Dr. Keith Mintz
Molecular Mechanisms of Bacterial Pathogenesis
Our laboratory studies the interaction of the oral pathogen Aggregatibacter (formerly Actinobacillus) actinomycetemcomitans with extracellular matrix proteins. A. actinomycetemcomitans is a gram-negative, capnophillic, coccobacillus that has been implicated as an important etiological agent in localized juvenile periodontitis and in cases of adult periodontitis, particularly rapid and refractory periodontitis. Periodontal diseases are chronic infections of the gingival tissue that lead to inflammation of the gingiva, destruction of the supporting connective tissue, alveolar bone loss and eventual loss of teeth. This pathogen has been associated with infections at extraoral sites, such as endocarditis, soft tissue abscesses, pneumonia, osteomyelitis and urinary tract infections. Furthermore, periodontal disease has been considered a risk factor for cardiovascular disease and DNA sequences specific for periodontal pathogens, including A. actinomycetemcomitans, have been found in atheromatous plaque of individuals with cardiovascular disease.
The bacterial outer membrane of bacteria serves as a platform for the expression of various determinants required for the colonization and survival of the bacterium. A. actinomycetemcomitans synthesizes an irregular outer membrane surface that supports the secretion or presentation of proteins associated with immuno-evasion and adhesion. A common theme amongst pathogens is the ability to initiate infection by adhesion to specific host macromolecules under stringent or hostile conditions. These molecules include proteins secreted by host cells that form the extracellular matrix. The A. actinomycetemcomitans gene, emaA (extracellular matrix protein adhesin A), which encodes a 202 kDa outer membrane protein is required for the adhesion of this bacterium to collagen. EmaA contains sequence and inferred structural domains which define members of a novel class of nonfimbrial adhesins. Inactivation of the gene results in the loss of surface appendages, which are composed of three monomers of EmaA, and of adhesion of the bacterium to collagen fibers in a rabbit heart valve model. Absence of the appendages results in a diminished ability of the bacterium to initiate infection in an infective endocarditis animal model. In-frame deletion and substitution mutagenesis studies have defined the biologically active domain of the adhesin and an initial 3D structure has been generated by electron tomography.
The expression of EmaA is independent of the irregular membrane morphology. This morphology is associated with the expression of a novel gene, morC (morphogenesis protein C). MorC is a 141 kDa inner membrane protein that is conserved in gram-negative bacteria. Inactivation of the gene not only results in loss of the membrane convolutions but also affects the sensitivity of the bacterium to bile salts and abolishes the secretion of leukotoxin.
The goals of our research are to identify and characterize bacterial genes and gene products associated with the colonization and survival of A. actinomycetemcomitans within the body. Understanding the molecular mechanisms of these molecules can be applied to the development of targeted therapeutics or synergistically with existing therapies to reduce the pathogenic potential of A. actinomycetemcomitans and other pathogens.
322B Stafford Hall
117 &118 Stafford Hall
Ruiz, T., Lenox, C., Radermacher, M., and Mintz, K.P. Novel surface structures are associated with the adhesion of Actinobacillus actinomycetemcomitans to collagen. Infect Immun. 2006 Nov;74(11):6163-70.
Yu, C., Ruiz, T., Lenox, T. and Mintz, K.P. Functional mapping of an oligomeric autotransporter adhesin of Aggregatibacter actinomycetemcomitans. J Bacteriol. 2008 May;190(9):3098-109.
Tang, G, Kitten, T., Munro, C, Wellman, G. and Mintz, K.P. EmaA, a potential virulence determinant of Aggregatibacter (Actinobacillus) actinomycetemcomitans in infective endocarditis. Infect Immun. 2008 Jun;76(6):2316-24.
Gallant, C.V., Sedic, M., Chicoine, E.A., Ruiz, T. and Mintz, K.P. Membrane morphology and leukotoxin secretion are associated with a novel membrane protein of Aggregatibacter actinomycetemcomitans. J Bacteriol. 2008 Sep;190(17):5972-80.
Yu, C., Mintz, K.P. and Ruiz, T. Investigation of the 3D architecture of the collagen adhesin EmaA of Aggregatibacter actinomycetemcomitans by electron tomography. J Bacteriol. 2009 Oct;191(20):6253-61