Virulence mechanisms of Tannerella forsythia.

The subgingival periodontal pocket of humans harbors more than 500 bacterial species. Periodontitis is a chronic inflammation of the periodontium with multi-factorial etiology. It is initiated due to colonization as subgingival biofilms by a group of gram-negative anaerobes. The disease progresses as a result of the direct effects of bacterial virulence factors on host tissues as well as the self-damaging host responses to the colonizing bacteria (83). While no single species has been implicated as the primary pathogen and the available evidence is consistent with a polymicrobial disease etiology, the red-complex bacteria consisting of Porphyromonas gingivalis, Treponema denticola and Tannerella forsythia has been strongly implicated in the onset of periodontitis (83). On the other hand, investigations utilizing the 16S ribotyping have also implicated novel phylotypes in the absence of detectable red-complex bacteria associated with periodontal lesions (44). In support of T. forsythia as being a suspected periodontal pathogen, the organism satisfies the necessary criteria postulated by Socransky and co-workers (82, 83). For instance: (i) its association and increased levels in periodontitis (83), (ii) evidence of host responses to its antigens (2, 81, 94) (iii) its ability to cause disease in animal models (2, 40, 79, 84), and (iv) expression of virulence factors which can potentially contribute to the disease process (described in detail in this review). T. forsythia is an anaerobic gram-negative member of the Cytophaga-Bacteroides family which was initially described as Bacteroides forsythus by Tanner et al. (87) and later reclassified as Tannerella forsythia by Sakamoto et al. (74) based on 16S rRNA phylogenetic analysis. T. forsythia is associated more frequently and/or in higher levels with various forms of the disease, including gingivitis, chronic and aggressive periodontitis, than with health (for review see Ref. (86)). Several studies have also implicated T. forsythia in the progression of clinical attachment loss associated with periodontitis (11, 18, 19, 50, 85). Moreover, a recent study has suggested that T. forsythia infection is more likely to cause periodontitis in overweight women than in normal weight women (7). According to another recent study, overweight or obese individuals have an overgrowth of T. forsythia compared to normal weight individuals, thus subjecting overweight and obese individuals to a higher risk of developing periodontal disease (20). In spite of the overwhelming evidence implicating T. forsythia in pathogenesis, this bacterium remains an understudied organism. This is partly due to the fastidious growth requirement for culturing this bacterium, as well as the fact that genetic manipulations of this organism are difficult to perform (30, 73). Moreover, there are no gene complementation systems currently available for the organism. While T. forsythia is the sole member of the new genus Tannerella, uncultivated oral phylotypes BU045, BU063, 97 and 997 are its closest relatives (95). These phylotypes have long rod-like segmented structure, and though they are frequently found in various periodontal disease-associated plaques, they are present only in low numbers, do not proliferate to high densities and therefore, are considered not relevant to disease pathogenesis (95). Studies in animal models have demonstrated the virulence potential of T. forsythia. For example, T. forsythia caused skin abscesses in rabbits (84) and mice (2, 93) as well as alveolar bone loss in mice (79) and rats (40). These in vivo studies also showed that the pathogenic potential of T. forsythia was enhanced in the presence of other bacteria. For instance, abscess formation in rabbits and in mice was enhanced synergistically when Fusobacterium nucleatum or P. gingivalis were the coinfecting partners of T. forsythia. Similarly, a synergy was observed relative to alveolar bone loss in rats following oral infection with the red-complex consortium, P. gingivalis, T. denticola and T. forsythia (40). These results demonstrate that T. forsythia is a pathogenic organism which might play synergistic roles in inflammation along with other periodontal pathogens. Therefore, in order to fully understand the mechanisms underlying the pathogenesis associated with T. forsythia, it would be important to identify the virulence functions of the organism and determine how these factors are regulated in response to coexisting bacteria and to host-derived factors. It is likely that T. forsythia might influence the physiology and virulence of coexisting periodontal pathogens. For this purpose, physical, chemical, and metabolic interactions are expected to occur, which might further involve bacterial two component sensor-regulator systems. So far, only a few putative virulence factors have been identified in T. forsythia: trypsin-like (17) and PrtH proteases (72), sialidases SiaH (6, 35) and NanH (88), a leucine-rich repeat cell-surface-associated and secreted protein BspA (81), an apoptosis-inducing activity (61), alpha-D-glucosidase and N-acetyl-beta-glucosaminidase (32), a hemagglutinin (59), components of the bacterial S-layer (71, 73), and methylglyoxal production (53).