There is significant evidence implicating A. actinomycetemcomitans as a microorganism that is highly associated with an aggressive form of periodontal disease found in young adults. Much of the enthusiasm for studies of the role of A. actinomycetemcomitans in localized aggressive periodontitis has diminished over the last 10 years for reasons that are inexplicable and inconsistent with the progress that has been made in efforts to understand the molecular biology of this important organism and its association with disease pathogenesis. This review has attempted to depict the involvement of A. actinomycetemcomitans in each of the steps required for an infection to proceed from its inception. In that manner we have described events that are associated with the transmission of A. actinomycetemcomitans from one individual to another, pointing out the complexity of this event and why it may be necessary to examine and refine the way in which we document transmission in future studies. Our review points out that new genetic methods may have to be used to account for the horizontal transfer of genetic material from one organism to another in the plaque matrix and how this transfer may account for new phenotypes that are critical for disease pathogenesis. As for attachment and colonization phenotypes, a great deal of new information has resulted from in silico identification of genes that have been revealed as a result of completion of the A. actinomycetemcomitans genome sequence. The similarity of the A. actinomycetemcomitans genes to genes expressing attachment and colonization phenotypes encoded by other gram-negative bacteria has provided us with a window into the world of bacterial biology that was impossible to study before these genomes were described. A search of the A. actinomycetemcomitans genome revealed homology with genes and proteins related to the attachment of sequenced organisms. Comparative genomics has allowed for in silico identification of the aae gene in A. actinomycetemcomitans, a gene that is similar to the hap (i.e. Haemophilus adhesive protein) gene described for H. influenzae (104) and the api gene in A. actinomycetemcomitans, a gene with similarity to the yadA (Yersinia adhesion) gene of Y. pestis (107). In a similar manner, A. actinomycetemcomitans biologists have been able to enlighten microbiologists in other disciplines to the importance of genes and operons expressed in A. actinomycetemcomitans that could have broad significance in the world of general microbiology. Thus, the flp-tad operon was shown to be widespread in nature, first identified in A. actinomycetemcomitans and found to be present in many pathogenic bacteria and in all archea sequenced to date (221). This operon undoubtedly is responsible for a phenotype that has great biological significance. The dsp B genes have been shown to produce an enzyme that enables dispersion of A. actinomycetemcomitans biofilm colonies. These genes have also been shown to have an effect on the carbohydrate substrate produced by S. epidermidis that results in biofilms which stick to abiotic surfaces (132). Application of A. actinomycetemcomitans dispersin B enzyme to S. epidermidis biofilms on indwelling catheters results in almost immediate and complete clearance of biofilms and could have significant efficacy in the prevention of S. epidermidis biofilm formation on indwelling catheters. This medical problem is widespread and is estimated to cost 10,000 lives per year and annual hospital costs of over $11 billion. While A. actinomycetemcomitans does not present itself as a clear exogenous pathogen in the mold of Treponema pallidum, Mycobacterium tuberculosis or Clostridium botulinum, A. actinomycetemcomitans does provide an interesting perspective on pathogenic events seen in chronic infections caused by members of the resident flora. The evidence is incomplete but it does seem that in the case of A. actinomycetemcomitans, disease takes place by means of direct expression of A. actinomycetemcomitans virulence traits in the earliest stages of disease, and by means of the reaction of the host defense system to traits expressed by A. actinomycetemcomitans in the later, tissue-destructive, stages. These two distinctly different modes of pathogenesis are more than likely not unique to A. actinomycetemcomitans. However, our current understanding may make it possible to put the puzzle pieces together and help resolve some of the secrets hidden in the biology of other less well-understood diseases. The evidence is based on clinical, microbiological and immunological studies that demonstrate a robust association between A. actinomycetemcomitans and localized aggressive periodontitis. Questions that still remain unanswered are as follows. • Does this organism initiate the disease? • If so, does A. actinomycetemcomitans act as the sole or main initiator, or does it act in concert with other organisms in the plaque biofilm? • Are there other organisms that initiate the disease and does A. actinomycetemcomitans act only after the initial stages of disease have taken place? Is A. actinomycetemcomitans responsible for disease progression? • Alternatively, is A. actinomycetemcomitans a marker organism and thus only present as a result of "others" that have set up the environment and produced the disease? In the last scenario, A. actinomycetemcomitans would be a bystander organism. These questions are particularly pertinent to oral infections because these infections are chronic in nature and occur in a polymicrobial matrix composed of a diverse community of microorganisms that provide characteristic feedback signals from the host (302). As such, our efforts to study these oral infections present us with complicated microbial community interactions superimposed on equally complicated host signaling pathways (264). As presented in this review, A. actinomycetemcomitans possesses traits that enable it to colonize, invade, avoid the host-defensive strategies and cause tissue destruction (Fig. 10). All of this evidence would lead one to believe that there is a cause and effect relationship between A. actinomycetemcomitans and localized aggressive periodontitis. This logic is further complemented by studies which suggest that A. actinomycetemcomitans is related to disease initiation and by studies which show that failure to remove A. actinomycetemcomitans leads to disease progression. Moreover, repopulation of diseased sites by A. actinomycetemcomitans leads to disease recurrence. Nevertheless, the exact mechanism of A. actinomycetemcomitans interaction with its fellow community inhabitants, and the collective or individual influence of these associations on host cell signaling, are just at the earliest stages of investigation. In this part of the world, we have an expression, "there is no such thing as a free lunch". In most cases this sentiment is true, but to their credit bacteria have figured out how to obtain housing, food and transportation at no cost. They live with us and on us. They were here before us and will be here after us. As single-cell creatures they have figured out how to live and survive in complex competitive communities. They have learned how to mimic many of the things we humans express and, in some cases, we cannot distinguish between them and us. They deserve and have gained the authors' respect and as such (pardon the pun) we remain attached to A. actinomycetemcomitans.
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