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Mobley HLT, Mendz GL, Hazell SL, editors. Helicobacter pylori: Physiology and Genetics. Washington (DC): ASM Press; 2001.

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Helicobacter pylori: Physiology and Genetics.

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Chapter 28Genetic Exchange

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Division of Gastroenterology, Vanderbilt University School of Medicine, 1161 21st Avenue South, C-2104 Medical Center North, Nashville, TN, 37232-2605

Horizontal gene transfer is defined as the acquisition and incorporation of genetic material from another organism. The first example of genetic exchange, transformation, was described in 1928 in Streptococcus pneumoniae (16). In 1944, DNA was identified as the "transforming principle" in experiments that were pivotal in understanding the nature of genetics and the genetic material (7). It has since become evident that such exchange events have occurred frequently during the evolution of microbes, resulting in tremendous genetic diversity. Indeed, some have suggested that horizontal gene transfer is the major contributing factor in the development of bacterial diversity (24, 47). That such transfer occurs is of clinical as well as practical interest since genes encoding virulence factors, antigenic determinants, and antibiotic resistance each can be acquired by organisms, resulting in altered pathogenicity (31, 41).

Helicobacter pylori exhibits remarkable genetic diversity as a species, as evidenced by variation of gene order among strains, differences in genetic content of strains, the mosaic nature of some genes, and sequence diversity within conserved genes (2, 3, 6, 13, 25, 29, 51, 53, 55). H. pylori has a recombinational, or panmictic, population structure, which is indicative of frequent genetic exchange among strains (1, 13, 40, 50). Additionally, there is evidence that exchange between H. pylori can occur in vivo during a naturally occurring mixed infection (26).

The availability of complete genomic sequences from two independent H. pylori isolates suggests that this organism may have incorporated genetic material from other organisms during the course of its existence. First, there are regions of the chromosome with a significantly different GC content than is otherwise typical for this bacterium, suggestive of DNA acquisition from unrelated sources (3, 53). Further, predicted H. pylori homologs such as RpoD, RpoA, and TyrA are significantly more similar to the respective proteins of gram-positive than gram-negative bacterial species (3, 48, 53). There are also putative restriction modification systems present that have strong homology to those of other organisms (3, 53, 58). Collectively, these data indicate that H. pylori has not only acquired DNA from within its own species, but also from completely unrelated organisms.

Horizontal gene exchange may occur via three classical mechanisms: natural transformation, conjugation, and transduction (Table 1). The aim of this chapter is to review what is known about each of these mechanisms of exchange in the context of H. pylori.

Table 1. Characteristics of mechanisms for genetic exchange.

Table 1

Characteristics of mechanisms for genetic exchange.

Transformation

The first example of bacterial transformation, when a rough, avirulent strain of S. pneumoniae was "transformed" into a smooth, virulent strain, was described over 70 years ago (16). It was later determined that this phenotypic change was due to the transfer of free DNA from a heat-killed, smooth strain to the live, rough strain (7). Currently, transformation is defined as the mechanism by which exogenous DNA is taken up by bacteria and the DNA becomes heritable. Naturally transformable (competent) bacteria, such as S. pneumoniae, Haemophilus influenzae, and H. pylori, can incorporate DNA from their environment without special in vitro treatment of the cells. Of the three basic mechanisms for DNA transfer, transformation has been the most well studied in H. pylori.

Approximately 75% of all H. pylori strains tested have been found to be competent for natural transformation by H. pylori chromosomal DNA (17, 36, 54, 57). However, reported frequencies of transformation vary greatly (10−8 to 10−3 transformants/μg of DNA/CFU for chromosomal DNA markers) depending upon the strain (5, 17, 22, 54). This wide variation in frequency is more closely related to the particular strain being transformed rather than the donor H. pylori strain from which the chromosomal DNA is derived (5, 22).

Most H. pylori strains are resistant to natural transformation by hybrid Escherichia coliH. pylori shuttle plasmids isolated from E. coli (5, 10, 57), although there are reports in which such transformants were obtained (19, 46). Similarly, transformation by plasmids derived from heterologous H. pylori strains occurs at a low frequency (5, 57). In contrast, H. pylori can be readily transformed by plasmid DNA derived from a homologous strain at frequencies similar to those for chromosomal markers, suggesting that transformation by plasmids from E. coli or heterologous H. pylori strains may be prevented by the activity of endogenous restriction endonucleases (5, 57). The disparity in transformation frequencies using chromosomal and shuttle plasmid DNA suggests that, although strong restriction barriers exist between strains of H. pylori, chromosomal markers can be rescued by efficient homologous recombination. Therefore, DNA restriction is less of a factor in transformation when the DNA from an unrelated strain of H. pylori is chromosomal as opposed to a plasmid (5, 10).

Transformation frequencies have also been found to vary according to the medium used, with BHI-YE agar (3.5% [vol/vol] brain-heart infusion agar, 0.2% yeast extract, 5% horse serum) resulting in the highest frequencies when compared with Mueller-Hinton and M9CA agar (57). Additionally, the time at which DNA is added also affects transformation frequencies. One report has indicated that the optimal time for DNA addition is 5 to 10 h after initial subculture (57), while another report indicated that transformation frequencies are highest when the DNA is added simultaneously with subculture (0 h) (22). Further, the maximum number of transformants per total colony-forming units was found to occur approximately 24 h after subculture, regardless of the timing of DNA addition (22).

From the sequences of strains 26695 and J99, several proteins may be predicted to be involved in transformation by homology to proteins in other naturally competent bacteria (Table 2) (3, 53). Thus far, few of these genes have been examined to determine whether they are required for transformation. The predicted product of open reading frame HP0333 of strain 26695 is a homolog of DprA, which is required for transformation in H. influenzae. Two independent studies have confirmed that HP0333 has a role in H. pylori transformation (4, 46). Disruption of this gene causes transformation frequencies by chromosomal and plasmid DNA to decrease by 85 to 99.9%, respectively, depending on the strain (4, 46). Similarly, HP0041/42 (comB3) encodes a homolog of TrbI from Agrobacterium tumefaciens and its disruption leads to decreases in chromosomal and plasmid transformation frequencies by 99 and 100%, respectively (20, 46). Another open reading frame, HP1006, is predicted to encode a product with homology to TraG of A. tumefaciens. In contrast to dprA and comB3, this gene is not required for wild-type levels of transformation in H. pylori. In A. tumefaciens, both TrbI and TraG have roles in conjugation, though their putative roles in H. pylori conjugation remain unknown (46). Further, although the cag island contains at least two genes with potential roles in transformation (HP0525 and HP0527), the frequency of transformation does not change even if the entire cag island is deleted (22). Whether other putative homologs have a role in transformation has yet to be determined.

Table 2. H. pylori predicted proteins with putative roles in transformation or conjugation.

Table 2

H. pylori predicted proteins with putative roles in transformation or conjugation.

Most gram-negative bacteria such as Neisseria and Haemophilus spp. require the presence of genus-specific sequences for DNA uptake (8, 9, 11, 14, 15, 44). These sequences are found at frequencies much higher than would be predicted if they were present randomly (12, 38, 52). Recently, computer analysis of the H. pylori genome sequences suggested that there are no similar sequences in the H. pylori genomes that exist at such high frequencies (42). This suggests that uptake sequences may not be present in H. pylori, though currently there are little biological data regarding this possibility. In one study, it was determined that transformation of H. pylori could be inhibited by the addition of chromosomal DNA from H. pylori or Helicobacter bilis, but not from E. coli, indicating some specificity for Helicobacter spp. DNA (22). However, another study found similar competition by DNA from H. pylori, Campylobacter jejuni, and E. coli (57). Due to differences in strains and methodology, it is difficult to reconcile these conflicting results. However, there is at least one known example of a gram-negative bacterium, Acinetobacter calcoaceticus, which does not require uptake sequences for transformation and can take up DNA from all sources tested (30, 37). Whether such sequences exist in H. pylori must be tested more directly by examining competition for the uptake step in vivo before definitive conclusions can be drawn.

Electroporation is a method of transformation that utilizes electric current to increase transformation frequency and has been used successfully to transform bacteria that are not naturally competent. Many investigators have used electroporation to attempt to increase the number of H. pylori transformants recovered, with varying success. In the case of transformation by chromosomal DNA, frequencies have been increased 2- to >1010-fold over natural transformation, depending on the study (45, 54). For transformation by autonomously replicating plasmids, if the source of the plasmid is a homolgous H. pylori strain, transformation frequencies are approximately 5 to 10 times greater than by natural transformation (4, 57). However, if the source of plasmid is heterologous, transformants may be recovered, but at very low frequencies, if at all (4, 57). From these data, the value of electroporation is difficult to determine, although it may be useful in some situations.

Conjugation

Conjugation is the mechanism of DNA transfer in which a donor bacterium comes in direct contact with a recipient cell, a pilus or pore is formed between two bacteria, and DNA is subsequently replicated and transferred to the recipient cell. This type of DNA transfer was first described in 1953 in E. coli by Lederberg and Tatum (28). In the classical E. coli paradigm, an F (fertility) plasmid mediates the transfer from an F+ bacterium to an F bacterium, resulting in two F+ bacteria. There has been one report of H. pyloriH. pylori conjugation in vitro (27). In this study, a chromosomal antibiotic resistance marker was transferred from one strain to another. In contrast to conjugation between E. coli cells, chromosomal DNA transfer was determined to be bidirectional for H. pylori (27). Transfer was DNase I-resistant and required cell-cell contact, which are hallmarks of the conjugative process. In the strains studied, plasmids did not appear to be required for such transfer. The biological significance of H. pylori conjugation may be great in that conjugation could provide a mechanism of direct cell-cell DNA exchange in which the DNA is protected from the acidic environment of the stomach where it would likely be unstable.

In another case, conjugation was used as a tool to deliver DNA to recipient H. pylori from donor E. coli (19). A shuttle vector was successfully moved into seven different H. pylori strains via conjugation and was maintained as a stable extrachromosomal element. Previous experiments demonstrated that some of these strains could not be transformed by either chromosomal markers or shuttle vectors, possibly due to restriction barriers (19). Other experiments have demonstrated that conjugation could also be used to generate allelic exchange mutants by the transfer of suicide plasmids (19). Therefore, conjugation may provide an important method for performing genetic manipulations in strains resistant to transformation. In Neisseria gonorrhoeae, in contrast to E. coli, DNA transferred by conjugation was not subject to restriction (49). On the basis of current data, this is likely to be the case for H. pylori, though it has not yet been rigorously demonstrated. If correct, the use of conjugation as a mechanism for DNA delivery may have the advantage of bypassing restriction barriers that could inhibit genetic exchange by natural transformation.

Transduction

First described in Salmonella enterica serovar Typhimurium by Zinder and Lederberg in 1952, transduction is the movement of DNA from one bacterium to another via bacteriophage (59). Bacteriophage, or phage, are infectious agents and consist of genetic material (DNA or RNA) enclosed in a protein capsid. Phage are parasites and are not capable of replication outside a bacterial host. To date, there have been few reports of bacteriophage existence in H. pylori (18, 35, 43). The first report was a side note to an unrelated study in which phage-like particles within H. pylori cells were detected by electron microscopy and were determined to be approximately 40 nm in diameter (35). In 1990, phage particles within H. pylori cells were seen again by electron microscopy with hexagonal phage heads approximately 50 nm in diameter, tails 170 nm in length, and a double-stranded genome of approximately 22,000 bp (18, 43). However, despite the observation of these phage, DNA transfer by transduction has yet to be demonstrated in H. pylori.

Barriers to Genetic Exchange

Several potential barriers exist to genetic exchange for H. pylori. The first is its environmental gastric niche. Although much DNA presumably traverses the stomach, the amount that may come into contact with resident H. pylori is unknown. After release from a donor, free DNA may be subject to physical shearing, digestion by nucleases, and acid hydrolysis. Further, since H. pylori is the major, persistent inhabitant of the stomach, release of DNA in close proximity to H. pylori or opportunities for exchange with other organisms via conjugation may be limited in this environment. The physical isolation of H. pylori suggests that the most likely sources of DNA for acquisition are other H. pylori that may be present.

Another barrier is genetic isolation, which can inhibit interspecies transfer on the basis of amount of sequence homology required for homologous recombination. In bacteria such as E. coli, S. pneumoniae, and Bacillus subtilis, it has been demonstrated that an increase in DNA sequence divergence results in an exponential decrease in recombination (3234, 56). Although there are little experimental data available in this regard for H. pylori, it has been noted that Helicobacter mustelae could not be transformed to streptomycin resistance (StrR) by DNA from a StrR H. pylori strain, nor could H. pylori be transformed by DNA from a StrR E. coli strain (21, 57). The extent to which sequence divergence is an obstacle for recombination in H. pylori is currently unknown.

Restriction endonucleases are quite likely to be the strongest barrier to the horizontal gene exchange via transformation for H. pylori. There are increasing data indicating that virtually every strain of H. pylori possesses a large and unique complement of restriction and modification enzymes (3, 5, 23, 39, 53, 58). As described above, this restriction barrier has little effect on the ability of H. pylori to be transformed by H. pylori chromosomal DNA from homologous or heterologous strains with a point mutation (5, 22, 57). In contrast, transformation by an autonomously replicating plasmid from a heterologous H. pylori donor is dramatically infrequent, presumably due to a strong restriction barrier (5). If there is no DNA uptake sequence requirement to prohibit transformation by DNA from unrelated sources, H. pylori might have acquired numerous restriction modification systems as an alternative mechanism to protect its genome from extensive adulteration.

Such restriction barriers may serve the organism well in its natural environment but also pose a formidable obstacle for researchers who wish to perform genetic manipulations in H. pylori. Although investigators have successfully created mutant strains and introduced shuttle vectors by natural transformation or electroporation, such work has often been limited by the strain in use. Recently, a method for overcoming this barrier was introduced (10). In this approach, the donor DNA is modified in vitro to "match" the modification pattern of the desired strain. For strains in which transformants were often impossible to obtain, this promises to be a valuable technique and important step in the development of genetic tools for the study of H. pylori.

Conclusion

Although the information regarding genetic exchange in H. pylori continues to expand, there remain many unanswered questions. There are little available data regarding transduction in H. pylori. If H. pylori phage exist, they could be important as genetic tools, as well as a potential typing method. Conjugation has been described in vitro, but whether it occurs in vivo is unknown. The mechanism by which H. pylori conjugation occurs is not known, but it appears to be somewhat different from that in E. coli. Although transformation has been studied, there is still much to discover regarding the mechanism and conditions that might favor or inhibit transformation. It is not known how DNA is bound, enters the cell, or is stabilized within the cell. Again, it seems that the mechanism of H. pylori transformation may not be the same as that of the classical gram-negative system. Further, the genes whose products may be predicted to play a role in conjugation or transformation have not yet been well studied, and nothing is known about the regulation of such genes. Finally, although there is one study that indicates gene transfer can occur in vivo based on strains isolated from a human subject, in vivo animal studies need to be performed to shed light on the significance of all three methods for genetic exchange in an environment that recapitulates human gastric mucosa. Ultimately, elucidating the mechanisms of genetic exchange in H. pylori will lead to a better understanding of the immense diversity that exists, as well as further development of genetic tools for the study of H. pylori.

Acknowledgments

The author thanks John Donahue, Mark Forsyth, and Richard Peek for valuable discussions and helpful review of this manuscript.

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