Tobacco upregulates P. gingivalis fimbrial proteins which induce TLR2 hyposensitivity.
BACKGROUND
Tobacco smokers are more susceptible to periodontitis than non-smokers but exhibit reduced signs of clinical inflammation. The underlying mechanisms are unknown. We have previously shown that cigarette smoke extract (CSE) represents an environmental stress to which P. gingivalis adapts by altering the expression of several virulence factors - including major and minor fimbrial antigens (FimA and Mfa1, respectively) and capsule - concomitant with a reduced pro-inflammatory potential of intact P. gingivalis.


RESULTS
We hypothesized that CSE-regulation of capsule and fimbrial genes is reflected at the ultrastructural and functional levels, alters the nature of host-pathogen interactions, and contributes to the reduced pro- inflammatory potential of smoke exposed P. gingivalis. CSE induced ultrastructural alterations were determined by electron microscopy, confirmed by Western blot and physiological consequences studied in open-flow biofilms. Inflammatory profiling of specific CSE-dysregulated proteins, rFimA and rMfa1, was determined by quantifying cytokine induction in primary human innate and OBA-9 cells. CSE up-regulates P. gingivalis FimA at the protein level, suppresses the production of capsular polysaccharides at the ultrastructural level, and creates conditions that promote biofilm formation. We further show that while FimA is recognized by TLR2/6, it has only minimal inflammatory activity in several cell types. Furthermore, FimA stimulation chronically abrogates the pro-inflammatory response to subsequent TLR2 stimulation by other TLR-2-specific agonists (Pam3CSK4, FSL, Mfa1) in an IkappaBalpha- and IRAK-1-dependent manner.


CONCLUSIONS
These studies provide some of the first information to explain, mechanistically, how tobacco smoke changes the P. gingivalis phenotype in a manner likely to promote P. gingivalis colonization and infection while simultaneously reducing the host response to this major mucosal pathogen.
Bagaitkar
Juhi
J
Department of Microbiology and Immunology, School of Medicine, University of Louisville, Louisville, Kentucky, United States of America.
Demuth
Donald R
DR
Daep
Carlo Amorin
CA
Renaud
Diane E
DE
Pierce
Deanne L
DL
Scott
David A
DA
D000818:Animals; D016667:Bacterial Capsules / Q000276:immunology; D001426:Bacterial Proteins / Q000276:immunology* / Q000378:metabolism; D018441:Biofilms / Q000254:growth & development; D002417:Cattle; D002460:Cell Line; D036781:Fimbriae Proteins / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism; D007108:Immune Tolerance / Q000276:immunology; D007113:Immunity, Innate / Q000276:immunology; D007249:Inflammation / Q000276:immunology; D018836:Inflammation Mediators / Q000276:immunology; D053592:Interleukin-1 Receptor-Associated Kinases / Q000378:metabolism; D000072000:NF-KappaB Inhibitor alpha; D016966:Porphyromonas gingivalis / Q000276:immunology* / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D012907:Smoking / Q000276:immunology / Q000503:physiopathology*; D051195:Toll-Like Receptor 2 / Q000276:immunology*; D015854:Up-Regulation
D001426:Bacterial Proteins; D020672:I-kappa B Proteins; D018836:Inflammation Mediators; C545438:Mfa1 protein, Porphyromonas gingivalis; C000606204:NFKBIA protein, human; C495342:TLR2 protein, human; D051195:Toll-Like Receptor 2; C063055:fimbrillin; D000072000:NF-KappaB Inhibitor alpha; D036781:Fimbriae Proteins; C507768:IRAK1 protein, human; D053592:Interleukin-1 Receptor-Associated Kinases
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