Polysaccharide capsules are important virulence factors in pathogenic microbes that provide a protective coat against host immunity. Cryptococcus neoformans is a pathogenic encapsulated yeast that is a major opportunistic infection, causing approximately 600,000 cases of meningitis per year in AIDS patients globally, and whose polysaccharide capsule is a major virulence factor. While extensive work has detailed the chemical components forming the cryptococcal capsule, the molecular events leading to the higher order assembly of the capsule, and its consequences on immune subterfuge remain unknown. In the present studies we used a proteomics method to identify a novel hydrolytic enzyme, lactonohydrolase (Lhc1) and used a variety of biophysical methods including dynamic and static light scattering as well as motility studies to show that extracted capsular polysaccharide undergoes remodeling in a LHC1-dependent fashion. This results in a more tightly compacted capsular structure that alters binding of anti-capsular antibodies and reduces binding by both human as well as mouse serum complement. Furthermore, LHC1-dependent capsular alterations serve to increase the virulence of the fungus in a mouse model, suggesting a novel role for this class of enzyme in capsular remodeling and immune evasion in microbial pathogenesis.
Vyšlo v časopise: A Role for in Higher Order Structure and Complement Binding of the Capsule. PLoS Pathog 10(5): e32767. doi:10.1371/journal.ppat.1004037 Kategorie: Research Article prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1004037
1. RobertsIS, SaundersFK, BoulnoisGJ (1989) Bacterial capsules and interactions with complement and phagocytes. Biochem Soc Trans 17 : 462–464.
2. HorwitzMA, SilversteinSC (1980) Influence of the Escherichia coli capsule on complement fixation and on phagocytosis and killing by human phagocytes. J Clin Invest 65 : 82–94.
3. SchneiderMC, ExleyRM, RamS, SimRB, TangCM (2007) Interactions between Neisseria meningitidis and the complement system. Trends Microbiol 15 : 233–240.
4. VecchiarelliA (2000) Immunoregulation by capsular components of Cryptococcus neoformans. Med Mycol 38 : 407–417.
5. KisengePR, HawkinsAT, MaroVP, McHeleJP, SwaiNS, et al. (2007) Low CD4 count plus coma predicts cryptococcal meningitis in Tanzania. BMC Infect Dis 7 : 39.
6. ParkBJ, WannemuehlerKA, MarstonBJ, GovenderN, PappasPG, et al. (2009) Estimation of the current global burden of cryptococcal meningitis among persons living with HIV/AIDS. Aids 23 : 525–530.
7. KumarP, YangM, HaynesBC, SkowyraML, DoeringTL (2011) Emerging themes in cryptococcal capsule synthesis. Curr Opin Struct Biol 21 : 597–602.
8. CherniakR, SundstromJB (1994) Polysaccharide antigens of the capsule of Cryptococcus neoformans. Infect Immun 62 : 1507–1512.
9. DoeringTL (2009) How sweet it is! Cell wall biogenesis and polysaccharide capsule formation in Cryptococcus neoformans. Annu Rev Microbiol 63 : 223–247.
10. CorderoRJ, FrasesS, GuimaraesAJ, RiveraJ, CasadevallA (2011) Evidence for branching in cryptococcal capsular polysaccharides and consequences on its biological activity. Mol Microbiol 79 : 1101–1117.
11. GorenMB, MiddlebrookGM (1967) Protein conjugates of polysaccharide from Cryptococcus neoformans. J Immunol 98 : 901–913.
12. RodriguesML, NakayasuES, OliveiraDL, NimrichterL, NosanchukJD, et al. (2008) Extracellular vesicles produced by Cryptococcus neoformans contain protein components associated with virulence. Eukaryot Cell 7 : 58–67.
13. KataokaM, YamamotoK, ShimizuS, OhtaM, KitaA, et al. (1998) Crystallization and preliminary X-ray diffraction study of lactonohydrolase from Fusarium oxysporum. Acta Crystallogr D Biol Crystallogr 54 : 1432–1434.
14. MalikA, FirozA, JhaV, AhmadS (2010) PROCARB: A Database of Known and Modelled Carbohydrate-Binding Protein Structures with Sequence-Based Prediction Tools. Adv Bioinformatics 436036.
15. SvenssonC, TenebergS, NilssonCL, KjellbergA, SchwarzFP, et al. (2002) High-resolution crystal structures of Erythrina cristagalli lectin in complex with lactose and 2′-alpha-L-fucosyllactose and correlation with thermodynamic binding data. J Mol Biol 321 : 69–83.
16. BicanicT, HarrisonTS (2004) Cryptococcal meningitis. Br Med Bull 72 : 99–118.
17. ShimizuS, KataokaM, ShimizuK, HirakataM, SakamotoK, et al. (1992) Purification and characterization of a novel lactonohydrolase, catalyzing the hydrolysis of aldonate lactones and aromatic lactones, from Fusarium oxysporum. Eur J Biochem 209 : 383–390.
18. CasellasM, GrifollM, BayonaJM, SolanasAM (1997) New metabolites in the degradation of fluorene by Arthrobacter sp. strain F101. Appl Environ Microbiol 63 : 819–826.
19. ZhuX, GibbonsJ, Garcia-RiveraJ, CasadevallA, WilliamsonPR (2001) Laccase of Cryptococcus neoformans is a cell wall-associated virulence factor. Infect Immun 69 : 5589–5596.
20. JanbonG, HimmelreichU, MoyrandF, ImprovisiL, DromerF (2001) Cas1p is a membrane protein necessary for the O-acetylation of the Cryptococcus neoformans capsular polysaccharide. Mol Microbiol 42 : 453–467.
21. GatesMA, ThorkildsonP, KozelTR (2004) Molecular architecture of the Cryptococcus neoformans capsule. Mol Microbiol 52 : 13–24.
22. FonsecaFL, NimrichterL, CorderoRJ, FrasesS, RodriguesJ, et al. (2009) Role for chitin and chitooligomers in the capsular architecture of Cryptococcus neoformans. Eukaryot Cell 8 : 1543–1553.
23. FrasesS, PontesB, NimrichterL, VianaNB, RodriguesML, et al. (2009) Capsule of Cryptococcus neoformans grows by enlargement of polysaccharide molecules. Proc Natl Acad Sci U S A 106 : 1228–1233.
24. MullerRH, JacobsC, KayserO (2001) Nanosuspensions as particulate drug formulations in therapy. Rationale for development and what we can expect for the future. Adv Drug Deliv Rev 47 : 3–19.
25. ZhangS, HachamM, PanepintoJ, HuG, ShinS, et al. (2006) The Hsp70 member, Ssa1 acts as a DNA-binding transcriptional co-activator in Cryptococcus neoformans. Mol Microbol 62 : 1090–1101.
26. WangX, WangP, SunS, DarwicheS, IdnurmA, et al. (2012) Transgene induced co-suppression during vegetative growth in Cryptococcus neoformans. PLoS Genet 8: e1002885.
27. De JesusM, ChowSK, CorderoRJ, FrasesS, CasadevallA (2010) Galactoxylomannans from Cryptococcus neoformans varieties neoformans and grubii are structurally and antigenically variable. Eukaryot Cell 9 : 1018–1028.
28. MukherjeeJ, NussbaumG, ScharffMD, CasadevallA (1995) Protective and nonprotective monoclonal antibodies to Cryptococcus neoformans originating from one B cell. J Exp Med 181 : 405–409.
29. FeldmesserM, KressY, NovikoffP, CasadevallA (2000) Cryptococcus neoformans is a facultative intracellular pathogen in murine pulmonary infection. Infect Immun 68 : 4225–4237.
30. TabordaCP, CasadevallA (2002) CR3 (CD11b/CD18) and CR4 (CD11c/CD18) are involved in complement-independent antibody-mediated phagocytosis of Cryptococcus neoformans. Immunity 16 : 791–802.
31. KozelTR (1993) Opsonization and phagocytosis of Cryptococcus neoformans. Arch Med Res 24 : 211–218.
32. KozelTR, WilsonMA, MurphyJW (1991) Early events in initiation of alternative complement pathway activation by the capsule of Cryptococcus neoformans. Infect Immun 59 : 3101–3110.
33. Mershon-ShierKL, VasuthasawatA, TakahashiK, MorrisonSL, BeenhouwerDO (2011) In vitro C3 deposition on Cryptococcus capsule occurs via multiple complement activation pathways. Mol Immunol 48 : 2009–2018.
34. KozelTR, PfrommerGS (1986) Activation of the complement system by Cryptococcus neoformans leads to binding of iC3b to the yeast. Infect Immun 52 : 1–5.
35. PanepintoJ, LiuL, RamosJ, ZhuX, Valyi-NagyT, et al. (2005) The DEAD-box RNA helicase Vad1 regulates multiple virulence-associated genes in Cryptococcus neoformans. J Clin Invest 115 : 632–641.
36. ShapiroS, BeenhouwerDO, FeldmesserM, TabordaC, CarrollMC, et al. (2002) Immunoglobulin G monoclonal antibodies to Cryptococcus neoformans protect mice deficient in complement component C3. Infect Immun 70 : 2598–2604.
37. Casadevall A, Perfect J (1998) Cryptococcus neoformans. Wash D.C.: ASM Press.
38. CherniakR, ValafarH, MorrisLC, ValafarF (1998) Cryptococcus neoformans chemotyping by quantitative analysis of 1H nuclear magnetic resonance spectra of glucuronoxylomannans with a computer-simulated artificial neural network. Clin Diagn Lab Immunol 5 : 146–159.
39. FevrierB, RaposoG (2004) Exosomes: endosomal-derived vesicles shipping extracellular messages. Curr Opin Cell Biol 16 : 415–421.
40. ShimizuS, KataokaM, HondaK, SakamotoK (2001) Lactone-ring-cleaving enzymes of microorganisms: their diversity and applications. J Biotechnol 92 : 187–194.
41. NilssonL, LeemanM, WahlundKG, BergenstahlB (2006) Mechanical degradation and changes in conformation of hydrophobically modified starch. Biomacromolecules 7 : 2671–2679.
42. MurakamiT, UchidaS, IshizuK (2008) Architecture of hyperbranched polymers consisting of a stearyl methacrylate sequence via a living radical copolymerization. J Colloid Interface Sci 323 : 242–246.
43. NimrichterL, FrasesS, CinelliLP, VianaNB, NakouziA, et al. (2007) Self-aggregation of Cryptococcus neoformans capsular glucuronoxylomannan is dependent on divalent cations. Eukaryot Cell 6 : 1400–1410.
44. McFaddenDC, De JesusM, CasadevallA (2006) The physical properties of the capsular polysaccharides from Cryptococcus neoformans suggest features for capsule construction. J Biol Chem 281 : 1868–1875.
45. McFaddenDC, FriesBC, WangF, CasadevallA (2007) Capsule structural heterogeneity and antigenic variation in Cryptococcus neoformans. Eukaryot Cell 6 : 1464–1473.
46. ZaragozaO, TelzakA, BryanRA, DadachovaE, CasadevallA (2006) The polysaccharide capsule of the pathogenic fungus Cryptococcus neoformans enlarges by distal growth and is rearranged during budding. Mol Microbiol 59 : 67–83.
47. ChunCD, LiuOW, MadhaniHD (2007) A link between virulence and homeostatic responses to hypoxia during infection by the human fungal pathogen Cryptococcus neoformans. PLoS Pathog 3: e22.
48. DiamondRD, MayJE, KaneM, FrankMM, BennettJE (1973) The role of late complement components and the alternate complement pathway in experimental cryptococcosis. Proc Soc Exp Biol Med 144 : 312–315.
49. MershonKL, VasuthasawatA, LawsonGW, MorrisonSL, BeenhouwerDO (2009) Role of complement in protection against Cryptococcus gattii infection. Infect Immun 77 : 1061–1070.
50. DiamondRD, MayJE, KaneMA, FrankMM, BennettJE (1974) The role of the classical and alternate complement pathways in host defenses against Cryptococcus neoformans infection. J Immunol 112 : 2260–2270.
51. ZhuX, WilliamsonPR (2004) Role of laccase in the biology and virulence of Cryptococcus neoformans. FEMS Yeast Res 5 : 1–10.
52. WilliamsonPR (1994) Biochemical and molecular characterization of the diphenol oxidase of Cryptococcus neoformans: identification as a laccase. J Bacteriol 176 : 656–664.
53. MerkelGJ, ScofieldBA (1994) Comparisons between in vitro glial cell adherence and internalization of non-encapsulated and encapsulated strains of Cryptococcus neoformans. J Med Vet Mycol 32 : 361–372.
54. MoyrandF, KlaprothB, HimmelreichU, DromerF, JanbonG (2002) Isolation and characterization of capsule structure mutant strains of Cryptococcus neoformans. Mol Microbiol 45 : 837–849.
55. DuusJ, GotfredsenCH, BockK (2000) Carbohydrate structural determination by NMR spectroscopy: modern methods and limitations. Chem Rev 100 : 4589–4614.
56. EricksonT, LiuL, GueyikianA, ZhuX, GibbonsJ, et al. (2001) Multiple virulence factors of Cryptococcus neoformans are dependent on VPH1. Mol Microbiol 42 : 1121–1131.
57. CoxG, MukherjeeJ, ColeG, CasadevallA, PerfectJ (2000) Urease as a virulence factor in experimental cryptococcosis. Infect Immun 68 : 443–448.
58. LiuL, WakamatsuK, ItoS, WilliamsonPR (1999) Catecholamine oxidative products, but not melanin, are produced by Cryptococcus neoformans during neuropathogenesis in mice. Infect Immun 67 : 108–112.
59. SalasSD, BennettJE, Kwon-ChungKJ, PerfectJR, WilliamsonPR (1996) Effect of the laccase gene CNLAC1, on virulence of Cryptococcus neoformans. J Exp Med 184 : 377–386.
60. MillerMF, MitchellTG (1991) Killing of Cryptococcus neoformans strains by human neutrophils and monocytes. Infect Immun 59 : 24–28.
Zvýšte si kvalifikáciu online z pohodlia domova
Nemáte účet? Registrujte sa
Zadajte e-mailovú adresu, s ktorou ste vytvárali účet. Budú Vám na ňu zasielané informácie k nastaveniu nového hesla.
