1887

Abstract

The host and bacterial factors that lead to development of pneumococcal haemolytic uraemic syndrome (pHUS) remain poorly defined; however, it is widely believed that pneumococcal exposure of the Thomsen–Friedenreich antigen (T-antigen) on host surfaces is a key step in pathogenesis. Two enzymatic activities encoded by pneumococci determine the level of T-antigen exposed. Neuraminidases cleave terminal sialic acid to expose the T-antigen which is subsequently cleaved by -glycosidase Eng. While a handful of studies have examined the role of neuraminidases in T-antigen exposure, no studies have addressed the potential role of -glycosidase. This study used 29 pHUS isolates from the USA and 31 serotype-matched controls. All isolates contained , and no significant correlation between enzymatic activity and disease state (pHUS and blood non-pHUS isolates) was observed. A prior study from Taiwan suggested that neuraminidase NanC contributes to the development of pHUS. However, we observed no difference in distribution. Similar to previously published data, we found no significant correlation between neuraminidase activity and disease state. Accurate quantification of these enzymatic activities from bacteria grown in whole blood is currently impossible, but we confirmed that there were no significant correlations between disease state and neuraminidase and -glycosidase transcript levels after incubation in blood. Genomic sequencing of six pHUS isolates did not identify any genetic elements possibly contributing to haemolytic uraemic syndrome. These findings support the hypothesis that while exposure of T-antigen may be an important step in disease pathogenesis, host factors likely play a substantial role in determining which individuals develop haemolytic uraemic syndrome after pneumococcal invasive disease.

Loading

Article metrics loading...

/content/journal/jmm/10.1099/jmm.0.000322
2016-09-01
2020-01-20
Loading full text...

Full text loading...

/deliver/fulltext/jmm/65/9/975.html?itemId=/content/journal/jmm/10.1099/jmm.0.000322&mimeType=html&fmt=ahah

References

  1. Altschul S. F., Gish W., Miller W., Myers E. W., Lipman D. J.. 1990; Basic local alignment search tool. J Mol Biol215:403–410 [CrossRef][PubMed]
    [Google Scholar]
  2. Ault B. H.. 2000; Factor H and the pathogenesis of renal diseases. Pediatr Nephrol14:1045–1053 [CrossRef][PubMed]
    [Google Scholar]
  3. Banerjee R., Hersh A. L., Newland J., Beekmann S. E., Polgreen P. M., Bender J., Shaw J., Copelovitch L., Kaplan B. S. et al. 2011; Streptococcus pneumoniae-associated hemolytic uremic syndrome among children in North America. Pediatr Infect Dis J30:736–739 [CrossRef][PubMed]
    [Google Scholar]
  4. Bankevich A., Nurk S., Antipov D., Gurevich A. A., Dvorkin M., Kulikov A. S., Lesin V. M., Nikolenko S. I., Pham S. et al. 2012; SPAdes: a new genome assembly algorithm and its applications to single-cell sequencing. J Comput Biol19:455–477 [CrossRef][PubMed]
    [Google Scholar]
  5. Bender J. M., Ampofo K., Byington C. L., Grinsell M., Korgenski K., Daly J. A., Mason E. O., Pavia A. T.. 2010; Epidemiology of Streptococcus pneumoniae-induced hemolytic uremic syndrome in Utah children. Pediatr Infect Dis J29:712–716 [CrossRef][PubMed]
    [Google Scholar]
  6. Berry A. M., Lock R. A., Paton J. C.. 1996; Cloning and characterization of nanB, a second Streptococcus pneumoniae neuraminidase gene, and purification of the NanB enzyme from recombinant Escherichia coli . J Bacteriol178:4854–4860[PubMed]
    [Google Scholar]
  7. Bhavanandan V. P., Umemoto J., Davidson E. A.. 1976; Characterization of an endo-alpha-N-acetyl galactosaminidase from Diplococcus pneumoniae . Biochem Biophys Res Commun70:738–745 [CrossRef][PubMed]
    [Google Scholar]
  8. Brandt J., Wong C., Mihm S., Roberts J., Smith J., Brewer E., Thiagarajan R., Warady B.. 2002; Invasive pneumococcal disease and hemolytic uremic syndrome. Pediatrics110:371–376 [CrossRef][PubMed]
    [Google Scholar]
  9. Bray J., Lemieux R. U., McPherson T. A.. 1981; Use of a synthetic hapten in the demonstration of the Thomsen-Friedenreich (T) antigen on neuraminidase-treated human red blood cells and lymphocytes. J Immunol126:1966–1969[PubMed]
    [Google Scholar]
  10. Cabrera G. R., Fortenberry J. D., Warshaw B. L., Chambliss C. R., Butler J. C., Cooperstone B. G.. 1998; Hemolytic uremic syndrome associated with invasive Streptococcus pneumoniae infection. Pediatrics101:699–703 [CrossRef][PubMed]
    [Google Scholar]
  11. Caines M. E., Zhu H., Vuckovic M., Willis L. M., Withers S. G., Wakarchuk W. W., Strynadka N. C.. 2008; The structural basis for T-antigen hydrolysis by Streptococcus pneumoniae: a target for structure-based vaccine design. J Biol Chem283:31279–31283 [CrossRef][PubMed]
    [Google Scholar]
  12. Cámara M., Boulnois G. J., Andrew P. W., Mitchell T. J.. 1994; A neuraminidase from Streptococcus pneumoniae has the features of a surface protein. Infect Immun62:3688–3695[PubMed]
    [Google Scholar]
  13. Cantarel B. L., Coutinho P. M., Rancurel C., Bernard T., Lombard V., Henrissat B.. 2009; The Carbohydrate-Active EnZymes database (CAZy): an expert resource for Glycogenomics. Nucleic Acids Res37:D233–238 [CrossRef][PubMed]
    [Google Scholar]
  14. Chen S. Y., Wu C. Y., Tsai I. J., Tsau Y. K., Su Y. T.. 2011; Nonenteropathic hemolytic uremic syndrome: the experience of a medical center. Pediatr Neonatol52:73–77 [CrossRef][PubMed]
    [Google Scholar]
  15. Coats M. T., Murphy T., Paton J. C., Gray B., Briles D. E.. 2011; Exposure of Thomsen-Friedenreich antigen in Streptococcus pneumoniae infection is dependent on pneumococcal neuraminidase A. Microb Pathog50:343–349 [CrossRef][PubMed]
    [Google Scholar]
  16. Cochran J. B., Panzarino V. M., Maes L. Y., Tecklenburg F. W.. 2004; Pneumococcus-induced T-antigen activation in hemolytic uremic syndrome and anemia. Pediatr Nephrol19:317–321 [CrossRef][PubMed]
    [Google Scholar]
  17. Constantinescu A. R., Bitzan M., Weiss L. S., Christen E., Kaplan B. S., Cnaan A., Trachtman H.. 2004; Non-enteropathic hemolytic uremic syndrome: causes and short-term course. Am J Kidney Dis43:976–982 [CrossRef][PubMed]
    [Google Scholar]
  18. Copelovitch L., Kaplan B. S.. 2008; Streptococcus pneumoniae-associated hemolytic uremic syndrome. Pediatr Nephrol23:1951–1956 [CrossRef][PubMed]
    [Google Scholar]
  19. Copelovitch L., Kaplan B. S.. 2010; Streptococcus pneumoniae-associated hemolytic uremic syndrome: classification and the emergence of serotype 19A. Pediatrics125:e174182 [CrossRef][PubMed]
    [Google Scholar]
  20. Crookston K. P., Reiner A. P., Cooper L. J., Sacher R. A., Blajchman M. A., Heddle N. M.. 2000; RBC T activation and hemolysis: implications for pediatric transfusion management. Transfusion40:801–812 [CrossRef][PubMed]
    [Google Scholar]
  21. Darling A. C., Mau B., Blattner F. R., Perna N. T.. 2004; Mauve: multiple alignment of conserved genomic sequence with rearrangements. Genome Res14:1394–1403 [CrossRef][PubMed]
    [Google Scholar]
  22. Eber S. W., Polster H., Quentin S. H., Rumpf K. W., Lynen R.. 1993; Hemolytic-uremic syndrome in pneumococcal meningitis and infection. Importance of T-transformation. Monatsschr Kinderheilkd141:219–222[PubMed]
    [Google Scholar]
  23. Enright M. C., Spratt B. G.. 1998; A multilocus sequence typing scheme for Streptococcus pneumoniae: identification of clones associated with serious invasive disease. Microbiology144:3049–3060 [CrossRef][PubMed]
    [Google Scholar]
  24. Feil E. J., Li B. C., Aanensen D. M., Hanage W. P., Spratt B. G.. 2004; eBURST: inferring patterns of evolutionary descent among clusters of related bacterial genotypes from multilocus sequence typing data. J Bacteriol186:1518–1530 [CrossRef][PubMed]
    [Google Scholar]
  25. Geary D. F.. 2007; Hemolytic uremic syndrome and Streptococcus pneumoniae: improving our understanding. J Pediatr151:113–114 [CrossRef][PubMed]
    [Google Scholar]
  26. Giefing C., Meinke A. L., Hanner M., Henics T., Bui M. D., Gelbmann D., Lundberg U., Senn B. M., Schunn M. et al. 2008; Discovery of a novel class of highly conserved vaccine antigens using genomic scale antigenic fingerprinting of pneumococcus with human antibodies. J Exp Med205:117–131 [CrossRef][PubMed]
    [Google Scholar]
  27. Giefing C., Jelencsics K. E., Gelbmann D., Senn B. M., Nagy E.. 2010; The pneumococcal eukaryotic-type serine/threonine protein kinase StkP co-localizes with the cell division apparatus and interacts with FtsZ in vitro . Microbiology156:1697–1707 [CrossRef][PubMed]
    [Google Scholar]
  28. Gilbert R. D., Nagra A., Haq M. R.. 2013; Does dysregulated complement activation contribute to haemolytic uraemic syndrome secondary to Streptococcus pneumoniae? . Med Hypotheses81:400–403 [CrossRef][PubMed]
    [Google Scholar]
  29. Gut H., King S. J., Walsh M. A.. 2008; Structural and functional studies of Streptococcus pneumoniae neuraminidase B: an intramolecular trans-sialidase. FEBS Lett582:3348–3352 [CrossRef][PubMed]
    [Google Scholar]
  30. Hsiao H. J., Wu C. T., Huang J. L., Chiu C. H., Huang Y. C., Lin J. J., Huang I. A., Chan O. W., Chou I. J., Hsia S. H.. 2015; Clinical features and outcomes of invasive pneumococcal disease in a pediatric intensive care unit. BMC Pediatr15:85 [CrossRef][PubMed]
    [Google Scholar]
  31. Huang D. T., Chi H., Lee H. C., Chiu N. C., Huang F. Y.. 2006; T-antigen activation for prediction of pneumococcus-induced hemolytic uremic syndrome and hemolytic anemia. Pediatr Infect Dis J25:608–610 [CrossRef][PubMed]
    [Google Scholar]
  32. Imai S., Ito Y., Ishida T., Hirai T., Ito I., Yoshimura K., Maekawa K., Takakura S., Niimi A. et al. 2011; Distribution and clonal relationship of cell surface virulence genes among Streptococcus pneumoniae isolates in Japan. Clin Microbiol Infect17:1409–1414 [CrossRef][PubMed]
    [Google Scholar]
  33. Janapatla R. P., Hsu M. H., Hsieh Y. C., Lee H. Y., Lin T. Y., Chiu C. H.. 2013; Necrotizing pneumonia caused by nanC-carrying serotypes is associated with pneumococcal haemolytic uraemic syndrome in children. Clin Microbiol Infect19:480–486 [CrossRef][PubMed]
    [Google Scholar]
  34. Johnston J. W.. 2009; Example of use of taqman real-time RT-PCR to analyze bacterial gene transcript levels: Haemophilus influenzae . Curr Protoc Microbiol Chapter 1, Unit 1D
    [Google Scholar]
  35. Kim Y. D., Prakash U., Weber G. F., Hargie M.. 1979; Nature of human serum blood group T antibodies. Immunol Commun8:397–406 [CrossRef][PubMed]
    [Google Scholar]
  36. King S. J., Hippe K. R., Gould J. M., Bae D., Peterson S., Cline R. T., Fasching C., Janoff E. N., Weiser J. N.. 2004; Phase variable desialylation of host proteins that bind to Streptococcus pneumoniae in vivo and protect the airway. Mol Microbiol54:159–171 [CrossRef][PubMed]
    [Google Scholar]
  37. King S. J., Whatmore A. M., Dowson C. G.. 2005; NanA, a neuraminidase from Streptococcus pneumoniae, shows high levels of sequence diversity, at least in part through recombination with Streptococcus oralis . J Bacteriol187:5376–5386 [CrossRef][PubMed]
    [Google Scholar]
  38. King S. J.. 2010; Pneumococcal modification of host sugars: a major contributor to colonization of the human airway?. Mol Oral Microbiol25:15–24 [CrossRef][PubMed]
    [Google Scholar]
  39. Klein P. J., Bulla M., Newman R. A., Müller P., Uhlenbruck G., Schaefer H. E., Krüger G., Fisher R.. 1977; Thomsen-Friedenreich antigen in haemolytic-uraemic syndrome. Lancet2:1024–1025[PubMed][CrossRef]
    [Google Scholar]
  40. Lacks S., Hotchkiss R. D.. 1960; A study of the genetic material determining an enzyme in Pneumococcus . Biochim Biophys Acta39:508–518 [CrossRef][PubMed]
    [Google Scholar]
  41. Lee C. S., Chen M. J., Chiou Y. H., Shen C. F., Wu C. Y., Chiou Y. Y.. 2012; Invasive pneumococcal pneumonia is the major cause of paediatric haemolytic-uraemic syndrome in Taiwan. Nephrology17:48–52 [CrossRef][PubMed]
    [Google Scholar]
  42. Linke C. M., Woodiga S. A., Meyers D. J., Buckwalter C. M., Salhi H. E., King S. J.. 2013; The ABC transporter encoded at the pneumococcal fructooligosaccharide utilization locus determines the ability to utilize long- and short-chain fructooligosaccharides. J Bacteriol195:1031–1041 [CrossRef][PubMed]
    [Google Scholar]
  43. Marion C., Limoli D. H., Bobulsky G. S., Abraham J. L., Burnaugh A. M., King S. J.. 2009; Identification of a pneumococcal glycosidase that modifies O-linked glycans. Infect Immun77:1389–1396 [CrossRef][PubMed]
    [Google Scholar]
  44. Martin B., Humbert O., Camara M., Guenzi E., Walker J., Mitchell T., Andrew P., Prudhomme M., Alloing G. et al. 1992; A highly conserved repeated DNA element located in the chromosome of Streptococcus pneumoniae . Nucleic Acids Res20:3479–3483 [CrossRef][PubMed]
    [Google Scholar]
  45. McGraw M. E., Lendon M., Stevens R. F., Postlethwaite R. J., Taylor C. M.. 1989; Haemolytic uraemic syndrome and the Thomsen Friedenreich antigen. Pediatr Nephrol3:135–139 [CrossRef][PubMed]
    [Google Scholar]
  46. Nathanson S., Deschênes G.. 2001; Prognosis of Streptococcus pneumoniae-induced hemolytic uremic syndrome. Pediatr Nephrol16:362–365 [CrossRef][PubMed]
    [Google Scholar]
  47. Pareja-Tobes P., Manrique M., Pareja-Tobes E., Pareja E., Tobes R.. 2012; BG7: a new approach for bacterial genome annotation designed for next generation sequencing data. PLoS One7:e49239 [CrossRef][PubMed]
    [Google Scholar]
  48. Pettigrew M. M., Fennie K. P., York M. P., Daniels J., Ghaffar F.. 2006; Variation in the presence of neuraminidase genes among Streptococcus pneumoniae isolates with identical sequence types. Infect Immun74:3360–3365 [CrossRef][PubMed]
    [Google Scholar]
  49. Poulsen M. P. E.. Polyagglutinability and T transformation (Engl Summary). Disseration. University of Copenhagen, Copenhagen, Denmark;p. 186
  50. Smith A., Johnston C., Inverarity D., Slack M., Paterson G. K., Diggle M., Mitchell T.. 2013; Investigating the role of pneumococcal neuraminidase A activity in isolates from pneumococcal haemolytic uraemic syndrome. J Med Microbiol62:1735–1742 [CrossRef][PubMed]
    [Google Scholar]
  51. Solovyev V., Saloamov A.. 2011; Automatic annotation of microbial genomes and metagenomic sequences. In Metagenomics and Its Applications in Agriculture, Biomedicine and Environmental Studies pp66–78 Edited by Li R.. Hauppauge: Nova Science;
    [Google Scholar]
  52. Springer G. F., Tegtmeyer H.. 1981; Origin of anti-Thomsen-Friedenreich (T) and Tn agglutinins in man and in White Leghorn chicks. Br J Haematol47:453–460 [CrossRef][PubMed]
    [Google Scholar]
  53. Szilágyi Á., Györke Z., Bereczki C., Kelen K., Tóth-Heyn P., Tulassay T., Reusz G. S., Szabó A. J., Prohászka Z.. 2015; The use of a rapid fluorogenic neuraminidase assay to differentiate acute Streptococcus pneumoniae-associated hemolytic uremic syndrome (HUS) from other forms of HUS. Clin Chem Lab Med53:e117119 [CrossRef][PubMed]
    [Google Scholar]
  54. Szilágyi A., Kiss N., Bereczki C., Tálosi G., Rácz K., Túri S., Györke Z., Simon E., Horváth E. et al. 2013; The role of complement in Streptococcus pneumoniae-associated haemolytic uraemic syndrome. Nephrol Dial Transplant28:2237–2245 [CrossRef][PubMed]
    [Google Scholar]
  55. Tettelin H., Hollingshead S. K.. 2004; Comparative genomics of Streptococcus pneumoniae: intra-strain diversity and genome plasticity. In The Pneumococcus pp.15–29 Edited by Tuomanen E., Mitchell T. J., Morrison D. A., Spratt B. G.. Washington, D.C.: ASM Press;
    [Google Scholar]
  56. Trappetti C., Kadioglu A., Carter M., Hayre J., Iannelli F., Pozzi G., Andrew P. W., Oggioni M. R.. 2009; Sialic acid: a preventable signal for pneumococcal biofilm formation, colonization, and invasion of the host. J Infect Dis199:1497–1505 [CrossRef][PubMed]
    [Google Scholar]
  57. Treangen T. J., Ondov B. D., Koren S., Phillippy A. M.. 2014; The Harvest suite for rapid core-genome alignment and visualization of thousands of intraspecific microbial genomes. Genome Biol15:524 [CrossRef][PubMed]
    [Google Scholar]
  58. Vandesompele J., De Preter K., Pattyn F., Poppe B., Van Roy N., De Paepe A., Speleman F.. 2002; Accurate normalization of real-time quantitative RT-PCR data by geometric averaging of multiple internal control genes. Genome Biol3:RESEARCH0034[PubMed][CrossRef]
    [Google Scholar]
  59. Waters A. M., Kerecuk L., Luk D., Haq M. R., Fitzpatrick M. M., Gilbert R. D., Inward C., Jones C., Pichon B. et al. 2007; Hemolytic uremic syndrome associated with invasive pneumococcal disease: the United Kingdom experience. J Pediatr151:140–144 [CrossRef][PubMed]
    [Google Scholar]
  60. Whatmore A. M., Barcus V. A., Dowson C. G.. 1999; Genetic diversity of the streptococcal competence (com) gene locus. J Bacteriol181:3144–3154[PubMed]
    [Google Scholar]
  61. Willis L. M., Zhang R., Reid A., Withers S. G., Wakarchuk W. W.. 2009; Mechanistic investigation of the endo-alpha-N-acetylgalactosaminidase from Streptococcus pneumoniae R6. Biochemistry48:10334–10341 [CrossRef][PubMed]
    [Google Scholar]
  62. Xu G., Potter J. A., Russell R. J., Oggioni M. R., Andrew P. W., Taylor G. L.. 2008; Crystal structure of the NanB sialidase from Streptococcus pneumoniae . J Mol Biol384:436–449 [CrossRef][PubMed]
    [Google Scholar]
  63. Xu G., Kiefel M. J., Wilson J. C., Andrew P. W., Oggioni M. R., Taylor G. L.. 2011; Three Streptococcus pneumoniae sialidases: three different products. J Am Chem Soc133:1718–1721 [CrossRef][PubMed]
    [Google Scholar]
http://instance.metastore.ingenta.com/content/journal/jmm/10.1099/jmm.0.000322
Loading
/content/journal/jmm/10.1099/jmm.0.000322
Loading

Data & Media loading...

Supplements

Supplementary File 1

PDF
This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error