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. 2014 Mar 1;52(3):188–199. doi: 10.1007/s12275-014-4067-3

Mechanisms of synergy in polymicrobial infections

Justine L Murray 1, Jodi L Connell 1, Apollo Stacy 1, Keith H Turner 1,, Marvin Whiteley 1,
PMCID: PMC7090983  PMID: 24585050

Abstract

Communities of microbes can live almost anywhere and contain many different species. Interactions between members of these communities often determine the state of the habitat in which they live. When these habitats include sites on the human body, these interactions can affect health and disease. Polymicrobial synergy can occur during infection, in which the combined effect of two or more microbes on disease is worse than seen with any of the individuals alone. Powerful genomic methods are increasingly used to study microbial communities, including metagenomics to reveal the members and genetic content of a community and metatranscriptomics to describe the activities of community members. Recent efforts focused toward a mechanistic understanding of these interactions have led to a better appreciation of the precise bases of polymicrobial synergy in communities containing bacteria, eukaryotic microbes, and/or viruses. These studies have benefited from advances in the development of in vivo models of polymicrobial infection and modern techniques to profile the spatial and chemical bases of intermicrobial communication. This review describes the breadth of mechanisms microbes use to interact in ways that impact pathogenesis and techniques to study polymicrobial communities.

Keywords: polymicrobial, synergy, infection, metatranscriptomics, quorum sensing, imaging mass spectrometry, 3D printing

Contributor Information

Keith H. Turner, Email: khturner@utexas.edu

Marvin Whiteley, Phone: +1-512-471-5493, Email: mwhiteley@austin.utexas.edu.

References

  1. Aguzzi A, Baumann F, Bremer J. The prion’s elusive reason for being. Annu. Rev. Neurosci. 2008;31:439–477. doi: 10.1146/annurev.neuro.31.060407.125620. [DOI] [PubMed] [Google Scholar]
  2. Armbruster, C.E., Hong, W., Pang, B., Weimer, K.E., Juneau, R.A., Turner, J., and Swords, W.E. 2010. Indirect pathogenicity of Haemophilus influenzae and Moraxella catarrhalis in polymicrobial otitis media occurs via interspecies quorum signaling. mBio1. [DOI] [PMC free article] [PubMed]
  3. Asakawa R, Komatsuzawa H, Kawai T, Yamada S, Goncalves RB, Izumi S, Fujiwara T, Nakano Y, Suzuki N, Uchida Y. Outer membrane protein 100, a versatile virulence factor of Actinobacillus actinomycetemcomitans. Mol. Microbiol. 2003;50:1125–1139. doi: 10.1046/j.1365-2958.2003.03748.x. [DOI] [PubMed] [Google Scholar]
  4. Bakaletz LO. Developing animal models for polymicrobial diseases. Nat. Rev. Microbiol. 2004;2:552–568. doi: 10.1038/nrmicro928. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Bakaletz, L.O. 2009. Chinchilla as a robust, reproducible and polymicrobial model of otitis media and its prevention. Expert Rev. Vaccines8. [DOI] [PubMed]
  6. Bjornson HS. Bacterial synergy, virulence factors, and host defense mechanisms in the pathogenesis of intraabdominal infections. In: Simmons RL, editor. Topics in intraabdominal surgical infection. Norwalk, CT, USA: Appleton-Century-Crofts; 1982. pp. 65–78. [Google Scholar]
  7. Brogden KA, Guthmiller JM. Polymicrobial diseases. Washington, USA: ASM Press; 2002. [PubMed] [Google Scholar]
  8. Brook I, Hunter V, Walker RI. Synergistic effect of Bacteroides, Clostridium, Fusobacterium, anaerobic cocci, and aerobic bacteria on mortality and induction of subcutaneous abscesses in mice. J. Infect. Dis. 1984;149:924–928. doi: 10.1093/infdis/149.6.924. [DOI] [PubMed] [Google Scholar]
  9. Brown SA, Whiteley M. A novel exclusion mechanism for carbon resource partitioning in Aggregatibacter actinomycetemcomitans. J. Bacteriol. 2007;189:6407–6414. doi: 10.1128/JB.00554-07. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Chen PB, Davern LB, Katz J, Eldridge JH, Michalek SM. Host responses induced by co-infection with Porphyromonas gingivalis and Actinobacillus actinomycetemcomitans in a murine model. Oral Microbiol. Immunol. 1996;11:274–281. doi: 10.1111/j.1399-302x.1996.tb00181.x. [DOI] [PubMed] [Google Scholar]
  11. Chen T, Duncan MJ. Gingipain adhesin domains mediate Porphyromonas gingivalis adherence to epithelial cells. Microb. Pathog. 2004;36:205–209. doi: 10.1016/j.micpath.2003.12.001. [DOI] [PubMed] [Google Scholar]
  12. Connell JL, Ritschdorff ET, Whiteley M, Shear JB. 3D printing of microscopic bacterial communities. Proc. Natl. Acad. Sci. USA. 2013;110:18380–18385. doi: 10.1073/pnas.1309729110. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Connell JL, Whiteley M, Shear JB. Sociomicrobiology in engineered landscapes. Nat. Chem. Biol. 2012;8:10–13. doi: 10.1038/nchembio.749. [DOI] [PubMed] [Google Scholar]
  14. Cook LC, LaSarre B, Federle MJ. Interspecies communication among commensal and pathogenic streptococci. mBio. 2013;4:e00382–13. doi: 10.1128/mBio.00382-13. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Costerton JW, Montanaro L, Arciola CR. Biofilm in implant infections: its production and regulation. Int. J. Artif. Organs. 2005;28:1062–1068. doi: 10.1177/039139880502801103. [DOI] [PubMed] [Google Scholar]
  16. Craven DE, Steger KA. Epidemiology of nosocomial pneumonia. New perspectives on an old disease. Chest. 1995;108:1S–16S. doi: 10.1378/chest.108.2_supplement.1s. [DOI] [PubMed] [Google Scholar]
  17. Dalton T, Dowd SE, Wolcott RD, Sun Y, Watters C, Griswold JA, Rumbaugh KP. An in vivo polymicrobial biofilm wound infection model to study interspecies interactions. PLoS One. 2011;6:e27317. doi: 10.1371/journal.pone.0027317. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Darouiche RO. Device-associated infections: a macroproblem that starts with microadherence. Clin. Infect. Dis. 2001;33:1567–1572. doi: 10.1086/323130. [DOI] [PubMed] [Google Scholar]
  19. Domann E, Hong G, Imirzalioglu C, Turschner S, Kuhle J, Watzel C, Hain T, Hossain H, Chakraborty T. Culture-independent identification of pathogenic bacteria and polymicrobial infections in the genitourinary tract of renal transplant recipients. J. Clin. Microbiol. 2003;41:5500–5510. doi: 10.1128/JCM.41.12.5500-5510.2003. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Doughty DM, Dieterle M, Sessions AL, Fischer WW, Newman DK. Probing the subcellular localization of hopanoid lipids in bacteria using nanoSIMS. PLoS One. 2014;9:e84455. doi: 10.1371/journal.pone.0084455. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Duan K, Dammel C, Stein J, Rabin H, Surette MG. Modulation of Pseudomonas aeruginosa gene expression by host microflora through interspecies communication. Mol. Microbiol. 2003;50:1477–1491. doi: 10.1046/j.1365-2958.2003.03803.x. [DOI] [PubMed] [Google Scholar]
  22. Dymock D, Weightman AJ, Scully C, Wade WG. Molecular analysis of microflora associated with dentoalveolar abscesses. J. Clin. Microbiol. 1996;34:537–542. doi: 10.1128/jcm.34.3.537-542.1996. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Eberth CJ. Neue Untersuchungen über den bacillus des Abdominaltyphus. Virchows Arch. Pathol. Anat. Physiol. Klin. Med. 1881;83:486–501. [Google Scholar]
  24. Fouchier RA, Kuiken T, Schutten M, van Amerongen G, van Doornum GJ, van den Hoogen BG, Peiris M, Lim W, Stohr K, Osterhaus AD. Aetiology: Koch’s postulates fulfilled for SARS virus. Nature. 2003;423:240. doi: 10.1038/423240a. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Frias-Lopez J, Shi Y, Tyson GW, Coleman ML, Schuster SC, Chisholm SW, Delong EF. Microbial community gene expression in ocean surface waters. Proc. Natl. Acad. Sci. USA. 2008;105:3805–3810. doi: 10.1073/pnas.0708897105. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Gaffky G. Zur Ätiologie des Abdominal-Typhus. Mitteillungen aus dem Kaiserlichen Gesundheitsamt. 1884;2:372–420. [Google Scholar]
  27. Gans J, Wolinsky M, Dunbar J. Computational improvements reveal great bacterial diversity and high metal toxicity in soil. Science. 2005;309:1387–1390. doi: 10.1126/science.1112665. [DOI] [PubMed] [Google Scholar]
  28. Giebink GS, Berzins IK, Marker SC, Schiffman G. Experimental otitis media after nasal inoculation of Streptococcus pneumoniae and influenza A virus in chinchillas. Infect. Immun. 1980;30:445–450. doi: 10.1128/iai.30.2.445-450.1980. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Giebink GS, Payne EE, Mills EL, Juhn SK, Quie PG. Experimental otitis media due to Streptococcus pneumoniae: immunopathogenic response in the chinchilla. J. Infect. Dis. 1976;134:595–604. doi: 10.1093/infdis/134.6.595. [DOI] [PubMed] [Google Scholar]
  30. Gonzalez DJ, Haste NM, Hollands A, Fleming TC, Hamby M, Pogliano K, Nizet V, Dorrestein PC. Microbial competition between Bacillus subtilis and Staphylococcus aureus monitored by imaging mass spectrometry. Microbiology. 2011;157:2485–2492. doi: 10.1099/mic.0.048736-0. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Gordon HA, Pesti L. The gnotobiotic animal as a tool in the study of host microbial relationships. Bacteriol. Rev. 1971;35:390–429. doi: 10.1128/br.35.4.390-429.1971. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Grenier D. Demonstration of a bimodal coaggregation reaction between Porphyromonas gingivalis and Treponema denticola. Oral Microbiol. Immunol. 1992;7:280–284. doi: 10.1111/j.1399-302x.1992.tb00589.x. [DOI] [PubMed] [Google Scholar]
  33. Harriott MM, Noverr MC. Candida albicans and Staphylococcus aureus form polymicrobial biofilms: effects on antimicrobial resistance. Antimicrob. Agents Chemother. 2009;53:3914–3922. doi: 10.1128/AAC.00657-09. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Holley JL, Bernardini J, Piraino B. Polymicrobial peritonitis in patients on continuous peritoneal dialysis. Am. J. Kidney Dis. 1992;19:162–166. doi: 10.1016/s0272-6386(12)70126-9. [DOI] [PubMed] [Google Scholar]
  35. Hsu CC, White NM, Hayashi M, Lin EC, Poon T, Banerjee I, Chen J, Pfaff SL, Macagno ER, Dorrestein PC. Microscopy ambient ionization top-down mass spectrometry reveals developmental patterning. Proc. Natl. Acad. Sci. USA. 2013;110:14855–14860. doi: 10.1073/pnas.1310618110. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Imirzalioglu C, Hain T, Chakraborty T, Domann E. Hidden pathogens uncovered: metagenomic analysis of urinary tract infections. Andrologia. 2008;40:66–71. doi: 10.1111/j.1439-0272.2007.00830.x. [DOI] [PubMed] [Google Scholar]
  37. Jacobsen F, Fisahn C, Sorkin M, Thiele I, Hirsch T, Stricker I, Klaassen T, Roemer A, Fugmann B, Steinstraesser L. Efficacy of topically delivered moxifloxacin against wound infection by Pseudomonas aeruginosa and methicillin-resistant Staphylococcus aureus. Antimicrob. Agents Chemother. 2011;55:2325–2334. doi: 10.1128/AAC.01071-10. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Jander G, Rahme LG, Ausubel FM. Positive correlation between virulence of Pseudomonas aeruginosa mutants in mice and insects. J. Bacteriol. 2000;182:3843–3845. doi: 10.1128/jb.182.13.3843-3845.2000. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Jurcisek JA, Durbin JE, Kusewitt DF, Bakaletz LO. Anatomy of the nasal cavity in the chinchilla. Cells Tissues Organs. 2003;174:136–152. doi: 10.1159/000071154. [DOI] [PubMed] [Google Scholar]
  40. Kämmerer H. Beiträge zur Bedeutung des Bakteriellen Synergismus für die Biologie. Klinische Wochenschrift. 1924;3:723–727. [Google Scholar]
  41. Kaplan AH, Weber DJ, Oddone EZ, Perfect JR. Infection due to Actinobacillus actinomycetemcomitans: 15 cases and review. Rev. Infect. Dis. 1989;11:46–63. doi: 10.1093/clinids/11.1.46. [DOI] [PubMed] [Google Scholar]
  42. Kaplan CW, Lux R, Haake SK, Shi W. The Fusobacterium nucleatum outer membrane protein RadD is an arginine-inhibitable adhesin required for inter-species adherence and the structured architecture of multispecies biofilm. Mol. Microbiol. 2009;71:35–47. doi: 10.1111/j.1365-2958.2008.06503.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Kesavalu L, Holt SC, Ebersole JL. Virulence of a polymicrobic complex, Treponema denticola and Porphyromonas gingivalis, in a murine model. Oral Microbiol. Immunol. 1998;13:373–377. doi: 10.1111/j.1399-302x.1998.tb00694.x. [DOI] [PubMed] [Google Scholar]
  44. Kesavalu L, Sathishkumar S, Bakthavatchalu V, Matthews C, Dawson D, Steffen M, Ebersole JL. Rat model of polymicrobial infection, immunity, and alveolar bone resorption in periodontal disease. Infect. Immun. 2007;75:1704–1712. doi: 10.1128/IAI.00733-06. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Kim HJ, Boedicker JQ, Choi JW, Ismagilov RF. Defined spatial structure stabilizes a synthetic multispecies bacterial community. Proc. Natl. Acad. Sci. USA. 2008;105:18188–18193. doi: 10.1073/pnas.0807935105. [DOI] [PMC free article] [PubMed] [Google Scholar]
  46. Kim HJ, Du WB, Ismagilov RF. Complex function by design using spatially pre-structured synthetic microbial communities: degradation of pentachlorophenol in the presence of Hg(II) Integr Biol-Uk. 2011;3:126–133. doi: 10.1039/c0ib00019a. [DOI] [PMC free article] [PubMed] [Google Scholar]
  47. Kline KA, Schwartz DJ, Gilbert NM, Hultgren SJ, Lewis AL. Immune modulation by group B Streptococcus influences host susceptibility to urinary tract infection by uropathogenic Escherichia coli. Infect. Immun. 2012;80:4186–4194. doi: 10.1128/IAI.00684-12. [DOI] [PMC free article] [PubMed] [Google Scholar]
  48. Koch R. Untersuchungen über Bakterien: V. Die Ätiologie der Milzbrand-Krankheit, begründet auf die Entwicklungsgeschichte des Bacillus anthracis. Cohns Beitrage zur Biologie der Pflanzen. 1876;2:277–310. [Google Scholar]
  49. Koch R. Untersuchungen über die Ätiologie der Wundinfektionskrankheiten. Leipzig, Germany: Vogel; 1878. [Google Scholar]
  50. Koch R. Die Ätiologie der Tuberkulose. Berliner. Klinische. Wochenschrift. 1882;19:221–230. [Google Scholar]
  51. Koch R. Über den augenblicklichen Stand der bakteriologischen Choleradiagnose. Zeitschrift für Hygiene und Infectionskrankheiten. 1893;14:319–333. [Google Scholar]
  52. Kolenbrander PE, London J. Adhere today, here tomorrow: oral bacterial adherence. J. Bacteriol. 1993;175:3247–3252. doi: 10.1128/jb.175.11.3247-3252.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  53. Kolenbrander PE, Palmer RJ, Jr., Periasamy S, Jakubovics NS. Oral multispecies biofilm development and the key role of cell-cell distance. Nat. Rev. Microbiol. 2010;8:471–480. doi: 10.1038/nrmicro2381. [DOI] [PubMed] [Google Scholar]
  54. Korgaonkar A, Trivedi U, Rumbaugh KP, Whiteley M. Community surveillance enhances Pseudomonas aeruginosa virulence during polymicrobial infection. Proc. Natl. Acad. Sci. USA. 2013;110:1059–1064. doi: 10.1073/pnas.1214550110. [DOI] [PMC free article] [PubMed] [Google Scholar]
  55. Kozarov EV, Dorn BR, Shelburne CE, Dunn WA, Jr., Progulske-Fox A. Human atherosclerotic plaque contains viable invasive Actinobacillus actinomycetemcomitans and Porphyromonas gingivalis. Arterioscler. Thromb. Vasc. Biol. 2005;25:e17–18. doi: 10.1161/01.ATV.0000155018.67835.1a. [DOI] [PubMed] [Google Scholar]
  56. Laufer AS, Metlay JP, Gent JF, Fennie KP, Kong Y, Pettigrew MM. Microbial communities of the upper respiratory tract and otitis media in children. mBio. 2011;2:e00245–00210. doi: 10.1128/mBio.00245-10. [DOI] [PMC free article] [PubMed] [Google Scholar]
  57. Laveran A. Note sur un nouveau parasite trouvè dans le sang de plusieurs malades atteints de fièvre palustre. Bull. Acad. Natl. Med. 1880;9:1235–1236. [Google Scholar]
  58. Lavigne JP, Nicolas-Chanoine MH, Bourg G, Moreau J, Sotto A. Virulent synergistic effect between Enterococcus faecalis and Escherichia coli assayed by using the Caenorhabditis elegans model. PLoS One. 2008;3:e3370. doi: 10.1371/journal.pone.0003370. [DOI] [PMC free article] [PubMed] [Google Scholar]
  59. Lim YW, Schmieder R, Haynes M, Willner D, Furlan M, Youle M, Abbott K, Edwards R, Evangelista J, Conrad D, Rohwer F. Metagenomics and metatranscriptomics: Windows on CF-associated viral and microbial communities. J. Cyst. Fibros. 2012;12:154–164. doi: 10.1016/j.jcf.2012.07.009. [DOI] [PMC free article] [PubMed] [Google Scholar]
  60. Ling Z, Kong J, Liu F, Zhu H, Chen X, Wang Y, Li L, Nelson KE, Xia Y, Xiang C. Molecular analysis of the diversity of vaginal microbiota associated with bacterial vaginosis. BMC Genomics. 2010;11:488. doi: 10.1186/1471-2164-11-488. [DOI] [PMC free article] [PubMed] [Google Scholar]
  61. Liu X, Ramsey MM, Chen X, Koley D, Whiteley M, Bard AJ. Real-time mapping of a hydrogen peroxide concentration profile across a polymicrobial bacterial biofilm using scanning electrochemical microscopy. Proc. Natl. Acad. Sci. USA. 2011;108:2668–2673. doi: 10.1073/pnas.1018391108. [DOI] [PMC free article] [PubMed] [Google Scholar]
  62. Lynch AS, Robertson GT. Bacterial and fungal biofilm infections. Annu. Rev. Med. 2008;59:415–428. doi: 10.1146/annurev.med.59.110106.132000. [DOI] [PubMed] [Google Scholar]
  63. Macklaim JM, Fernandes AD, Di Bella JM, Hammond J, Reid G, Gloor GB. Comparative meta-RNA-seq of the vaginal microbiota and differential expression by Lactobacillus iners in health and dysbiosis. Microbiome. 2013;1:1–11. doi: 10.1186/2049-2618-1-12. [DOI] [PMC free article] [PubMed] [Google Scholar]
  64. Mahajan-Miklos S, Tan MW, Rahme LG, Ausubel FM. Molecular mechanisms of bacterial virulence elucidated using a Pseudomonas aeruginosa Caenorhabditis elegans pathogenesis model. Cell. 1999;96:47–56. doi: 10.1016/s0092-8674(00)80958-7. [DOI] [PubMed] [Google Scholar]
  65. Marra AR, Bearman GM, Wenzel RP, Edmond MB. Comparison of the systemic inflammatory response syndrome between monomicrobial and polymicrobial Pseudomonas aeruginosa nosocomial bloodstream infections. BMC Infect. Dis. 2005;5:94. doi: 10.1186/1471-2334-5-94. [DOI] [PMC free article] [PubMed] [Google Scholar]
  66. Mashburn LM, Jett AM, Akins DR, Whiteley M. Staphylococcus aureus serves as an iron source for Pseudomonas aeruginosa during in vivo coculture. J. Bacteriol. 2005;187:554–566. doi: 10.1128/JB.187.2.554-566.2005. [DOI] [PMC free article] [PubMed] [Google Scholar]
  67. Mastropaolo MD, Evans NP, Byrnes MK, Stevens AM, Robertson JL, Melville SB. Synergy in polymicrobial infections in a mouse model of type 2 diabetes. Infect. Immun. 2005;73:6055–6063. doi: 10.1128/IAI.73.9.6055-6063.2005. [DOI] [PMC free article] [PubMed] [Google Scholar]
  68. Mestas J, Hughes CC. Of mice and not men: differences between mouse and human immunology. J. Immunol. 2004;172:2731–2738. doi: 10.4049/jimmunol.172.5.2731. [DOI] [PubMed] [Google Scholar]
  69. Miller WD. Micro-organisms of the human mouth. Philadelphia, USA: White Dental MFG. Co; 1890. p. 25. [PMC free article] [PubMed] [Google Scholar]
  70. Moree WJ, Phelan VV, Wu CH, Bandeira N, Cornett DS, Duggan BM, Dorrestein PC. Interkingdom metabolic transformations captured by microbial imaging mass spectrometry. Proc. Natl. Acad. Sci. USA. 2012;109:13811–13816. doi: 10.1073/pnas.1206855109. [DOI] [PMC free article] [PubMed] [Google Scholar]
  71. Mylonakis E, Casadevall A, Ausubel FM. Exploiting amoeboid and non-vertebrate animal model systems to study the virulence of human pathogenic fungi. PLoS Pathog. 2007;3:e101. doi: 10.1371/journal.ppat.0030101. [DOI] [PMC free article] [PubMed] [Google Scholar]
  72. Nagashima H, Takao A, Maeda N. Abscess forming ability of Streptococcus milleri group: synergistic effect with Fusobacterium nucleatum. Microb. Immunol. 1999;43:207–216. doi: 10.1111/j.1348-0421.1999.tb02395.x. [DOI] [PubMed] [Google Scholar]
  73. Nelson A, De Soyza A, Perry JD, Sutcliffe IC, Cummings SP. Polymicrobial challenges to Koch’s postulates: ecological lessons from the bacterial vaginosis and cystic fibrosis microbiomes. Innate Immun. 2012;18:774–783. doi: 10.1177/1753425912439910. [DOI] [PubMed] [Google Scholar]
  74. Nguyen DD, Wu CH, Moree WJ, Lamsa A, Medema MH, Zhao XL, Gavilan RG, Aparicio M, Atencio L, Jackson C. MS/MS networking guided analysis of molecule and gene cluster families. Proc. Natl. Acad. Sci. USA. 2013;110:E2611–E2620. doi: 10.1073/pnas.1303471110. [DOI] [PMC free article] [PubMed] [Google Scholar]
  75. Orth RK, O’Brien-Simpson NM, Dashper SG, Reynolds EC. Synergistic virulence of Porphyromonas gingivalis and Treponema denticola in a murine periodontitis model. Mol. Oral Microbiol. 2011;26:229–240. doi: 10.1111/j.2041-1014.2011.00612.x. [DOI] [PubMed] [Google Scholar]
  76. Ovchinnikova OS, Kjoller K, Hurst GB, Pelletier DA, Van Berkel GJ. Atomic force microscope controlled topographical imaging and proximal probe thermal desorption/ionization mass spectrometry imaging. Anal. Chem. 2014;86:1083–1090. doi: 10.1021/ac4026576. [DOI] [PubMed] [Google Scholar]
  77. Pace NR, Stahl DA, Lane DJ, Olsen GJ. The analysis of natural microbial populations by rRNA sequences. Adv. Microb. Ecol. 1986;9:1–55. [Google Scholar]
  78. Partida-Martinez LP, Hertweck C. Pathogenic fungus harbours endosymbiotic bacteria for toxin production. Nature. 2005;437:884–888. doi: 10.1038/nature03997. [DOI] [PubMed] [Google Scholar]
  79. Paster BJ, Boches SK, Galvin JL, Ericson RE, Lau CN, Levanos VA, Sahasrabudhe A, Dewhirst FE. Bacterial diversity in human subgingival plaque. J. Bacteriol. 2001;183:3770–3783. doi: 10.1128/JB.183.12.3770-3783.2001. [DOI] [PMC free article] [PubMed] [Google Scholar]
  80. Paster BJ, Olsen I, Aas JA, Dewhirst FE. The breadth of bacterial diversity in the human periodontal pocket and other oral sites. Periodontology. 2006;2000:80–87. doi: 10.1111/j.1600-0757.2006.00174.x. [DOI] [PubMed] [Google Scholar]
  81. Pasteur L, Joubert J. Charbon et septicemie. Compt. Rend. Acad. 1877;85:101–105. [Google Scholar]
  82. Peleg AY, Tampakakis E, Fuchs BB, Eliopoulos GM, Moellering RC, Jr., Mylonakis E. Prokaryote-eukaryote interactions identified by using Caenorhabditis elegans. Proc. Natl. Acad. Sci. USA. 2008;105:14585–14590. doi: 10.1073/pnas.0805048105. [DOI] [PMC free article] [PubMed] [Google Scholar]
  83. Percival SL, Thomas JG, Williams DW. Biofilms and bacterial imbalances in chronic wounds: anti-Koch. Int. Wound J. 2010;7:169–175. doi: 10.1111/j.1742-481X.2010.00668.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  84. Peters BM, Jabra-Rizk MA, O’May GA, Costerton JW, Shirtliff ME. Polymicrobial interactions: impact on pathogenesis and human disease. Clin. Microbiol. Rev. 2012;25:193–213. doi: 10.1128/CMR.00013-11. [DOI] [PMC free article] [PubMed] [Google Scholar]
  85. Peters BM, Ovchinnikova ES, Krom BP, Schlecht LM, Zhou H, Hoyer LL, Busscher HJ, van der Mei HC, Jabra-Rizk MA, Shirtliff ME. Staphylococcus aureus adherence to Candida albicans hyphae is mediated by the hyphal adhesin Als3p. Microbiology. 2012;158:2975–2986. doi: 10.1099/mic.0.062109-0. [DOI] [PMC free article] [PubMed] [Google Scholar]
  86. Phelan VV, Liu WT, Pogliano K, Dorrestein PC. Microbial metabolic exchange-the chemotype-to-phenotype link. Nat. Chem. Biol. 2012;8:26–35. doi: 10.1038/nchembio.739. [DOI] [PMC free article] [PubMed] [Google Scholar]
  87. Price LB, Liu CM, Melendez JH, Frankel YM, Engelthaler D, Aziz M, Bowers J, Rattray R, Ravel J, Kingsley C, Keim PS, Lazarus GS, Zenilman JM. Community analysis of chronic wound bacteria using 16S rRNA gene-based pyrosequencing: impact of diabetes and antibiotics on chronic wound microbiota. PLoS One. 2009;4:e6462. doi: 10.1371/journal.pone.0006462. [DOI] [PMC free article] [PubMed] [Google Scholar]
  88. Qin J, Li R, Raes J, Arumugam M, Burgdorf KS, Manichanh C, Nielsen T, Pons N, Levenez F, Yamada T. A human gut microbial gene catalogue established by metagenomic sequencing. Nature. 2010;464:59–65. doi: 10.1038/nature08821. [DOI] [PMC free article] [PubMed] [Google Scholar]
  89. Ramos C, Licht TR, Sternberg C, Krogfelt KA, Molin S. Monitoring bacterial growth activity in biofilms from laboratory flow chambers, plant rhizosphere, and animal intestine. Methods Enzymol. 2001;337:21–42. doi: 10.1016/s0076-6879(01)37004-0. [DOI] [PubMed] [Google Scholar]
  90. Ramsey MM, Rumbaugh KP, Whiteley M. Metabolite cross-feeding enhances virulence in a model polymicrobial infection. PLoS Pathog. 2011;7:e1002012. doi: 10.1371/journal.ppat.1002012. [DOI] [PMC free article] [PubMed] [Google Scholar]
  91. Ramsey MM, Whiteley M. Polymicrobial interactions stimulate resistance to host innate immunity through metabolite perception. Proc. Natl. Acad. Sci. USA. 2009;106:1578–1583. doi: 10.1073/pnas.0809533106. [DOI] [PMC free article] [PubMed] [Google Scholar]
  92. Rath CM, Alexandrov T, Higginbottom SK, Song J, Milla ME, Fischbach MA, Sonnenburg JL, Dorrestein PC. Molecular analysis of model gut microbiotas by imaging mass spectrometry and nanodesorption electrospray ionization reveals dietary metabolite transformations. Anal. Chem. 2012;84:9259–9267. doi: 10.1021/ac302039u. [DOI] [PMC free article] [PubMed] [Google Scholar]
  93. Rath CM, Yang JY, Alexandrov T, Dorrestein PC. Data-independent microbial metabolomics with ambient ionization mass spectrometry. J. Am. Soc. Mass Spectrom. 2013;24:1167–1176. doi: 10.1007/s13361-013-0608-y. [DOI] [PMC free article] [PubMed] [Google Scholar]
  94. Ravel J, Gajer P, Abdo Z, Schneider GM, Koenig SS, McCulle SL, Karlebach S, Gorle R, Russell J, Tacket CO. Vaginal microbiome of reproductive-age women. Proc. Natl. Acad. Sci. USA. 2011;108Suppl1:4680–4687. doi: 10.1073/pnas.1002611107. [DOI] [PMC free article] [PubMed] [Google Scholar]
  95. Rivers TM. Viruses and Koch’s postulates. J. Bacteriol. 1937;33:1–12. doi: 10.1128/jb.33.1.1-12.1937. [DOI] [PMC free article] [PubMed] [Google Scholar]
  96. Rogers GB, Carroll MP, Serisier DJ, Hockey PM, Jones G, Bruce KD. Characterization of bacterial community diversity in cystic fibrosis lung infections by use of 16S ribosomal DNA terminal restriction fragment length polymorphism profiling. J. Clin. Microbiol. 2004;42:5176–5183. doi: 10.1128/JCM.42.11.5176-5183.2004. [DOI] [PMC free article] [PubMed] [Google Scholar]
  97. Rogers GB, Hart CA, Mason JR, Hughes M, Walshaw MJ, Bruce KD. Bacterial diversity in cases of lung infection in cystic fibrosis patients: 16S ribosomal DNA (rDNA) length heterogeneity PCR and 16S rDNA terminal restriction fragment length polymorphism profiling. J. Clin. Microbiol. 2003;41:3548–3558. doi: 10.1128/JCM.41.8.3548-3558.2003. [DOI] [PMC free article] [PubMed] [Google Scholar]
  98. Ronald A. The etiology of urinary tract infection: traditional and emerging pathogens. Am. J. Med. 2002;113(Suppl1A):14S–19S. doi: 10.1016/s0002-9343(02)01055-0. [DOI] [PubMed] [Google Scholar]
  99. Ross R. Report on the cultivation of proteosoma, labbé, in grey mosquitos. Calcutta, India: Office of the Superintendent of Government Printing; 1898. [Google Scholar]
  100. Roth WJ, Kissinger CB, McCain RR, Cooper BR, Marchant-Forde JN, Vreeman RC, Hannou S, Knipp GT. Assessment of juvenile pigs to serve as human pediatric surrogates for preclinical formulation pharmacokinetic testing. AAPS J. 2013;15:763–774. doi: 10.1208/s12248-013-9482-6. [DOI] [PMC free article] [PubMed] [Google Scholar]
  101. Rotstein OD, Pruett TL, Simmons RL. Mechanisms of microbial synergy in polymicrobial surgical infections. Rev. Infect. Dis. 1985;7:151–170. doi: 10.1093/clinids/7.2.151. [DOI] [PubMed] [Google Scholar]
  102. Safdar N, Crnich CJ, Maki DG. The pathogenesis of ventilator-associated pneumonia: its relevance to developing effective strategies for prevention. Respir. Care. 2005;50:725–739. [PubMed] [Google Scholar]
  103. Schillinger C, Petrich A, Lux R, Riep B, Kikhney J, Friedmann A, Wolinsky LE, Gobel UB, Daims H, Moter A. Co-localized or randomly distributed? Pair cross correlation of in vivo grown subgingival biofilm bacteria quantified by digital image analysis. PLoS One. 2012;7:e37583. doi: 10.1371/journal.pone.0037583. [DOI] [PMC free article] [PubMed] [Google Scholar]
  104. Sibley CD, Duan K, Fischer C, Parkins MD, Storey DG, Rabin HR, Surette MG. Discerning the complexity of community interactions using a Drosophila model of polymicrobial infections. PLoS Pathog. 2008;4:e1000184. doi: 10.1371/journal.ppat.1000184. [DOI] [PMC free article] [PubMed] [Google Scholar]
  105. Sibley CD, Parkins MD, Rabin HR, Duan K, Norgaard JC, Surette MG. A polymicrobial perspective of pulmonary infections exposes an enigmatic pathogen in cystic fibrosis patients. Proc. Natl. Acad. Sci. USA. 2008;105:15070–15075. doi: 10.1073/pnas.0804326105. [DOI] [PMC free article] [PubMed] [Google Scholar]
  106. Socransky SS, Haffajee AD, Cugini MA, Smith C, Kent RL., Jr Microbial complexes in subgingival plaque. J. Clin. Periodontol. 1998;25:134–144. doi: 10.1111/j.1600-051x.1998.tb02419.x. [DOI] [PubMed] [Google Scholar]
  107. Tampakakis E, Peleg AY, Mylonakis E. Interaction of Candida albicans with an intestinal pathogen, Salmonella enterica serovar Typhimurium. Eukaryotic Cell. 2009;8:732–737. doi: 10.1128/EC.00016-09. [DOI] [PMC free article] [PubMed] [Google Scholar]
  108. Turnbaugh PJ, Ley RE, Hamady M, Fraser-Liggett CM, Knight R, Gordon JI. The human microbiome project. Nature. 2007;449:804–810. doi: 10.1038/nature06244. [DOI] [PMC free article] [PubMed] [Google Scholar]
  109. Twin J, Bradshaw CS, Garland SM, Fairley CK, Fethers K, Tabrizi SN. The potential of metatranscriptomics for identifying screening targets for bacterial vaginosis. PLoS One. 2013;8:e76892. doi: 10.1371/journal.pone.0076892. [DOI] [PMC free article] [PubMed] [Google Scholar]
  110. Valm AM, Mark Welch JL, Rieken CW, Hasegawa Y, Sogin ML, Oldenbourg R, Dewhirst FE, Borisy GG. Systems-level analysis of microbial community organization through combinatorial labeling and spectral imaging. Proc. Natl. Acad. Sci. USA. 2011;108:4152–4157. doi: 10.1073/pnas.1101134108. [DOI] [PMC free article] [PubMed] [Google Scholar]
  111. van der Gast CJ, Walker AW, Stressmann FA, Rogers GB, Scott P, Daniels TW, Carroll MP, Parkhill J, Bruce KD. Partitioning core and satellite taxa from within cystic fibrosis lung bacterial communities. ISME J. 2011;5:780–791. doi: 10.1038/ismej.2010.175. [DOI] [PMC free article] [PubMed] [Google Scholar]
  112. Vega NM, Allison KR, Samuels AN, Klempner MS, Collins JJ. Salmonella typhimurium intercepts Escherichia coli signaling to enhance antibiotic tolerance. Proc. Natl. Acad. Sci. USA. 2013;110:14420–14425. doi: 10.1073/pnas.1308085110. [DOI] [PMC free article] [PubMed] [Google Scholar]
  113. Wang J, Qi J, Zhao H, He S, Zhang Y, Wei S, Zhao F. Metagenomic sequencing reveals microbiota and its functional potential associated with periodontal disease. Sci. Rep. 2013;3:1843–1852. doi: 10.1038/srep01843. [DOI] [PMC free article] [PubMed] [Google Scholar]
  114. Watanabe T, Tada M, Nagai H, Sasaki S, Nakao M. Helicobacter pylori infection induces gastric cancer in mongolian gerbils. Gastroenterology. 1998;115:642–648. doi: 10.1016/s0016-5085(98)70143-x. [DOI] [PubMed] [Google Scholar]
  115. Watrous J, Roach P, Alexandrov T, Heath BS, Yang JY, Kersten RD, van der Voort M, Pogliano K, Gross H, Raaijmakers JM. Mass spectral molecular networking of living microbial colonies. Proc. Natl. Acad. Sci. USA. 2012;109:E1743–E1752. doi: 10.1073/pnas.1203689109. [DOI] [PMC free article] [PubMed] [Google Scholar]
  116. Watrous JD, Alexandrov T, Dorrestein PC. The evolving field of imaging mass spectrometry and its impact on future biological research. J. Mass Spectrom. 2011;46:209–222. doi: 10.1002/jms.1876. [DOI] [PMC free article] [PubMed] [Google Scholar]
  117. Watrous JD, Dorrestein PC. Imaging mass spectrometry in microbiology. Nat. Rev. Microbiol. 2011;9:683–694. doi: 10.1038/nrmicro2634. [DOI] [PMC free article] [PubMed] [Google Scholar]
  118. Watrous JD, Phelan VV, Hsu CC, Moree WJ, Duggan BM, Alexandrov T, Dorrestein PC. Microbial metabolic exchange in 3D. ISME J. 2013;7:770–780. doi: 10.1038/ismej.2012.155. [DOI] [PMC free article] [PubMed] [Google Scholar]
  119. Weibel DB, DiLuzio WR, Whitesides GM. Microfabrication meets microbiology. Nat. Rev. Microbiol. 2007;5:209–218. doi: 10.1038/nrmicro1616. [DOI] [PubMed] [Google Scholar]
  120. Wessel AK, Hmelo L, Parsek MR, Whiteley M. Going local: technologies for exploring bacterial microenvironments. Nat. Rev. Microbiol. 2013;11:337–348. doi: 10.1038/nrmicro3010. [DOI] [PMC free article] [PubMed] [Google Scholar]
  121. Williams BL, McCann GF, Schoenknecht FD. Bacteriology of dental abscesses of endodontic origin. J. Clin. Microbiol. 1983;18:770–774. doi: 10.1128/jcm.18.4.770-774.1983. [DOI] [PMC free article] [PubMed] [Google Scholar]
  122. Wong SM, Bernui M, Shen H, Akerley BJ. Genome-wide fitness profiling reveals adaptations required by Haemophilus in coinfection with influenza A virus in the murine lung. Proc. Natl. Acad. Sci. USA. 2013;110:15413–15418. doi: 10.1073/pnas.1311217110. [DOI] [PMC free article] [PubMed] [Google Scholar]
  123. Wright JB, Lam K, Buret AG, Olson ME, Burrell RE. Early healing events in a porcine model of contaminated wounds: effects of nanocrystalline silver on matrix metalloproteinases, cell apoptosis, and healing. Wound Repair Regen. 2002;10:141–151. doi: 10.1046/j.1524-475x.2002.10308.x. [DOI] [PubMed] [Google Scholar]
  124. Yaguchi T, Dwidar M, Byun CK, Leung B, Lee S, Cho YK, Mitchell RJ, Takayama S. Aqueous two-phase system-derived biofilms for bacterial interaction studies. Biomacromolecules. 2012;13:2655–2661. doi: 10.1021/bm300500y. [DOI] [PubMed] [Google Scholar]
  125. Yamada M, Ikegami A, Kuramitsu HK. Synergistic biofilm formation by Treponema denticola and Porphyromonas gingivalis. FEMS Microbiol. Lett. 2005;250:271–277. doi: 10.1016/j.femsle.2005.07.019. [DOI] [PubMed] [Google Scholar]
  126. Yang JY, Phelan VV, Simkovsky R, Watrous JD, Trial RM, Fleming TC, Wenter R, Moore BS, Golden SS, Pogliano K, Dorrestein PC. Primer on agar-based microbial imaging mass spectrometry. J. Bacteriol. 2012;194:6023–6028. doi: 10.1128/JB.00823-12. [DOI] [PMC free article] [PubMed] [Google Scholar]
  127. Zhao J, Schloss PD, Kalikin LM, Carmody LA, Foster BK, Petrosino JF, Cavalcoli JD, Van Devanter DR, Murray S, Li JZ, Young VB, LiPuma JJ. Decade-long bacterial community dynamics in cystic fibrosis airways. Proc. Natl. Acad. Sci. USA. 2012;109:5809–5814. doi: 10.1073/pnas.1120577109. [DOI] [PMC free article] [PubMed] [Google Scholar]
  128. Zhao L. The gut microbiota and obesity: from correlation to causality. Nat. Rev. Microbiol. 2013;11:639–647. doi: 10.1038/nrmicro3089. [DOI] [PubMed] [Google Scholar]
  129. Zhu Y, Dashper SG, Chen YY, Crawford S, Slakeski N, Reynolds EC. Porphyromonas gingivalis and Treponema denticola synergistic polymicrobial biofilm development. PLoS One. 2013;8:e71727. doi: 10.1371/journal.pone.0071727. [DOI] [PMC free article] [PubMed] [Google Scholar]

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