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Activation of HIF-1α and LL-37 by commensal bacteria inhibits Candida albicans colonization

Nature Medicine volume 21, pages 808–814 (2015)Cite this article

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Abstract

Candida albicans colonization is required for invasive disease1,2,3. Unlike humans, adult mice with mature intact gut microbiota are resistant to C. albicans gastrointestinal (GI) colonization2,4, but the factors that promote C. albicans colonization resistance are unknown. Here we demonstrate that commensal anaerobic bacteria—specifically clostridial Firmicutes (clusters IV and XIVa) and Bacteroidetes—are critical for maintaining C. albicans colonization resistance in mice. Using Bacteroides thetaiotamicron as a model organism, we find that hypoxia-inducible factor-1α (HIF-1α), a transcription factor important for activating innate immune effectors, and the antimicrobial peptide LL-37 (CRAMP in mice) are key determinants of C. albicans colonization resistance. Although antibiotic treatment enables C. albicans colonization, pharmacologic activation of colonic Hif1a induces CRAMP expression and results in a significant reduction of C. albicans GI colonization and a 50% decrease in mortality from invasive disease. In the setting of antibiotics, Hif1a and Camp (which encodes CRAMP) are required for B. thetaiotamicron–induced protection against C. albicans colonization of the gut. Thus, modulating C. albicans GI colonization by activation of gut mucosal immune effectors may represent a novel therapeutic approach for preventing invasive fungal disease in humans.

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Figure 1: Gastrointestinal colonization levels of Candida spp. in antibiotic-treated adult, germ-free adult mice and in infant to adolescent mice.
Figure 2: Clostridial Firmicutes and Bacteroidetes promote C. albicans GI colonization resistance.
Figure 3: B. theta induces Hif1a and Camp in mouse colons.
Figure 4: L-mimosine–dependent activation of HIf1a and Camp in vivo decreases C. albicans GI colonization and dissemination.

References

  1. Miranda, L.N. et al. Candida colonisation as a source for candidaemia. J. Hosp. Infect. 72, 9–16 (2009).

    Article  CAS  PubMed  Google Scholar 

  2. Nucci, M. & Anaissie, E. Revisiting the source of candidemia: skin or gut? Clin. Infect. Dis. 33, 1959–1967 (2001).

    Article  CAS  PubMed  Google Scholar 

  3. Pizzo, P.A. & Poplack, D. (eds.) Principles and Practice of Pediatric Oncology, 6th Edition 1531 (Lippincott Williams & Wilkins, Philadelphia, 2011).

  4. Koh, A.Y., Kohler, J.R., Coggshall, K.T., Van Rooijen, N. & Pier, G.B. Mucosal damage and neutropenia are required for Candida albicans dissemination. PLoS Pathog. 4, e35 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Iliev, I.D. et al. Interactions between commensal fungi and the C-type lectin receptor Dectin-1 influence colitis. Science 336, 1314–1317 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Samonis, G. et al. Prospective evaluation of effects of broad-spectrum antibiotics on gastrointestinal yeast colonization of humans. Antimicrob. Agents Chemother. 37, 51–53 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. van der Waaij, D. Colonization resistance of the digestive tract: clinical consequences and implications. J. Antimicrob. Chemother. 10, 263–270 (1982).

    Article  CAS  PubMed  Google Scholar 

  8. Lawley, T.D. & Walker, A.W. Intestinal colonization resistance. Immunology 138, 1–11 (2013).

    Article  CAS  PubMed  Google Scholar 

  9. Berg, R.D. Promotion of the translocation of enteric bacteria from the gastrointestinal tracts of mice by oral treatment with penicillin, clindamycin, or metronidazole. Infect. Immun. 33, 854–861 (1981).

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Wang, Y. et al. 16S rRNA gene-based analysis of fecal microbiota from preterm infants with and without necrotizing enterocolitis. ISME J. 3, 944–954 (2009).

    Article  CAS  PubMed  Google Scholar 

  11. Ley, R.E. et al. Obesity alters gut microbial ecology. Proc. Natl. Acad. Sci. USA 102, 11070–11075 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Ringel-Kulka, T. et al. Intestinal microbiota in healthy U.S. young children and adults–a high-throughput microarray analysis. PLoS ONE 8, e64315 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Garrod, L.P. The relative antibacterial activity of four penicillins. BMJ 2, 1695–1696 (1960).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Nizet, V. & Johnson, R.S. Interdependence of hypoxic and innate immune responses. Nat. Rev. Immunol. 9, 609–617 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Peyssonnaux, C. et al. HIF-1α expression regulates the bactericidal capacity of phagocytes. J. Clin. Invest. 115, 1806–1815 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. López-Garcia, B., Lee, P.H., Yamasaki, K. & Gallo, R.L. Anti-fungal activity of cathelicidins and their potential role in Candida albicans skin infection. J. Invest. Dermatol. 125, 108–115 (2005).

    Article  PubMed  Google Scholar 

  17. Tsai, P.W., Yang, C.Y., Chang, H.T. & Lan, C.Y. Human antimicrobial peptide LL-37 inhibits adhesion of Candida albicans by interacting with yeast cell-wall carbohydrates. PLoS ONE 6, e17755 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Atarashi, K. et al. Treg induction by a rationally selected mixture of Clostridia strains from the human microbiota. Nature 500, 232–236 (2013).

    Article  CAS  PubMed  Google Scholar 

  19. Smith, P.M. et al. The microbial metabolites, short-chain fatty acids, regulate colonic Treg cell homeostasis. Science 341, 569–573 (2013).

    Article  CAS  PubMed  Google Scholar 

  20. Cummings, J.H., Pomare, E.W., Branch, W.J., Naylor, C.P. & Macfarlane, G.T. Short chain fatty acids in human large intestine, portal, hepatic and venous blood. Gut 28, 1221–1227 (1987).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Zinkernagel, A.S., Peyssonnaux, C., Johnson, R.S. & Nizet, V. Pharmacologic augmentation of hypoxia-inducible factor-1α with mimosine boosts the bactericidal capacity of phagocytes. J. Infect. Dis. 197, 214–217 (2008).

    Article  CAS  PubMed  Google Scholar 

  22. Argimón, S., Fanning, S., Blankenship, J.R. & Mitchell, A.P. Interaction between the Candida albicans high-osmolarity glycerol (HOG) pathway and the response to human β-defensins 2 and 3. Eukaryot. Cell 10, 272–275 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Evans, D.F. et al. Measurement of gastrointestinal pH profiles in normal ambulant human subjects. Gut 29, 1035–1041 (1988).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. He, G. et al. Noninvasive measurement of anatomic structure and intraluminal oxygenation in the gastrointestinal tract of living mice with spatial and spectral EPR imaging. Proc. Natl. Acad. Sci. USA 96, 4586–4591 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Odds, F.C. Molecular phylogenetics and epidemiology of Candida albicans. Future Microbiol. 5, 67–79 (2010).

    Article  CAS  PubMed  Google Scholar 

  26. Bougnoux, M.E. et al. Multilocus sequence typing reveals intrafamilial transmission and microevolutions of Candida albicans isolates from the human digestive tract. J. Clin. Microbiol. 44, 1810–1820 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Angebault, C. et al. Candida albicans is not always the preferential yeast colonizing humans: a study in Wayampi Amerindians. J. Infect. Dis. 208, 1705–1716 (2013).

    Article  PubMed  Google Scholar 

  28. Xu, J. & Mitchell, T.G. Geographical differences in human oral yeast flora. Clin. Infect. Dis. 36, 221–224 (2003).

    Article  PubMed  Google Scholar 

  29. Guarner, F. & Malagelada, J.R. Gut flora in health and disease. Lancet 361, 512–519 (2003).

    Article  PubMed  Google Scholar 

  30. Beaugerie, L. & Petit, J.C. Microbial-gut interactions in health and disease. Antibiotic-associated diarrhoea. Best Pract. Res. Clin. Gastroenterol. 18, 337–352 (2004).

    Article  CAS  PubMed  Google Scholar 

  31. Vedantam, G. & Hecht, D.W. Antibiotics and anaerobes of gut origin. Curr. Opin. Microbiol. 6, 457–461 (2003).

    Article  CAS  PubMed  Google Scholar 

  32. Cash, H.L., Whitham, C.V., Behrendt, C.L. & Hooper, L.V. Symbiotic bacteria direct expression of an intestinal bactericidal lectin. Science 313, 1126–1130 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Hooper, L.V., Stappenbeck, T.S., Hong, C.V. & Gordon, J.I. Angiogenins: a new class of microbicidal proteins involved in innate immunity. Nat. Immunol. 4, 269–273 (2003).

    Article  CAS  PubMed  Google Scholar 

  34. Mazmanian, S.K., Liu, C.H., Tzianabos, A.O. & Kasper, D.L. An immunomodulatory molecule of symbiotic bacteria directs maturation of the host immune system. Cell 122, 107–118 (2005).

    Article  CAS  PubMed  Google Scholar 

  35. Zwolińska-Wcisło, M. et al. Are probiotics effective in the treatment of fungal colonization of the gastrointestinal tract? Experimental and clinical studies. J. Physiol. Pharmacol. 57 (suppl. 9), 35–49 (2006).

    PubMed  Google Scholar 

  36. Kühbacher, T. et al. Bacterial and fungal microbiota in relation to probiotic therapy (VSL#3) in pouchitis. Gut 55, 833–841 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Manzoni, P. et al. Oral supplementation with Lactobacillus casei subspecies rhamnosus prevents enteric colonization by Candida species in preterm neonates: a randomized study. Clin. Infect. Dis. 42, 1735–1742 (2006).

    Article  CAS  PubMed  Google Scholar 

  38. Hatakka, K. et al. Probiotics reduce the prevalence of oral Candida in the elderly–a randomized controlled trial. J. Dent. Res. 86, 125–130 (2007).

    Article  CAS  PubMed  Google Scholar 

  39. Semenza, G.L. Development of novel therapeutic strategies that target HIF-1. Expert Opin. Ther. Targets 10, 267–280 (2006).

    Article  CAS  PubMed  Google Scholar 

  40. Zarember, K.A. & Malech, H.L. HIF-1α: a master regulator of innate host defenses? J. Clin. Invest. 115, 1702–1704 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Goodman, A.L. et al. Extensive personal human gut microbiota culture collections characterized and manipulated in gnotobiotic mice. Proc. Natl. Acad. Sci. USA 108, 6252–6257 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  42. Goodman, A.L. et al. Identifying genetic determinants needed to establish a human gut symbiont in its habitat. Cell Host Microbe 6, 279–289 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Ghannoum, M.A. et al. Characterization of the oral fungal microbiome (mycobiome) in healthy individuals. PLoS Pathog. 6, e1000713 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Barman, M. et al. Enteric salmonellosis disrupts the microbial ecology of the murine gastrointestinal tract. Infect. Immun. 76, 907–915 (2008).

    Article  CAS  PubMed  Google Scholar 

  45. Claesson, M.J. et al. Comparison of two next-generation sequencing technologies for resolving highly complex microbiota composition using tandem variable 16S rRNA gene regions. Nucleic Acids Res. 38, e200 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Caporaso, J.G. et al. QIIME allows analysis of high-throughput community sequencing data. Nat. Methods 7, 335–336 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We would like to thank K. Nickerson (University of Nebraska, Lincoln, Nebraska), J. Patton-Vogt (Duquesne University, Pittsburgh, Pennsylvania), R. Wheeler (University of Maine, Orono, Maine) and M. Lorenz (University of Texas Health Science Center, Houston, Texas) for providing the C. albicans strains SN152 (from K. Nickerson), BWP17 (from J.Patton-Vogt), Can098 (from R. Wheeler), WO-1 (from M. Lorenz), 3153A (from M. Lorenz); C. Doern (Children's Medical Center Dallas, Dallas, Texas) for the C. glabrata, C. parapsilosis and C. tropicalis strains; and Y. Iwakura (Institute of Medical Science, Tokyo University, Tokyo, Japan) and J. Kolls (Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania) for the IL-17A–knockout mice. We would like to thank S. Skapek, J. Amatruda, R. DeBerardinis and D. Greenberg for providing helpful comments on the manuscript. This study was supported by the Roberta I. and Norman L. Pollock Fund (A.Y.K.), the Global Probiotics Council Young Investigator Grant for Probiotics (A.Y.K.), US National Institutes of Health (NIH) grant R01 DK060855 (L.V.H.), the Howard Hughes Medical Institute (L.V.H.) and NIH grant P30CA142543 (Y.X.).

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Authors and Affiliations

  1. Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas

    Di Fan, Laura A Coughlin, Megan M Neubauer, Tiffany R Simms-Waldrip & Andrew Y Koh

  2. Department of Clinical Science, University of Texas Southwestern Medical Center, Dallas, Texas

    Jiwoong Kim, Min Soo Kim, Xiaowei Zhan & Yang Xie

  3. Center for Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, Texas

    Xiaowei Zhan & Lora V Hooper

  4. Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas

    Yang Xie & Andrew Y Koh

  5. Department of Immunology, University of Texas Southwestern Medical Center, Dallas, Texas

    Lora V Hooper

  6. The Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, Texas

    Lora V Hooper

  7. Department of Microbiology, University of Texas Southwestern Medical Center, Dallas, Texas

    Lora V Hooper & Andrew Y Koh

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  1. Di Fan
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Contributions

A.Y.K. and L.V.H. conceived and designed the experiments. L.V.H. provided gnotobiotic mice and mucosal immunology instruction and support. A.Y.K., D.F., L.A.C., T.R.S.-W. and M.M.N. performed the experiments. A.Y.K., J.K., M.K., X.Z. and Y.X. conducted microbial profiling and statistical analysis. A.Y.K. and L.V.H. analyzed the data. A.Y.K. wrote the paper.

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Correspondence to Andrew Y Koh.

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Fan, D., Coughlin, L., Neubauer, M. et al. Activation of HIF-1α and LL-37 by commensal bacteria inhibits Candida albicans colonization. Nat Med 21, 808–814 (2015). https://doi.org/10.1038/nm.3871

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