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Phage Integrates into the ssrA Gene of Salmonella enterica Serovar Typhimurium A36 and Is Closely Related to the Fels-2 Prophage
Institute for Microbiology, D-BIOL, ETHZ, 8092 Zürich, Switzerland,1 Max von Pettenkofer Institute, 80336 Munich, Germany2
Received 7 April 2003/ Accepted 17 June 2003
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ABSTRACT |
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may represent an important mechanism in the adaptation of Salmonella spp. to specific hosts and to the emergence of new epidemic strains. Here, we have analyzed in more detail SopE, a P2-like phage from Salmonella enterica serovar Typhimurium DT204 that encodes the virulence factor SopE. We have cloned and characterized the attachment site (att) of SopE and found that its 47-bp core sequence overlaps the 3' terminus of the ssrA gene of serovar Typhimurium. Furthermore, we have demonstrated integration of SopE into the cloned attB site of serovar Typhimurium A36. Sequence analysis of the plasmid-borne prophage revealed that SopE is closely related to (60 to 100% identity over 80% of the genome) but clearly distinct from the Fels-2 prophage of serovar Typhimurium LT2 and from P2-like phages in the serovar Typhi CT18 genome. Our results demonstrate that there is considerable variation among the P2-like phages present in closely related Salmonella spp. |
INTRODUCTION |
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Work done in recent years has revealed that temperate phages, including the lambdoid GIFSY-1, -2, -3 phages and phages e, P22, Fels-1, and SopE, are important vehicles for horizontal gene transfer between different S. enterica strains (4). These phages encode extra gene cassettes (morons) that are not essential for the phage life cycle but enhance the proliferation of the prophage by improving the fitness and/or virulence of the lysogen. The moron-encoded functions include superoxide dismutases, enzymes for lipopolysaccharide modification, and toxins (effector proteins) that are injected by the bacteria into cells of the host animal by specialized type III secretion systems (17).
The P2-like phage SopE has been identified in serovar Typhimurium strain DT49/DT204, which caused an epidemic in the United Kingdom and the former East Germany during the 1970s and 1980s. In the tail fiber region of SopE, we had identified a moron encoding the type III effector protein SopE (27, 28). After injection into animal cells, SopE modulates host cellular signaling and leads to dramatic responses like membrane ruffling and invasion of host cells (12, 36). Disruption of the sopE gene reduces the invasiveness of the natural SopE lysogen serovar Typhimurium SL1344 (27, 33, 40). Also, lysogenic conversion of virulent serovar Typhimurium strain ATCC 14028 (normally SopE-) with SopE enhances its invasiveness in cultured cells (S. Mirold and W.-D. Hardt, unpublished data) and its enteropathogenesis in a bovine infection model (39). These observations indicate that lysogenic conversion by SopE has been an important step in the emergence of epidemic serovar Typhimurium strain DT49/DT204. For this reason, it was of interest to characterize the integration site (att) and the sequence of SopE in more detail.
Here we describe the identification of the attachment site of SopE. In addition, we have "captured" a plasmid-borne version of SopE by using a vector that harbors the bacterial attachment site (attB). This allowed purification of the prophage DNA, sequence analysis, and comparison of SopE with P2 and P2-like phages present in the genomes of serovar Typhimurium and serovar Typhi.
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MATERIALS AND METHODS |
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lysogen) and its isogenic derivative M106 (3351/78, a SopEsopE::aphT lysogen) have been described recently (28). M824 is a SopEsopE::aphT lysogen of A36.
Recombinant DNA techniques and sequencing.
pM36 has been described previously and harbors a 4.5-kb EcoRV/NcoI fragment of serovar Typhimurium M106 (3351/78, SopEsopE::aphT) comprising the right end of the SopEsopE::aphT prophage, attR, and the flanking bacterial sequences (28). This vector was used to sequence the attR region of the SopEsopE::aphT prophage.
pM47 harbors the attB core sequence of serovar Typhimurium A36. It was isolated via colony hybridization with the insert of pM36 as a probe from a library of 1- to 1.6-kb chromosomal EcoRI/EcoRV DNA fragments from serovar Typhimurium A36 cloned into the pBluescript SKII+ vector (Stratagene).
pM800 (Cmr) is a pACYC184 derivative harboring a 1.2-kb BamHI/HindIII fragment of pM47 that harbors the attB site.
pM802 (Cmr Kanr) was obtained by integration of SopEsopE::aphT into the attB site of pM800.
For Southern blot analysis, DNA was isolated (QIAamp DNA Mini Kit) and digested with endonucleases and the DNA fragments were resolved through 1% agarose gels. DNA was transferred to ZETA-Probe BT blotting membrane with a vacuum blotter (Bio-Rad Laboratories). Southern hybridization was performed overnight at 58°C. Fluorescein-modified probes and detection were prepared in accordance with the protocols of the manufacturer of the random prime labeling system, version II (Amersham Biosciences, Amersham, England).
The attB site of serovar Typhimurium A36 was amplified with primers 48F (5'-GATCGCTGGTCCGTTTCTTCT-3') and 36R (5'-CGGGGATCAAGAGAGGTCAAAC-3'). The attL site of SopE in M824 was amplified with primers attBF (5'-TCTGTGCTACGGGGCTTCGC-3') and 1R (5'-CATCCCCTTCAGCCAACGTC-5'), and the attR site was amplified with primers 36R and 36F (5'-CGGAAGCAAAACAGGGTGATTA-3'). The attP site of SopE was amplified with primers 2R (5'-GTTCTGCAGTTTGCTGGAGAGAGATGAATAGGC-3') and 36F. The initial denaturation step (94°C, 7 min) was followed by 35 cycles of denaturing, annealing, and extension and one final extension step. The annealing and extension temperatures were set according to the primers used (Metabion, Martinsried, Germany, and Microsynth GmbH, Balgach, Switzerland). PCR amplification products were subcloned into the 2.1-Topo vector (Invitrogen) in accordance with the manufacturer's protocol and sequenced with primers M13 and T7, which anneal inside the vector. All of the phage sequences described in the present report were retrieved from the database except for that of SopEsopE::aphT (this study). Shotgun-cloned fragments of the captured phage (pM802) were sequenced by AGOWA (Berlin, Germany). The sequence was assembled with the DNASTAR/Seqman 5.05 program (DNASTAR Inc., Madison, Wis.), and open reading frames (ORFs; start codons ATG and GTG) were predicted with the DNASTAR/GeneQuest 5.05 program. Assigned ORFs were compared to those in the database with the National Center for Biotechnology Information blastx program. To compare phage genomes, we aligned the deduced amino acid sequences by using blastx. The graphic representation of the alignments was prepared with PowerPoint XP software.
Lytic induction and propagation of phages.
Lysates of SopEsopE::aphT were produced as described recently (28). Briefly, overnight cultures of the lysogens M106 (3351/78, SopEsopE::aphT) were diluted 1:10 into fresh Luria-Bertani medium (LB; 1.5 ml) supplemented with 2 µg of mitomycin C (Sigma) per ml and grown for 6 h at 37°C. Lysates were processed by centrifugation (10,000 x g, 5 min, 4°C) and 0.45-µm-pore-size membrane filtration. Purification, determination of phage titers, and preparation of plate lysates on serovar Typhimurium A36 were performed in accordance with standard protocols for phage 
(31). Plate lysates typically had titers of about 107 PFU/ml. For the definition of the SopE-attP site, 7 ml of an overnight LB culture of strain M824 (carrying the phage integrated into the chromosome) was incubated with 2 µg of mitomycin C per ml. After 6 h of incubation, the cells were centrifuged. The pellet was resuspended in 200 µl of S1 (Qiagen protocol) buffer, and then 200 µl of S2 and S3 buffer was added. After centrifugation (10 min, 10,000 x g), the supernatant and 400 µl of isopropanol were centrifuged for an additional 30 min. Afterward, the pellet was washed (70% ethanol), dried, and resuspended in 140 µl of double-distilled H2O. Five microliters of this DNA preparation was used as the template for PCR amplification (50 µl) of the attP region.
Lysogenic conversion of bacterial strains.
Preparation of lysogens was performed as previously described (28). We incubated 106 PFU of SopEsopE::aphT for 15 min at 21°C with 4 x 107 bacteria (kanamycin sensitive) in a total volume of 100 µl of buffer. The mixture was plated on LB (50 µg of kanamycin per ml), and kanamycin-resistant clones were purified by streaking on selective agar plates.
Nucleotide sequence accession numbers.
The nucleotide sequences of pM36, pM47, and SopE have been deposited in the GenBank database and assigned the following accession numbers: pM36 (right terminal region of the SopE prophage), AY319520; pM47 (chromosomal region of serovar Typhimurium A36 harboring the SopE attachment site), AY316313; SopEsopE::aphT prophage, AY319521.
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RESULTS |
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We wanted to identify the attachment site of P2-like phage SopE. In previous work, the right end of the SopE prophage (pM36) from the natural lysogen serovar Typhimurium DT204 isolate 3351/78 had been subcloned (28). pM36 comprises the attR site of the SopE prophage, which is a hybrid attachment site with one part originating from the unoccupied attB site of the bacterial chromosome (Fig. 1). For this reason, the pM36 insert could be used as a probe to identify the attB site from serovar Typhimurium A36. A36 does not naturally harbor a SopE prophage but readily yields lysogens. A library of EcoRI/EcoRV-restricted chromosomal DNA fragments from serovar Typhimurium A36 was screened by colony hybridization, and a 1.3-kb DNA insert (pM47) harboring the attB region was retrieved (see Materials and Methods).
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from Vibrio cholerae, a filamentous phage encoding the Tcp adhesin (19). This suggested that the subcloned A36 fragment did indeed represent the attB site for SopE. Furthermore, the similarity to CP4-57 from E. coli (Fig. 2) suggested that this attB site is the remnant of a P4-like prophage.
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sopE-aphT into the plasmid-borne attB site of serovar Typhimurium A36.
In the next step, it was necessary to analyze whether the cloned serovar Typhimurium A36 fragment of pM47 can function as the attB site for SopE. For this purpose, the insert of pM47 was subcloned into pACYC184 and the resulting plasmid, pM800 (Cmr; see Materials and Methods), was transferred into serovar Typhimurium A36 (originally Cms Kms). We infected 107 CFU of serovar Typhimurium A36 (pM800) with SopEsopE::aphT (107 PFU/ml) and selected lysogens by plating on LB agar plates supplemented with kanamycin (50 µg/ml) and chloramphenicol (20 µg/ml). Plasmid (pM802) DNA was isolated from three independent clones (A, B, and C) and analyzed by agarose gel electrophoresis. All three pM802 clones had the same restriction pattern (data not shown) and were significantly larger than pM800, which suggested that SopEsopE::aphT had integrated into the attB site of pM800 (Fig. 3A).
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sopE::aphT prophage, Southern blot analysis was performed. Chromosomal DNA of strain M106 (the original SopEsopE::aphT lysogen) (28) and plasmid pM802A were digested with the enzymes EcoRV (Fig. 4, lanes 1 and 3) and HindIII. (Fig. 4, lanes 2 and 4). Hybridization was performed with the entire pM802A plasmid as a probe. The results shown in Fig. 4 confirm that pM802 harbors the SopEsopE::aphT prophage. Extra bands (e.g., >10 kb in lanes 2 and 4) are thought to represent the left and right junctions between the prophage and the chromosome (lane 2) or the plasmid (lane 4).
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sopE::aphT.
Next, we defined the core sequence of the SopE attachment site. Sequence alignment of the inserts of pM36 (attR region of the SopE prophage in serovar Typhimurium DT204 3351/78) and pM47 (attB region from serovar Typhimurium A36) suggested that the "right" end of the att core sequence maps to the 3' nucleotides of the ssrA gene. To identify the left att core sequence, we have determined the nucleotide sequence of the attL region from the SopE prophage present in pM802. The primer used for this purpose, attBF (Fig. 1 and 3B), was designed on the basis of the sequenced attB region present in pM36.
Alignment of the sequence obtained (the putative attL region) with the attB and attR region sequences indicated that the conserved core sequence of the SopE attachment site is 47 bp long and overlaps 45 nt of the ssrA 3' terminus (Fig. 5). This is in line with results of the sequence comparison of the integration sites of SopE-like prophages (35). Because of the duplication of these nucleotides during the integration process, the presence of SopE at this position is not expected to disrupt the function of the ssrA gene. On the basis of these sequences, the attP region of the circular, replicative SopE form could be predicted (Fig. 5).
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sopE::aphT lysogen (M824; see Materials and Methods) were performed. All PCR products were analyzed by agarose gel electrophoresis, cloning into the 2.1-Topo vector, and sequencing (Fig. 6 and data not shown). The PCR product corresponding to the attB sequence could be detected in the wild-type serovar Typhimurium A36 strain (Fig. 6, lane 4) but not in its lysogen (Fig. 6, lane 3). Conversely, the PCR products corresponding to the attL and attR regions could only be detected in the lysogen M824 (Fig. 6, lanes 5 and 7) but not in the parental strain (serovar Typhimurium A36; Fig. 6, lanes 6 and 8).
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sopE::aphT, the attB region of serovar Typhimurium A36, and the attL/attR regions for the SopEsopE::aphT prophage were assigned correctly as depicted in Fig. 5.
SopEsopE::aphT att sequences in the published S. enterica genomes.
Database searches revealed that two copies of the 47-bp SopE att core sequence are present in both completely sequenced S. enterica genomes (serovar Typhimurium strain LT2 and serovar Typhi strain CT18; Fig. 7A to D).
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g) and is located at the right end of a P2-like prophage that is inserted into the samAB operon (Fig. 7C). This 47-nt sequence is part of a truncated ssrA gene, and the left end of the prophage bore an 8-nt fragment of the 47-nt sequence. This suggested that the attL site of the cs 93 prophage had been destroyed. This may be ascribed to illegitimate recombination that occurred during the insertion into the 3' end of samA.
The cs 57 region of serovar Typhi CT18, which harbors the second 47-bp sequence, is remarkably similar to the attR region of the SopEsopE::aphT prophage in M824. It overlaps the 3' terminus of the ssrA gene and is located at the right end of the ca. 9-kb tail fragment of a P2-like prophage. No significant match for the attL site could be found in the cs 57 region of the serovar Typhi CT18 genome (Fig. 7D).
In serovar Typhimurium LT2, both copies of the 47-bp att core-like sequence are located 33.7 kb apart from each other in the cs 59 region of the chromosome (Fig. 7B). They represent the attL and attR sites of the P2-like prophage Fels-2. Interestingly, there are even more similarities between both prophages. (i) The chromosomal regions flanking the attR and attL core sequences are 98 to 100% identical between the SopEsopE::aphT prophage in pM802 and M824 and the Fels-2 prophage from serovar Typhimurium LT2 (Fig. 8). (ii) The right end of the SopE prophage directly adjacent to the att core sequence is 98% identical between the two prophages (Fig. 8). However, there are also differences between the two prophages: Fels-2 does not carry the sopE gene cassette of SopE, and the sequences at the left end of both prophages (phage part of attL) are entirely different (Fig. 8). Nevertheless, SopE and Fels-2 are clearly similar. This mosaic of similarity and clear differences prompted us to sequence SopEsopE::aphT and to compare the two phages in more detail.
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sopE::aphT.
As the titers of SopE lysates were generally too low (106 to 107 PFU/ml) for isolation of an amount of DNA sufficient for sequence analysis, the plasmid-borne SopEsopE::aphT prophage (pM802) was used to purify phage DNA. The DNA sequence of pM802 was determined as described in Materials and Methods. The sequence of wild-type SopE was deduced by replacing the inserted aphT cassette with the original sequence of the sopE region from serovar Typhimurium SL1344 (accession no. AF043239). We found that the SopE prophage was 36 kb in size and encoded 45 ORFs (Fig. 9; Table 1). In line with our earlier observations (14, 28), the phage is similar to the P2 phage in sequence (i.e., 40 to 67% amino acid identity in the tail fiber region) and genome organization (Fig. 9A). The similarity to P2-like prophage Fels-2 is even more striking. The two phages have 68 to 100% sequence identity over large parts of the genome (Fig. 9A). This also pertains to the orf1 to -8 region of SopE, which is similar to Fels-2 but not to P2 (Fig. 9A). Nevertheless, three regions of SopE are clearly different from Fels-2.
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prophage (Fig. 9A). It had limited similarity (27% identical on the amino acid level) to a gene of unknown function (yopC) from the Bacillus subtilis phage SPBc2. orfY was located between the integrase gene int and the attL site. In Fels-2 and P2, int is located directly adjacent to the att sites.
(ii) orf12 to -15, which probably represent the immunity region of SopE, show no similarity to Fels-2 and P2. At the equivalent position, P2 carries the tin and old genes, which block the growth of T-even and lambda phages. However, orf12 to -15 are similar to ORFs from Methanothermobacter wolfeii phages (29 and 39% identical on the amino acid level) and ORFs from Pyrococcus furiosus (gene 14; 22%) and Microbulbifer degradans (gene 15; 34%). Additional work is required to determine the function (i.e., phage exclusion, serovar Typhimurium pathogenesis) of orf12 to -15 of SopE.
(iii) As described earlier, the sopE gene is located in the tail fiber region of SopE at a hot spot for the insertion of additional gene cassettes (14, 17). In Fels-2 and P2, this position is occupied by orfSTM2703 and Z/fun (Fig. 9A).
In conclusion, these observations demonstrate that SopE from serovar Typhimurium DT204 is a close relative of but clearly distinct from the Fels-2 phage of serovar Typhimurium LT2.
Serovar Typhi CT18 prophages related to SopE.
In the serovar Typhi CT18 genome, we detected two prophages and one phage remnant with similarity to SopE (Fig. 9B). Of these, the cs 93 prophage was most similar to SopE. Most ORFs displayed 80 to 100% sequence identity (Fig. 9B). Moreover, the sopE moron was present and located at the same position in both phages. However, no similarity to the orf10 to -15 region of SopE was detected and the cs 93 phage lacked a gene with similarity to orfY between the attL site and int (Fig. 9B). As discussed above, this phage may be defective in excision from the chromosome (Fig. 7).
The cs 73 prophage displayed extensive but somewhat less sequence similarity to SopE (60 to 90% identity; Fig. 9B). It lacks genes similar to the orf11 to -15 region and to orfY of SopE and carries the ORFs (STY3693 and STY3694) in place of the sopE moron. The cs 73 prophage is integrated into the yifB gene, and we did not detect sequences with similarity to the att core sequences of SopE at either end of the prophage.
At cs 57, serovar Typhi CT18 carries a phage remnant similar to the tail region of SopE (Fig. 9B). As discussed above, the right end of this phage remnant harbors the 47-nt SopE att core sequence. However, in contrast to SopE, it harbors two additional ORFs between the orf42/ogr homolog and the 47-nt SopE att core sequence (Fig. 9B).
These data show that the sequence and genomic organization of SopE are similar but not identical to those of prophages and phage remnants present in serovar Typhi CT18.
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DISCUSSION |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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in more detail. This P2-like phage was isolated from an epidemic serovar Typhimurium strain and carries a moron encoding the virulence factor SopE (27, 28). Here, we have characterized the attachment site of SopE in the serovar Typhimurium chromosome, determined the sequence of the SopE prophage, and compared it to other P2-like phages form serovars Typhimurium and Typhi.
We have mapped the attachment site attB for SopE to the 3' terminus of ssrA (Fig. 7), which encodes the small stable tmRNA integration of SopE. The ssrA sequence is not disrupted by the integration of SopE. This may be important, since earlier work has shown that deletions in the ssrA region attenuate Salmonella virulence (18). Indeed, it has been reported that the virulence of a serovar Typhimurium ATCC 14028 SopEsopE::aphT lysogen is not attenuated in the bovine infection model (39). ssrA also serves as an integration site for several other phages, including VPI, a filamentous phage from V. cholerae that encodes the Tcp adhesin (19), and the P4-like cryptic prophage CP4-57 from E. coli (22). Moreover, ssrA has been identified as a hot spot of integration for various genetic elements. Among enterobacteria, at least four different integrase subfamilies mediate integration into the ssrA locus (35).
This lends further support to the notion that ssrA serves (very much like tRNA genes) as an integration site for pathogenicity islands and phages (7, 11, 35).
Interestingly, the chromosomal region of serovar Typhimurium A36 that harbors the SopE attachment site is similar to the P4-like cryptic prophage from E. coli (Fig. 2) (22). In both cases, a P4-like integrase is located downstream of the ssrA gene. This indicates that SopE may actually use the remnant of a P4-like cryptic prophage as an attachment site in the serovar Typhimurium A36 chromosome.
SopE had been isolated from epidemic serovar Typhimurium strain DT204 (28). The present work revealed that it is highly similar to the P2-like Fels-2 prophage from serovar Typhimurium LT2. The structural genes, the ori regions, and the integrases of both phages are 75 to 100% identical at the amino acid level, and the two phages seem to occupy the same chromosomal attachment sites (Fig. 7 and 9A). Nevertheless, the Fels-2 prophage encodes STM2703 in place of the sopE moron, the genes in the immunity region are different from those of SopE, and Fels-2 does not harbor an orfY-like gene at the attL site (Fig. 9A). This shows that SopE is a close relative of Fels-2 and indicates that the P2-like phages are diverse even between closely related S. enterica strains.
In the serovar Typhi CT18 genome, there are two prophages and one phage remnant with similarity to the P2 family. In line with the current "modular" model of phage evolution (3, 5, 6, 17, 32), different blocks of genes show different degrees of sequence similarity to SopE. Nevertheless, the majority of ORFs of SopE and the P2-like elements in serovar Typhi CT18 are 60 to 90% identical at the protein level (Fig. 9B). Again, the differences include the immunity region (orf10 to -15 of SopE) and the absence of orfY at the attL region. The sopE moron is absent from the cs 73 prophage and the phage remnant at cs 57. In contrast, the tail region of the cs 93 prophage harbors the sopE moron and is up to 99% identical on the amino acid level to the equivalent region of SopE (Fig. 9B). Taken together, these observations show that SopE is distinct from but closely related to the cs 93 phage from serovar Typhi.
It remains unclear whether the two phages have diverged from a single sopE-positive ancestor. Alternatively, the high sequence similarity in the tail fiber regions including the sopE moron suggests that this region was recently transferred en bloc between or into both phages and prophages.
Are the P2-like prophages at cs 93 and 73 of serovar Typhi functional? The cs 93 prophage is inserted into the samAB UV repair operon (Fig. 7). Its attL and attR sites seem to be disrupted and show signs of illegitimate recombination. This suggests that this prophage has lost the ability to excise. Alternatively, the 8-bp repeat of the samA sequence found at the two ends of the cs 93 prophage may present a secondary attachment site for this phage (35). It remains to be determined whether the "defective" att sequences prohibit excision from the chromosome or not.
It is interesting to speculate whether the disruption of prophage attachment sites may serve the stabilization of favorable phage-encoded genes in the bacterial chromosome or the avoidance of lytic induction.
In conclusion, our data show that SopE is highly similar but not identical to several P2-like prophages from Salmonella spp. There are even clear differences between SopE and the cs 93 prophage from serovar Typhi CT18, which both carry the sopE moron. Earlier work on sopE+ Salmonella spp. has provided evidence for the transfer of the sopE moron between a chromosomal site and the tail fiber regions of - and P2-like phages (27). The data presented here show that there is a diverse population of P2-like phages even in closely related Salmonella strains and suggest that the sopE moron has been transferred between different P2-like phages. The transfer of functional phage modules between chromosomal sites and phages, their transfer between different phage families, and their transfer between different members of the same phage family are well documented (17). However, to our knowledge, the Salmonella sopE moron provides the first example of a bacterial virulence factor being transferred to a similar extent as functional phage modules. Several other virulence factors also have a diverse distribution between different Salmonella strains, and some are carried by prophages (4, 10, 24). Evidence is accumulating that some of these virulence factors have also been transferred between chromosomal sites and phages (9, 10). It is tempting to speculate that the shuffling of virulence factors between different phages may enhance the exchange of virulence factors between different Salmonella spp. and play a role in adaptation to new animal hosts and the emergence of new epidemic strains.
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ACKNOWLEDGMENTS |
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This work was funded by a grant from the Kompetenznetzwerk "Genomforschung an pathogenen Bakterien"—Verbund 3 to W.-D. Hardt.
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FOOTNOTES |
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CTX, of Pseudomonas aeruginosa: structure of the attP-cos-ctx region and integration into the serine tRNA gene. Mol. Microbiol. 7:657-667.[CrossRef][Medline]
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