Tobacco Upregulates P. gingivalis Fimbrial Proteins Which Induce TLR2 Hyposensitivity

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.

Impact of cigarette smoke exposure on host–bacterial pathogen interactions

“…Interestingly, smoking cessation is associated with a reversion to the microflora found in never-smokers, thereby suggesting that cigarette smoke does indeed favour colonisation by pathogens [57]. Supporting this notion, cigarette smoke enhances bacterial attachment to epithelial cells and promotes changes in virulence by modifying bacterial gene expression [58][59][60].…”

Effects of Smoking and Smoking Cessation and Smoking Cessation Intervention

“…These findings explain the connection between smoking and periodontal tissue breakdown by pathogenic periodontal microorganisms. Another series of studies (Bagaitkar et al, 2009(Bagaitkar et al, , 2010Budneli et al, 2011) addressed the involvement of anaerobic bacterial periodontopathogens in the mechanism of suppression of the clinical inflammatory response in periodontal disease in smokers. As an environmental factor, the stress of cigarette smoke upregulates P. gingivalis fimbrial antigens and creates conditions that promote biofilm formation, though the proinflammatory response to the pathogen is inhibited.…”

Harmful Interactions of Non-Essential Heavy Metals with Cells of the Innate Immune System

“…Moreover, cigarette smoke exposure has also been reported to induce the formation of biofilm by various common respiratory and oral pathogens [106,107]. Encasement in biofilm, a self-generated extracellular polymer matrix, is a survival strategy utilised by bacteria to promote persistence by evasion of both host defences and antibiotics, and has been implicated in 60-80% of all microbial infections [108].…”