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Genomic Stability of Aggregatibacter actinomycetemcomitans during Persistent Oral Infection in Human.

ABSTRACT: The genome of periodontal pathogen Aggregatibacter actinomycetemcomitans exhibits substantial variations in gene content among unrelated strains primarily due to the presence or absence of genomic islands. This study examined the genomic stability of A. actinomycetemcomitans during its persistent infection in the same host. Four pairs of A. actinomycetemcomitans strains, each pair isolated from an individual over time (0-10 years), were examined for their gains/losses of genes by whole genome sequencing, comparative genomic hybridization by microarray and PCR analysis. Possible effects due to genomic changes were further assessed by comparative transcriptome analysis using microarrays. The results showed that each pair of strains was clonally identical based on phylogenetic analysis of 150 core genes. A novel 24.1-Kb plasmid found in strain S23A was apparently lost in the sibling strain I23C. A 353-bp inversion affecting two essential genes of the serotype-specific gene cluster was found in the serotype antigen-nonexpressing strain I23C, while the same gene cluster was intact in the serotype-expressing sibling strain S23A. A 2,293-bp deletion affecting a gene encoding oxaloacetate decarboxylase and its neighbor region was found in strain SCC2302 but not in the sibling strain AAS4a. However, no evidence of gains or losses of genomic islands was found in the paired strains. Transcriptome profiles showed little or no difference in the paired strains. In conclusion, the genome of A. actinomycetemcomitans appears to be relatively stable during short-term infection. Several types of genomic changes were observed in the paired strains of A. actinomycetemcomitans recovered from the same subjects, including a mutation in serotype-specific gene cluster that may allow the bacteria to evade host immune response.

SUBMITTER: Sun R

PROVIDER: S-EPMC3688926 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Genomic Stability of Aggregatibacter actinomycetemcomitans during Persistent Oral Infection in Human.

Sun Ruoxing R Kittichotirat Weerayuth W Wang Justin J Jan Minnie M Chen Weizhen W Asikainen Sirkka S Bumgarner Roger R Chen Casey C

PloS one 20130618 6

The genome of periodontal pathogen Aggregatibacter actinomycetemcomitans exhibits substantial variations in gene content among unrelated strains primarily due to the presence or absence of genomic islands. This study examined the genomic stability of A. actinomycetemcomitans during its persistent infection in the same host. Four pairs of A. actinomycetemcomitans strains, each pair isolated from an individual over time (0-10 years), were examined for their gains/losses of genes by whole genome se ...[more]

PMID: 23824402

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Project description:Aggregatibacter actinomycetemcomitans is a Gram-negative bacterial pathogen associated with severe periodontitis and nonoral diseases. Clinical isolates of A. actinomycetemcomitans display a rough (R) colony phenotype with strong adherent properties. Upon prolonged culturing, nonadherent strains with a smooth (S) colony phenotype emerge. To date, most virulence studies on A. actinomycetemcomitans have been performed with S strains of A. actinomycetemcomitans, whereas the virulence of clinical R isolates has received relatively little attention. Since the extracellular proteome is the main bacterial reservoir of virulence factors, the present study was aimed at a comparative analysis of this subproteome fraction for a collection of R isolates and derivative S strains, in order to link particular proteins to the virulence of A. actinomycetemcomitans with serotype b. To assess the bacterial virulence, we applied different infection models based on larvae of the greater wax moth Galleria mellonella, a human salivary gland-derived epithelial cell line, and freshly isolated neutrophils from healthy human volunteers. A total number of 351 extracellular A. actinomycetemcomitans proteins was identified by mass spectrometry, with the S strains consistently showing more extracellular proteins than their parental R isolates. A total of 50 known extracellular virulence factors was identified, of which 15 were expressed by all investigated bacteria. Importantly, the comparison of differences in exoproteome composition and virulence highlights critical roles of 10 extracellular proteins in the different infection models. Together, our findings provide novel clues for understanding the virulence of A. actinomycetemcomitans and for development of potential preventive or therapeutic avenues to neutralize this important oral pathogen. IMPORTANCE Periodontitis is one of the most common inflammatory diseases worldwide, causing high morbidity and decreasing the quality of life of millions of people. The bacterial pathogen Aggregatibacter actinomycetemcomitans is strongly associated with aggressive forms of periodontitis. Moreover, it has been implicated in serious nonoral infections, including endocarditis and brain abscesses. Therefore, it is important to investigate how A. actinomycetemcomitans can cause disease. In the present study, we applied a mass spectrometry approach to make an inventory of the virulence factors secreted by different clinical A. actinomycetemcomitans isolates and derivative strains that emerged upon culturing. We subsequently correlated the secreted virulence factors to the pathogenicity of the investigated bacteria in different infection models. The results show that a limited number of extracellular virulence factors of A. actinomycetemcomitans have central roles in pathogenesis, indicating that they could be druggable targets to prevent or treat oral disease.

Project description:Gram-negative facultative Aggregatibacter actinomycetemcomitans is an oral pathogen associated with periodontitis. The genetic heterogeneity among A. actinomycetemcomitans strains has been long recognized. This study provides a comprehensive genomic analysis of A. actinomycetemcomitans and the closely related nonpathogenic Aggregatibacter aphrophilus. Whole genome sequencing by Illumina MiSeq platform was performed for 31 A. actinomycetemcomitans and 2 A. aphrophilus strains. Sequence similarity analysis shows a total of 3,220 unique genes across the 2 species, where 1,550 are core genes present in all genomes and 1,670 are variable genes (accessory genes) missing in at least 1 genome. Phylogenetic analysis based on 397 concatenated core genes distinguished A. aphrophilus and A. actinomycetemcomitans. The latter was in turn divided into 5 clades: clade b (serotype b), clade c (serotype c), clade e/f (serotypes e and f), clade a/d (serotypes a and d), and clade e' (serotype e strains). Accessory genes accounted for 14.1% to 23.2% of the A. actinomycetemcomitans genomes, with a majority belonging to the category of poorly characterized by Cluster of Orthologous Groups classification. These accessory genes were often organized into genomic islands (n = 387) with base composition biases, suggesting their acquisitions via horizontal gene transfer. There was a greater degree of similarity in gene content and genomic islands among strains within clades than between clades. Strains of clade e' isolated from human were found to be missing the genomic island that carries genes encoding cytolethal distending toxins. Taken together, the results suggest a pattern of sequential divergence, starting from the separation of A. aphrophilus and A. actinomycetemcomitans through gain and loss of genes and ending with the divergence of the latter species into distinct clades and serotypes. With differing constellations of genes, the A. actinomycetemcomitans clades may have evolved distinct adaptation strategies to the human oral cavity.

Dataset Information

Genomic Stability of Aggregatibacter actinomycetemcomitans during Persistent Oral Infection in Human.

Publications

Genomic Stability of Aggregatibacter actinomycetemcomitans during Persistent Oral Infection in Human.

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