The degree of microbiome complexity influences the epithelial response to infection.
BACKGROUND
The human microflora is known to be extremely complex, yet most pathogenesis research is conducted in mono-species models of infection. Consequently, it remains unclear whether the level of complexity of a host's indigenous flora can affect the virulence potential of pathogenic species. Furthermore, it remains unclear whether the colonization by commensal species affects a host cell's response to pathogenic species beyond the direct physical saturation of surface receptors, the sequestration of nutrients, the modulation of the physico-chemical environment in the oral cavity, or the production of bacteriocins. Using oral epithelial cells as a model, we hypothesized that the virulence of pathogenic species may vary depending on the complexity of the flora that interacts with host cells.


RESULTS
This is the first report that determines the global epithelial transcriptional response to co-culture with defined complex microbiota. In our model, human immortalized gingival keratinocytes (HIGK) were infected with mono- and mixed cultures of commensal and pathogenic species. The global transcriptional response of infected cells was validated and confirmed phenotypically. In our model, commensal species were able to modulate the expression of host genes with a broad diversity of physiological functions and antagonize the effect of pathogenic species at the cellular level. Unexpectedly, the inhibitory effect of commensal species was not correlated with its ability to inhibit adhesion or invasion by pathogenic species.


CONCLUSIONS
Studying the global transcriptome of epithelial cells to single and complex microbial challenges offers clues towards a better understanding of how bacteria-bacteria interactions and bacteria-host interactions impact the overall host response. This work provides evidence that the degree of complexity of a mixed microbiota does influence the transcriptional response to infection of host epithelial cells, and challenges the current dogma regarding the potential versus the actual pathogenicity of bacterial species. These findings support the concept that members of the commensal oral flora have evolved cellular mechanisms that directly modulate the host cell's response to pathogenic species and dampen their relative pathogenicity.
Mans
Jeffrey J
JJ
Department of Oral Biology, College of Dentistry, University of Florida, Gainesville, Florida, USA. jmans@dental.ufl.edu
von Lackum
Kate
K
Dorsey
Cassandra
C
Willis
Shaun
S
Wallet
Shannon M
SM
Baker
Henry V
HV
Lamont
Richard J
RJ
Handfield
Martin
M
D016866:Bacteroidaceae Infections / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D018920:Coculture Techniques; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D005881:Gingiva / Q000378:metabolism / Q000382:microbiology*; D054884:Host-Pathogen Interactions; D006801:Humans; D015603:Keratinocytes / Q000378:metabolism / Q000382:microbiology*; D054892:Metagenome; D020411:Oligonucleotide Array Sequence Analysis; D016966:Porphyromonas gingivalis / Q000472:pathogenicity; D013290:Streptococcal Infections / Q000235:genetics / Q000378:metabolism; D054773:Streptococcus gordonii / Q000472:pathogenicity
J Clin Periodontol. 1986 Nov;13(10):912-7
3466908
Nucleic Acids Res. 2007 Jul;35(Web Server issue):W206-11
17584796
Infect Immun. 2004 Jul;72(7):3743-51
15213114
Cell Microbiol. 2007 Aug;9(8):1997-2007
17419719
Bioinformatics. 2003 Dec 12;19(18):2448-55
14668230
J Periodontal Res. 2008 Aug;43(4):408-16
18942189
Nat Rev Mol Cell Biol. 2007 Feb;8(2):149-60
17245415
Cell Microbiol. 2002 May;4(5):305-14
12027958
Nucleic Acids Res. 2003 Jul 1;31(13):3775-81
12824416
Science. 2001 May 11;292(5519):1115-8
11352068
J Bacteriol. 2001 Jun;183(12):3770-83
11371542
Infect Immun. 2008 Sep;76(9):4163-75
18625732
Periodontol 2000. 2006;42:47-79
16930306
J Dent Res. 1984 Mar;63(3):412-21
6583243
J Dent Res. 2005 Jan;84(1):59-63
15615877
Cell Microbiol. 2005 Jun;7(6):811-23
15888084
Nucleic Acids Res. 2004 Jul 1;32(Web Server issue):W449-56
15215428
Science. 2004 Mar 12;303(5664):1662-5
15016999
Microbes Infect. 2008 Feb;10(2):122-8
18280195
J Clin Periodontol. 1998 Feb;25(2):134-44
9495612
Microbiology (Reading). 2002 Jun;148(Pt 6):1627-1636
12055284
Infect Disord Drug Targets. 2006 Sep;6(3):299-309
16918488
FEMS Microbiol Lett. 2001 Jun 25;200(2):145-9
11425466
Microbes Infect. 2000 Nov;2(13):1599-607
11113379
Proc Natl Acad Sci U S A. 2004 Nov 2;101(44):15718-23
15505215
J Dent Res. 2008 Mar;87(3):203-23
18296603
Infect Immun. 1995 Oct;63(10):3878-85
7558295
Proc Natl Acad Sci U S A. 2006 Jul 18;103(29):11027-32
16832066
Infect Immun. 2001 Sep;69(9):5736-41
11500450
Infect Immun. 2004 Mar;72(3):1341-8
14977937
J Bacteriol. 2000 Dec;182(24):7067-9
11092870
Science. 2000 Sep 1;289(5484):1560-3
10968793
Infect Immun. 2006 Nov;74(11):6419-28
16923784
Nucleic Acids Res. 2005 Jul 1;33(Web Server issue):W762-5
15980579
Infect Immun. 2007 May;75(5):2540-7
17307939
Microbiol Mol Biol Rev. 1998 Dec;62(4):1244-63
9841671
Periodontol 2000. 2002;30:61-9
12236896
Proc Natl Acad Sci U S A. 1998 Dec 8;95(25):14863-8
9843981
Periodontol 2000. 1999 Jun;20:341-62
10522230
J Clin Periodontol. 2000 Oct;27(10):722-32
11034118
Proc Natl Acad Sci U S A. 2000 Aug 15;97(17):9659-64
10931941
Infect Immun. 2000 May;68(5):2907-15
10768988
Exp Cell Res. 1996 Jul 10;226(1):164-9
8660952
Infect Immun. 2005 Jul;73(7):3983-9
15972485
Adv Dent Res. 1997 Apr;11(1):33-42
9524440
J Periodontol. 2008 Nov;79(11):2112-24
18980520
Infect Immun. 2001 Apr;69(4):2700-7
11254637
Chest. 2002 Mar;121(3 Suppl):36S-39S
11893678
Oral Microbiol Immunol. 1996 Feb;11(1):35-41
8604253