The normal oral microflora is very complex, consisting of over five hundred different species of bacteria (31). Changes in oral microflora composition have been noted to occur during the onset and progression of periodontal disease. In healthy individuals, the dental pellicle is rapidly colonized by a variety of Gram-positive, facultatively anaerobic bacteria. As periodontal disease develops, Gram-negative anaerobic rods begin to predominate. Bacteria most often isolated in advanced periondontitis include Bifidobacterium, Actinomyces, Porphyromonas, Treponema, and Fusobacterium (34). Of these, Fusobacteriumnucleatum is the most common clinical isolate. F. nucleatum is a Gram-negative anaerobe that appears as long tapered rods. This microbe produces a variety of virulence factors that may be involved in promoting periodontal disease. F. nucleatum is well known for its ability to adhere to a variety of materials. In addition to the pathogens mentioned earlier, pure cultures of this organism can form aggregates with a wide range of bacteria (25). Coaggregation has been shown to involve specific F. nucleatum surface proteins. These can be both lectin-like (22, 32, 42), and non-lectin-like (45) in their affinities. F. nucleatum also has demonstrable ability to bind to host tissues. This organism has been shown to bind to connective tissues through fibronectin (5). Additional lectin-like interactions with host cells have been implicated in binding (29, 30) and subsequent internalization (17). All of these interactions are likely important for colonizing and recruiting new bacterial species into the maturing periodontal biofilm. This has lead many to suggest that F. nucleatum plays a critical role in biofilm formation. F. nucleatum has also been shown to promote the survival of other periodontal pathogens in the presence of oxygen (8, 13). Furthermore, this bacterium appears to act synergistically with other periodontal pathogens (14). Association of with F. nucleatum with host cells is known to be responsible for altering the periodontal immune defenses. Accumulation of toxic metabolic end products results in inhibition of lymphocyte proliferation (26) and induction of apoptosis (27). This bacterium has also been shown to produce a protein that inhibits lymphocyte proliferation. The Fusobacterium inmmunosuppressive protein (FIP) blocks the lymphocyte cell cycle in G1 between the cyclin D2 and D3 restriction points (11, 43). The ability of F. nucleatum to modulate the host immune defenses has been suggested to enhance the virulence of other bacteria in mixed oral infections (9, 28). Perhaps the most significant role that F. nucleatum may play in periodontal disease is stimulation of the host inflammatory response. It is this phenomenon that is ultimately responsible for most of the host tissue damage that occurs in periondontitis. Although bacterial metabolites and virulence proteins may contribute to this process, stimulation is thought to be primarily due to the presence of lipopolysaccharide (LPS). Toll-like receptor 4 (TLR-4) binding of LPS is known to result in the production of the pro-inflammatory cytokines IL-1, IL-8 and TNF-a. Binding of whole F. nucleatum to gingival epithelial cells has been shown to stimulate IL-8 production (17). Additionally, artificial infections using live or heat killed F. nucleatum were sufficient to cause bone resorption in mice (48). The heat stability of this effect suggests that LPS may be involved. Furthermore, many groups have demonstrated the ability of F. nucleatum LPS preparations to elicit cytokine production (6, 47). The importance of LPS in periodontal disease was recently reinforced in a study using CH3/HeJ mice (19). These animals are defective for TLR-4 and are, therefore, less responsive to LPS. When challenged with F. nucleatum and other oral pathogens, the mutant mice produced significantly less cytokines and exhibited reduced bone resorption when compared to control animals.