1887

Abstract

is a significant human pathogen worldwide and is responsible for severe nosocomial and community-acquired infections. Although enterococcal meningitis is rare, mortality is considerable, reaching 21 %. Nevertheless, the pathogenetic mechanisms of this infection remain poorly understood, even though the ability of to avoid or survive phagocytic attack may be very important during the infection process. We previously showed that the manganese-cofactored superoxide dismutase (MnSOD) SodA of was implicated in oxidative stress responses and, interestingly, in the survival within mouse peritoneal macrophages using an infection model. In the present study, we investigated the role of MnSOD in the interaction of with microglia, the brain-resident macrophages. By using an infection model, murine microglial cells were challenged in parallel with the wild-type strain JH2-2 and its isogenic deletion mutant. While both strains were phagocytosed by microglia efficiently and to a similar extent, the Δ mutant was found to be significantly more susceptible to microglial killing than JH2-2, as assessed by the antimicrobial protection assay. In addition, a significantly higher percentage of acidic Δ-containing phagosomes was found and these also underwent enhanced maturation as determined by the expression of endolysosomal markers. In conclusion, these results show that the MnSOD of contributes to survival of the bacterium in microglial cells by influencing their antimicrobial activity, and this could even be important for intracellular killing in neutrophils and thus for pathogenesis.

Loading

Article metrics loading...

/content/journal/micro/10.1099/mic.0.047381-0
2011-06-01
2021-02-25
Loading full text...

Full text loading...

/deliver/fulltext/micro/157/6/1816.html?itemId=/content/journal/micro/10.1099/mic.0.047381-0&mimeType=html&fmt=ahah

References

  1. Beertsen W., Willenborg M., Everts V., Zirogianni A., Podschun R., Schröder B., Eskelinen E. L., Saftig P. ( 2008). Impaired phagosomal maturation in neutrophils leads to periodontitis in lysosomal-associated membrane protein-2 knockout mice. J Immunol 180:475–482[PubMed] [CrossRef]
    [Google Scholar]
  2. Bizzini A., Zhao C., Auffray Y., Hartke A. ( 2009). The Enterococcus faecalis superoxide dismutase is essential for its tolerance to vancomycin and penicillin. J Antimicrob Chemother 64:1196–1202 [CrossRef][PubMed]
    [Google Scholar]
  3. Blasi E., Barluzzi R., Bocchini V., Mazzolla R., Bistoni F. ( 1990). Immortalization of murine microglial cells by a v-raf/v-myc carrying retrovirus. J Neuroimmunol 27:229–237 [CrossRef][PubMed]
    [Google Scholar]
  4. Brett P. J., Burtnick M. N., Su H., Nair V., Gherardini F. C. ( 2008). iNOS activity is critical for the clearance of Burkholderia mallei from infected RAW 264.7 murine macrophages. Cell Microbiol 10:487–498[PubMed]
    [Google Scholar]
  5. Bylund J., Brown K. L., Movitz C., Dahlgren C., Karlsson A. ( 2010). Intracellular generation of superoxide by the phagocyte NADPH oxidase: how, where, and what for?. Free Radic Biol Med 49:1834–1845 [CrossRef][PubMed]
    [Google Scholar]
  6. CLSI ( 2010). Performance standards for antimicrobial susceptibility testing. CLSI document M100–S20 Wayne, PA: Clinical and Laboratory Standards Institute;
    [Google Scholar]
  7. Desjardins M. ( 1995). Biogenesis of phagolysosomes: the ‘kiss and run’ hypothesis. Trends Cell Biol 5:183–186 [CrossRef][PubMed]
    [Google Scholar]
  8. Desjardins M., Houde M., Gagnon E. ( 2005). Phagocytosis: the convoluted way from nutrition to adaptive immunity. Immunol Rev 207:158–165 [CrossRef][PubMed]
    [Google Scholar]
  9. Eskelinen E. L., Tanaka Y., Saftig P. ( 2003). At the acidic edge: emerging functions for lysosomal membrane proteins. Trends Cell Biol 13:137–145 [CrossRef][PubMed]
    [Google Scholar]
  10. Fernández Guerrero M. L., Goyenechea A., Verdejo C., Roblas R. F., de Górgolas M. ( 2007). Enterococcal endocarditis on native and prosthetic valves: a review of clinical and prognostic factors with emphasis on hospital-acquired infections as a major determinant of outcome. Medicine (Baltimore) 86:363–377[PubMed] [CrossRef]
    [Google Scholar]
  11. Gilmore M. S., Coburn P. S., Nallapareddy S. R., Murray B. E. ( 2002). Enterococcus virulence. The Enterococci: Phathogenesis, Molecular Biology, Antibiotic Resistance and Infection Control301–354 Gilmore M. S. Washington, DC: American Society for Microbiology;
    [Google Scholar]
  12. Hauwel M., Furon E., Canova C., Griffiths M., Neal J., Gasque P. ( 2005). Innate (inherent) control of brain infection, brain inflammation and brain repair: the role of microglia, astrocytes, “protective” glial stem cells and stromal ependymal cells. Brain Res Rev 48:220–233 [CrossRef][PubMed]
    [Google Scholar]
  13. Huycke M. M., Sahm D. F., Gilmore M. S. ( 1998). Multiple-drug resistant enterococci: the nature of the problem and an agenda for the future. Emerg Infect Dis 4:239–249 [CrossRef][PubMed]
    [Google Scholar]
  14. Huynh K. K., Eskelinen E. L., Scott C. C., Malevanets A., Saftig P., Grinstein S. ( 2007). LAMP proteins are required for fusion of lysosomes with phagosomes. EMBO J 26:313–324 [CrossRef][PubMed]
    [Google Scholar]
  15. Imlay J. A. ( 2003). Pathways of oxidative damage. Annu Rev Microbiol 57:395–418 [CrossRef][PubMed]
    [Google Scholar]
  16. Kinchen J. M., Ravichandran K. S. ( 2008). Phagosome maturation: going through the acid test. Nat Rev Mol Cell Biol 9:781–795 [CrossRef][PubMed]
    [Google Scholar]
  17. Lehnardt S. ( 2010). Innate immunity and neuroinflammation in the CNS: the role of microglia in Toll-like receptor-mediated neuronal injury. Glia 58:253–263[PubMed]
    [Google Scholar]
  18. Murray B. E. ( 2000). Vancomycin-resistant enterococcal infections. N Engl J Med 342:710–721 [CrossRef][PubMed]
    [Google Scholar]
  19. Neglia R., Colombari B., Peppoloni S., Orsi C., Tavanti A., Senesi S., Blasi E. ( 2006). Adaptive response of microglial cells to in vitro infection by Candida albicans isolates with different genomic backgrounds. Microb Pathog 41:251–256 [CrossRef][PubMed]
    [Google Scholar]
  20. Orsi C. F., Colombari B., Ardizzoni A., Peppoloni S., Neglia R., Posteraro B., Morace G., Fadda G., Blasi E. ( 2009). The ABC transporter-encoding gene AFR1 affects the resistance of Cryptococcus neoformans to microglia-mediated antifungal activity by delaying phagosomal maturation. FEMS Yeast Res 9:301–310 [CrossRef][PubMed]
    [Google Scholar]
  21. Peppoloni S., Ricci S., Orsi C. F., Colombari B., De Santi M. M., Messinò M., Fabio G., Zanardi A., Righi E. et al. ( 2010). The encapsulated strain TIGR4 of Streptococcus pneumoniae is phagocytosed but is resistant to intracellular killing by mouse microglia. Microbes Infect 12:990–1001 [CrossRef][PubMed]
    [Google Scholar]
  22. Pintado V., Cabellos C., Moreno S., Meseguer M. A., Ayats J., Viladrich P. F. ( 2003). Enterococcal meningitis: a clinical study of 39 cases and review of the literature. Medicine (Baltimore) 82:346–364 [CrossRef][PubMed]
    [Google Scholar]
  23. Rock R. B., Gekker G., Hu S., Sheng W. S., Cheeran M., Lokensgard J. R., Peterson P. K. ( 2004). Role of microglia in central nervous system infections. Clin Microbiol Rev 17:942–964 [CrossRef][PubMed]
    [Google Scholar]
  24. Sarkar S., Bhagat I., DeCristofaro J. D., Wiswell T. E., Spitzer A. R. ( 2006). A study of the role of multiple site blood cultures in the evaluation of neonatal sepsis. J Perinatol 26:18–22 [CrossRef][PubMed]
    [Google Scholar]
  25. Suppli M., Aabenhus R., Harboe Z. B., Andersen L. P., Tvede M., Jensen J. U. ( 2010). Mortality in enterococcal bloodstream infections increases with inappropriate antimicrobial therapy. Clin Microbiol Infect. [CrossRef][PubMed]
    [Google Scholar]
  26. Verneuil N., Mazé A., Sanguinetti M., Laplace J. M., Benachour A., Auffray Y., Giard J. C., Hartke A. ( 2006). Implication of (Mn)superoxide dismutase of Enterococcus faecalis in oxidative stress responses and survival inside macrophages. Microbiology 152:2579–2589 [CrossRef][PubMed]
    [Google Scholar]
  27. Willems R. J., Bonten M. J. ( 2007). Glycopeptide-resistant enterococci: deciphering virulence, resistance and epidemicity. Curr Opin Infect Dis 20:384–390 [CrossRef][PubMed]
    [Google Scholar]
http://instance.metastore.ingenta.com/content/journal/micro/10.1099/mic.0.047381-0
Loading
/content/journal/micro/10.1099/mic.0.047381-0
Loading

Data & Media loading...

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