D392.

21. KoppJ, SchwedeT (2006) The SWISS-MODEL repository: New features and functionalities. Nucleic Acids Res 34: D315–D318.

22. ZdobnovE, ApweilerR (2001) InterProScan -⁠ an integration platform for the signature-recognition methods in InterPro. Bioinformatics 17(9): 847–848.

23. BenkertP, KuenzliM, SchwedeT (2009) QMEAN server for protein model quality estimation. Nucleic Acids Res 37: W510–W514.

24. PaulRE, BonnetS, BoudinC, TchuinkamT, RobertV (2007) Age-structured gametocyte allocation links immunity to epidemiology in malaria parasites. Malar J 6 : 123.

25. BousemaT, DinglasanRR, MorlaisI, GouagnaLC, van WarmerdamT, et al. (2012) Mosquito feeding assays to determine the infectiousness of naturally infected Plasmodium falciparum gametocyte carriers. PLoS One 7(8): e42821.

26. LalK, PrietoJH, BromleyE, SandersonSJ, Yates,JohnRIII, et al. (2009) Characterisation of Plasmodium invasive organelles; an ookinete microneme proteome. Proteomics 9(5): 1142–1151.

27. SindenRE, WingerLA, HartleyRH, CarterHE, TirawancchaiN, DaviesCS, SluitersJG (1987) Ookinete antigens of Plasmodium berghei: a light and electron microscopic immunogold study of the 21 kD determinant recognized by transmission-blocking antibodies. P Roy Soc Lond B Bio 230 : 443–458.

28. Alejo BlancoAR, PaezA, GeroldP, DearslyAL, MargosG, et al. (1999) The biosynthesis and post-translational modification of Pbs21an ookinete-surface protein of Plasmodium berghei.. Mol Biochem Parasitol 98(2): 163–173.

29. MairGR, BraksJA, GarverLS, WiegantJC, HallN, et al. (2006) Regulation of sexual development of Plasmodium by translational repression. Science 313(5787): 667–669.

30. KanekoO, TempletonTJ, IrikoH, TachibanaM, OtsukiH, et al. (2006) The Plasmodium vivax homolog of the ookinete adhesive micronemal protein, CTRP. Parasitol Int 55(3): 227–231.

31. AdachiT, MatsushitaT, DongZ, KatsumiA, NakayamaT, et al. (2006) Identification of amino acid residues essential for heparin binding by the A1 domain of human von willebrand factor. Biochem Biophys Res Commun 339(4): 1178–1183.

32. EmsleyJ, CruzM, HandinR, LiddingtonR (1998) Crystal structure of the von willebrand factor A1 domain and implications for the binding of platelet glycoprotein ib. J Biol Chem 273(17): 10396–10401.

33. Rastegar-LariG, VilloutreixB, RibbaA, LegendreP, MeyerD, et al. (2002) Two clusters of charged residues located in the electropositive face of the von willebrand factor A1 domain are essential for heparin binding. Biochemistry (N Y) 41(21): 6668–6678.

34. TonkinML, GrujicO, PearceM, CrawfordJ, BoulangerMJ (2010) Structure of the micronemal protein 2 A/I domain from Toxoplasma gondii. Protein Sci 19(10): 1985–1990.

35. BoyleMJ, RichardsJS, GilsonPR, ChaiW, BeesonJG (2010) Interactions with heparin-like molecules during erythrocyte invasion by Plasmodium falciparum merozoites. Blood 115(22): 4559–4568.

36. CrandallIE, SzarekWA, VlahakisJZ, XuY, VohraR, et al. (2007) Sulfated cyclodextrins inhibit the entry of Plasmodium into red blood cells -⁠ implications for malarial therapy. Biochem Pharmacol 73(5): 632–642.

37. AchurRN, KakizakiI, GoelS, KojimaK, MadhunapantulaSV, et al. (2008) Structural interactions in chondroitin 4-sulfate mediated adherence of Plasmodium falciparum infected erythrocytes in human placenta during pregnancy-associated malaria. Biochemistry (NY) 47(47): 12635–12643.

38. ArmisteadJS, WilsonIB, van KuppeveltTH, DinglasanRR (2011) A role for heparan sulfate proteoglycans in Plasmodium falciparum sporozoite invasion of anopheline mosquito salivary glands. Biochem J 438(3): 475–483.

39. SinnisP, CoppiA (2007) A long and winding road: The Plasmodium sporozoite's journey in the mammalian host. Parasitol Int 56(3): 171–178.

40. HilemanR, FrommJ, WeilerJ, LinhardtR (1998) Glycosaminoglycan-protein interactions: Definition of consensus sites in glycosaminoglycan binding proteins. Bioessays 20(2): 156–167.

41. KuschertG, CoulinF, PowerC, ProudfootA, HubbardR, et al. (1999) Glycosaminoglycans interact selectively with chemokines and modulate receptor binding and cellular responses. Biochemistry (NY) 38(39): 12959–12968.

42. MartinL, BlanpainC, GarnierP, WittamerV, ParmentierM, et al. (2001) Structural and functional analysis of the RANTES-glycosaminoglycans interactions. Biochemistry (NY) 40(21): 6303–6318.

43. McCormickC, TuckwellD, CrisantiA, HumphriesM, HollingdaleM (1999) Identification of heparin as a ligand for the A-domain of Plasmodium falciparum thrombospondin-related adhesion protein. Mol Biochem Parasitol 100(1): 111–124.

44. AkhouriR, BhattacharyyaA, PattnaikP, MalhotraP, SharmaA (2004) Structural and functional dissection of the adhesive domains of Plasmodium falciparum thrombospondin-related anonymous protein (TRAP). Biochem J 379 : 815–822.

45. BaumJ, BillkerO, BousemaT, DinglasanR, McGovernV, et al. (2011) A research agenda for malaria eradication: Basic science and enabling technologies. PLoS Med 8(1): e1000399.