Insertion Sequences

Insertion sequences are autonomous genetic elements encoding only functions for their own mobility within genomes. They are detectable in all living organisms and play a significant role in genome organization. Comparison of S. aureus and S. epidermidis genomes revealed remarkable differences in the number and kind of IS elements. Thus, both S. epidermidis genomes contain 57 IS (some of them truncated or functionally inactive) distributed randomly throughout the chromosome, whereas S. aureus genomes contain on average only 10-17 copies of different IS. Since IS elements are supposed to play a role in genome flexibility and adaptation, this finding suggests that the two species might differ in this respect. It is tempting to speculate that S. epidermidis as a low-pathogenic, commensal bacterium depends much more on genome rearrangements to generate genetic diversity and to adapt to novel requirements than does S. aureus. Due to the large number of different virulence factors, S. aureus might have a priori much broader and better opportunities to cope with its host or a changing environment. The importance of virulence factors and genome flexibility for staphylococcal pathogenesis is highlighted by an ongoing genome sequencing project of the food-grade bacterium S. carnosus. This species contains neither virulence factors nor any insertion sequence or other repetitive DNA element, rendering the bacterium completely nonpathogenic (R. Rosenstein and F. Götz, personal communication).

Many of the known staphylococcal IS elements (e.g., IS1272, IS431, IS256, IS200 etc.) occur in S. aureus as well as in S. epidermidis, which is another clue about the possibility of lateral gene transfer and exchange between the two species. In the two S. epidermidis genomes a novel insertion sequence named ISSep1 was found which is not detectable in any of the sequenced S. aureus genomes [17]. ISSep1 is scattered throughout in multiple copies and at different insertion sites in the RP62A and ATCC 12228 genomes (Fig. 9.2). With 13 copies in RP62A (two of them degenerated) and 15 copies in the ATCC 12228 genome, ISsep1 represents the most abundant IS in S. epidermidis. However, currently no data are available on a possible occurrence ofthe element in other coagulase-negative staphylococcal species or the function of ISSep1 in the S. epidermidis chromosome.

Although S. epidermidis RP62A and ATCC 12228 do not vary in the number of IS, a difference with respect to the presence of IS256 can be observed. IS256 forms the ends of the composite transposon Tn4001 conferring aminoglycoside resistance on staphylococci and enterococci, but also occurs independently of the transposon in multiple copies on chromosomes or plasmids [120-122]. It was shown that, in contrast to commensal strains, the genomes of clinical S. epidermidis carry copies of IS256, whereas other typical staphylococcal insertion sequences such as IS257 and IS1272 are distributed equally among saprophytic and clinical isolates [105]. In accordance with this study, the RP62A genome was found to contain five IS256 elements: two transposon-associated and three independent copies. By contrast, no IS256 element was found in ATCC 12228. The IS256 element is involved in phase variation of biofilm expression by active transposition into the ica genes and participates in chromosomal rearrangements of the staphylococcal chromosome by homologous recombination [123, 124]. Obviously, the element is highly active and also interferes with antibiotic resistance expression. Thus, IS256 was found to influence teicoplanin resistance in S. aureus by insertional inactiva-tion of the tcaR regulatory gene [125]. Interestingly, IS256 also has a capacity to govern neighboring gene expression by internal promoter structures. Activation of resistance genes in the vicinity of IS256 has been shown for the aminoglycoside resistance genes in Tn4002 and methicillin resistance in S. aureus as well as in S.sciuri [121, 122, 126, 127].

The combined data imply that insertion sequences might play a significant role in the organization of the genome of pathogenic bacteria. On the one hand, multiple copies of IS in the genome force homologous recombination events and therefore contribute in turn to the flexibility and rearrangement of the genetic material. On the other hand, active transposition of IS contributes to heterogenous gene expression by mutation or activation of genes. The two processes together give rise to novel genotypic and phenotypic variants which are an advantage to the bacterium in adapting to changing external conditions or to moving into new ecological niches. The large number of IS in S. epidermidis may be a reflection of the extraordinary capacity of this species to deal with different environments and to assert itself as a commensal as well as a pathogenic bacterium in hospital settings.

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