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Infection and Immunity, September 2008, p. 4163-4175, Vol. 76, No. 9
0019-9567/08/$08.00+0     doi:10.1128/IAI.00188-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

The Commensal Streptococcus salivarius K12 Downregulates the Innate Immune Responses of Human Epithelial Cells and Promotes Host-Microbe Homeostasis{triangledown} ,{dagger}

Celine Cosseau,1 Deirdre A. Devine,2,# Edie Dullaghan,3,# Jennifer L. Gardy,1 Avinash Chikatamarla,1 Shaan Gellatly,1 Lorraine L. Yu,1 Jelena Pistolic,1 Reza Falsafi,1 John Tagg,4 and Robert E. W. Hancock1*

Centre for Microbial Diseases and Immunity Research, University of British Columbia, Vancouver, Canada,1 Department of Oral Biology, Leeds Dental Institute, University of Leeds, Leeds, United Kingdom,2 Inimex Pharmaceuticals, Vancouver, Canada,3 Department of Microbiology and Immunology, University of Otago, Dunedin, New Zealand4

Received 11 February 2008/ Returned for modification 25 March 2008/ Accepted 3 July 2008

Streptococcus salivarius is an early colonizer of human oral and nasopharyngeal epithelia, and strain K12 has reported probiotic effects. An emerging paradigm indicates that commensal bacteria downregulate immune responses through the action on NF-{kappa}B signaling pathways, but additional mechanisms underlying probiotic actions are not well understood. Our objective here was to identify host genes specifically targeted by K12 by comparing their responses with responses elicited by pathogens and to determine if S. salivarius modulates epithelial cell immune responses. RNA was extracted from human bronchial epithelial cells (16HBE14O- cells) cocultured with K12 or bacterial pathogens. cDNA was hybridized to a human 21K oligonucleotide-based array. Data were analyzed using ArrayPipe, InnateDB, PANTHER, and oPOSSUM. Interleukin 8 (IL-8) and growth-regulated oncogene alpha (Gro{alpha}) secretion were determined by enzyme-linked immunosorbent assay. It was demonstrated that S. salivarius K12 specifically altered the expression of 565 host genes, particularly those involved in multiple innate defense pathways, general epithelial cell function and homeostasis, cytoskeletal remodeling, cell development and migration, and signaling pathways. It inhibited baseline IL-8 secretion and IL-8 responses to LL-37, Pseudomonas aeruginosa, and flagellin in epithelial cells and attenuated Gro{alpha} secretion in response to flagellin. Immunosuppression was coincident with the inhibition of activation of the NF-{kappa}B pathway. Thus, the commensal and probiotic behaviors of S. salivarius K12 are proposed to be due to the organism (i) eliciting no proinflammatory response, (ii) stimulating an anti-inflammatory response, and (iii) modulating genes associated with adhesion to the epithelial layer and homeostasis. S. salivarius K12 might thereby ensure that it is tolerated by the host and maintained on the epithelial surface while actively protecting the host from inflammation and apoptosis induced by pathogens.

* Corresponding author. Mailing address: Centre for Microbial Diseases and Immunity Research, University of British Columbia, Vancouver, Canada. Phone: (604) 263-6718. Fax: (604) 822-6041. E-mail: bob{at}cmdr.ubc.ca

{triangledown} Published ahead of print on 14 July 2008.

{dagger} Supplemental material for this article may be found at http://iai.asm.org/.

Editor: A. J. Bäumler

# These authors contributed equally to this work.

Infection and Immunity, September 2008, p. 4163-4175, Vol. 76, No. 9
0019-9567/08/$08.00+0     doi:10.1128/IAI.00188-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



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