Abstract
BackgroundTobacco 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.Methodology/Principal FindingsWe 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 IκBα- and IRAK-1-dependent manner.Conclusions/SignificanceThese 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.
Highlights
Tobacco smokers are more susceptible than non-smokers to multiple infectious diseases, mucosal infections such as tuberculosis, pneumonia, Chlamydiasis, gonorrhoea, otitis media and periodontitis [1]
We further show that while FimA is recognized by TLR2/6, it has only minimal inflammatory activity in several cell types (PBMCs, neutrophils, and epithelial cells) and, FimA stimulation chronically abrogates the pro-inflammatory response to subsequent TLR2 stimulation by other TLR2-specific agonists (Pam3CSK4, Mfa1) in an IRAK-1-dependent but NFkB-independent manner
cigarette smoke extract (CSE) augments P. gingivalis biofilm formation Biofilms play an important role in the pathology of periodontal disease by mechanisms that include protection of plaque bacteria against phagocytosis and against antibiotics [25]
Summary
Tobacco smokers are more susceptible than non-smokers to multiple infectious diseases, mucosal infections such as tuberculosis, pneumonia, Chlamydiasis, gonorrhoea, otitis media and periodontitis [1]. The mechanisms underlying such increased susceptibility are not well understood. Periodontitis is a bacteria-induced, irreversible chronic inflammatory mucosal disease characterized by the destruction of the soft and hard supporting structures of the teeth. Smokers show reduced clinical signs of inflammation in response to dental plaque than non-smokers, the key diagnostic indices of gingival bleeding on probing and edema [9,10]. Tobacco smokers are more susceptible to periodontitis than non-smokers but exhibit reduced signs of clinical inflammation. 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 Mfa, respectively) and capsule – concomitant with a reduced proinflammatory potential of intact P. gingivalis
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