A. actinomycetemcomitans has clearly adapted well to its environs; its armamentarium of virulence factors (Table 2) ensures its survival in the oral cavity and enables it to promote disease. Factors that promote A. actinomycetemcomitans colonization and persistence in the oral cavity include adhesins, bacteriocins, invasins and antibiotic resistance. It can interact with and adhere to all components of the oral cavity (the tooth surface, other oral bacteria, epithelial cells or the extracellular matrix). The adherence is mediated by a number of distinct adhesins that are elements of the cell surface (outer membrane proteins, vesicles, fimbriae or amorphous material). A. actinomycetemcomitans enhances its chance of colonization by producing actinobacillin, an antibiotic that is active against both streptococci and Actinomyces, primary colonizers of the tooth surface. The fact that A. actinomycetemcomitans resistance to tetracyclines, a drug often used in the treatment of periodontal disease, is on the rise is an added weapon. Periodontal pathogens or their pathogenic products must be able to pass through the epithelial cell barrier in order to reach and cause destruction to underlying tissues (the gingiva, cementum, periodontal ligament and alveolar bone). A. actinomycetemcomitans is able to elicit its own uptake into epithelial cells and its spread to adjacent cells by usurping normal epithelial cell function. A. actinomycetemcomitans may utilize these remarkable mechanisms for host cell infection and migration to deeper tissues. A. actinomycetemcomitans also orchestrates its own survival by elaborating factors that interfere with the host's defense system (such as factors that kill phagocytes and impair lymphocyte activity, inhibit phagocytosis and phagocyte chemotaxis or interfere with antibody production). Once the organisms are firmly established in the gingiva, the host responds to the bacterial onslaught, especially to the bacterial lipopolysaccharide, by a marked and continual inflammatory response, which results in the destruction of the periodontal tissues. A. actinomycetemcomitans has at least three individual factors that cause bone resorption (lipopolysaccharide, proteolysis-sensitive factor and GroEL), as well as a number of activities (collagenase, fibroblast cytotoxin, etc.) that elicit detrimental effects on connective tissue and the extracellular matrix. It is of considerable interest to know that A. actinomycetemcomitans possesses so many virulence factors but unfortunate that only a few have been extensively studied. If we hope to understand and eradicate this pathogen, it is critical that in-depth investigations into the biochemistry, genetic expression, regulation and mechanisms of action of these factors be initiated.
Actinobacillus actinomycetemcomitans, an oral bacterial species associated with periodontal disease, was found to invade human cell lines. Invasion was demonstrated by recovery of viable organisms from gentamicin-treated KB cell monolayers and by light and electron microscopy. Internalization occurred through a cytochalasin D-sensitive process. Invasion efficiencies of some A. actinomycetemcomitans strains were comparable to those of invasive members of the family Enterobacteriaceae. Differences in invasiveness were correlated with bacterial colonial morphology. Smooth variants invaded more proficiently than rough variants. A. actinomycetemcomitans can undergo a smooth-to-rough colonial morphology shift which results in the loss of invasiveness. Coordinated regulation of genes involved in the rough-to-smooth phenotypic transitions may play a role in the episodic nature of periodontal disease.
The invasion process of Actinobacillus actinomycetemcomitans, a periodontopathogen, was studied with microscopy and viable quantitative assays using both KB and Madin-Darby canine kidney (MDCK) epithelial cells. Microscopy revealed that the events associated with the A. actinomycetemcomitans invasion process occurred rapidly. Scanning electron micrographs revealed A. actinomycetemcomitans associated with craters on the KB cell surface and others entering the KB cells through apertures with lip-like rims within 30 min of infection. Both transmission electron and immunofluorescence micrographs demonstrated that by this time some bacteria had, in fact, already entered, replicated, and exited host cells. Scanning electron micrographs revealed that infected KB cells exhibited fibrillar protrusions which contained bulges with the conformation of bacteria. Some protrusions formed intercellular connections between KB cells. Immunofluorescence micrographs revealed protrusions which harbored A. actinomycetemcomitans. The spread of internalized A. actinomycetemcomitans from one MDCK epithelial cell monolayer to another was demonstrated using a sandwich assay developed in our laboratory. Transcytosis of A. actinomycetemcomitans through polarized MDCK cells was also demonstrated. This study indicates that soon after entry of A. actinomycetemcomitans bacteria into epithelial cells, they undergo rapid multiplication and may subsequently be found in protrusions which sometimes extend between neighboring epithelial cells. The protrusions are thought to mediate the cell-to-cell spread of A. actinomycetemcomitans. Cell-to-cell spread may also occur by the endocytosis of A. actinomycetemcomitans bacteria which have been released into the medium via rudimentary protrusions which do not interconnect epithelial cells. The finding that the A. actinomycetemcomitans invasion process is so dynamic sheds significant new light on the interaction of this periodontopathogen with mammalian cells.
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