[Frontiers in Bioscience 14, 1661-1683, January 1, 2009]
Bacteriophages of Lactobacillus
Manuela Villion1,2, Sylvain Moineau1,2,3
1Departement de biochimie et de microbiologie, Faculte des sciences et de genie, 2Groupe de recherche en ecologie buccale, Faculte de medecine dentaire, 3 Felix d'Herelle Reference Center for Bacterial Viruses, Universite Laval, Quebec City, Quebec, Canada, G1V 0A6
TABLE OF CONTENTS
1. ABSTRACT
In this review, we are listing Lactobacillus phages that have been reported in peer-reviewed articles published since 1960. Putative phages that are defective or have not been shown to be infectious, such as phage-like particles, are not discussed. Our literature searches led to the identification of 231 Lactobacillus phages, 186 of which have been observed by electron microscopy, with 109 belonging to the Siphoviridae family, 76 to the Myoviridae family, and 1 to the Podoviridae family. Model phages infecting Lb delbrueckii, casei, rhamnosus, plantarum, and gasseri are highlighted, as well as prophages of Lactobacillus hosts. To date, nine complete Lactobacillus phage genomes are available for comparisons and evolution studies. Features such as phage receptors and endolysins are also reviewed, as well as phage-derived genetic tools. Lactobacillus phage research has progressed significantly over the past decade but a thorough understanding of their biology is still lacking. Because of the risks they represent and the knowledge gaps that need to be filled, the outlook for research on Lactobacillus phages is bright.
2. INTRODUCTION
Humans began consuming fermented dairy products in the Middle East at about the same time they began domesticating animals. Approximately ten years after the first bacteria was isolated (1878), defined starter cultures were already developed (1). Metchnikoff's studies on the diets of Bulgarian peasants later led to the probiotic hypothesis which fueled research on Lactobacillus (2). Factories manufacturing fermented milk products soon started to flourish, as did research on lactic acid bacteria. However, despite this, dairy plants had, and still have, to deal with the deadly enemy of lactic acid bacteria, namely virulent bacteriophages.
2.1. Lactobacillus species
Metchnikoff was one of the first researchers to be convinced of the health benefits of consuming yogurt on a regular basis. One hundred years later, it is becoming increasingly clear that lactic acid bacteria (LAB) have some beneficial effects (3). The genus Lactobacillus includes 106 validly described species (4). Perhaps because of their origins, people tend to associate Lactobacillus species with the dairy industry. However, Lactobacillus species are used in many other fermentation processes (5). For example, Lb. fermentum is used in sourdough (wheat and rye breads) and soy fermentation processes (6, 7) as well as in traditional sorghum beer by fermenting dolo and pito wort (8), and is a member of the microbial population in fermenting cocoa beans (9), caper berries (10), and cassava (11-14). Lactobacillus strains are also found in vegetable and meat fermentations as well as in sewage water and drains. Last, but not least, Lactobacilli can be found in human microbiota, including that of the vagina (5, 15).
2.2. Lactobacillus phages
One of the main problems encountered in food fermentations is the ubiquitous presence of virulent bacteriophages, which can alter the quality of fermented products or delay manufacturing processes. Even though a plethora of phage control measures have been introduced since the discovery of bacteriophages as the major cause of fermentation failures (16), phages remain a high risk for the dairy industry (17). Since the first Lactobacillus phage was isolated from New York City sewage water (18), other phages have been characterized from different species. In 1981, Sozzi et al. published the first review on Lactobacillus phages, which was limited to morphological information (19). A few years later, Sechaud et al. (20) published a review with additional information on genetic and growth characteristics, which was quickly followed by a general review of lactic acid bacteria phages (21). More recently, one book chapter highlighted phages released from vaginal Lactobacillus (22) and a second one insisted on the genomic aspects of Lactobacillus phages (23). The major aim of this review was to retrieve most of the peer-reviewed papers on Lactobacillus phages that were published mainly in English since 1960.
3. Lactobacillus phage overview
3.1. Habitats
Because of the risk that represents phage infections to dairy fermentation processes, many Lactobacillus phages have been isolated from milk products. However, for unknown reasons, Lactobacillus phage infections remains relatively low as compared to those affecting lactococci and Streptococcus thermophilus (23). Nevertheless, the isolation of Lb. delbrueckii subsp. bulgaricus phages from yogurt has been repeatedly documented (24-33), as well as phages infecting Lb. helveticus from various dairy factories (25, 34). Lb. acidophilus phages have been found in yogurts and acidophilus milks in the United States (35), Phages infecting Lb. plantarum were also found in dairy products, but also in fermented vegetables and meats, and plant materials such as silage (36-39). Lb. fermentum phages have been found in wheat bread sourdough, cheese whey, wheat meal (7), and Chinese yogurt (40), while Lb. sanfranciscensis phages were isolated from sourdough (41).
Lactobacilli are also part of the bacterial biota of the vagina (42) and likely play a beneficial role in vaginal health. In fact, phage infections may be involved in creating an ecological imbalance by decreasing the number of Lactobacillus cells in bacterial vaginosis, followed by "an increase in the number of anaerobic Gram-negative rods" (15, 22). In addition, chemicals such as activated form of benzo(alpha)pyrene found in cigarettes smoke, may induce the release of prophages from Lactobacillus spp. in the vagina (43).
Indeed, lysogeny is relatively frequent in Lactobacillus strains (44). The first report of lysogeny involved two strains of Lb. fermentum (45). Following this pioneering study, a larger study on 148 Lactobacillus strains (15 species) revealed that 27% of them released phages following exposure to mitomycin C (46). Phage-like particles have also been found in Lb. helveticus, Lb. casei, Lb. plantarum, Lb. brevis, Lb. buchneri, Lb. fermentum, and Lb. acidophilus. The various sources of Lactobacillus phages are reported in Tables 1 to 3.
3.2. Morphology of Lactobacillus phages
Because of early advances in staining methods for electron microscopy (47), most Lactobacillus phages were first characterized at the morphological level. To date, all of them possess an isomeric capsid and a tail, and thus belong to the Caudovirales order. In 2007, Ackermann reported that 190 Lactobacillus phages have been observed with an electron microscope, including 120 from the Siphoviridae family (long noncontractile tail) and 70 from the Myoviridae family (contractile tail) (48). Our own searches retrieved 231 Lactobacillus phages, 186 of which have been observed with an electron microscopy, with 109 belonging to the Siphoviridae family, 76 to the Myoviridae family, and only 1 to the Podoviridae family (Tables 1 and 2). Of note, the phages listed in this review were shown to inhibit the growth of a least one Lactobacillus strain. Putative phages that are defective or have not been shown to be infectious, such as phage-like particles, are not listed.
3.2.1. Myoviridae family
The first Lactobacillus myophages were isolated in 1965 and they infected strains of the fermentum species (49). Two more Lb. fermentum phages with a contractile tail have since been isolated, while the others belong to the Siphoviridae family (7, 50, 51). Phages with contractile tails that infect Lb. casei, Lb. brevis, and Lb. crispatus strains have also been observed, but have not been as extensively studied as Lb. plantarum myophages LP65 and fri. Interestingly, to our knowledge, all reported Lb. helveticus phages belong to the Myoviridae family (Table 1) (25, 34, 52), with the possible exception of an inducible but defective Siphoviridae phage (phi lh60) (53).
Overall, the tails of Lactobacillus myophages range from about 120 to 272 nm (Table 1). A neck is also a common feature of all Lactobacillus myophages, while baseplates or double baseplates are found in phages infecting Lb. plantarum strains, but are barely seen or not reported in others (data not shown). The icosahedral capsids of these Lactobacillus myophages range in diameter from 50 to 115 nm (Table 1), likely reflecting the difference in the size of their genomes.
3.2.2. Siphoviridae family
Almost 60% of the known Lactobacillus phages belong to the Siphoviridae family (48). They have an icosahedral capsid (B1 morphotype) of 40 to 76 nm in diameter (Table 2) and a tail of 116 to 500 nm in length. A few of them have a prolate head (morphotype B2) of 120 to 150 nm long by 40 to 50 nm wide (Table 2). The prolate phages described to date infect Lb. delbrueckii subsp. lactis (phages JCL1032, 0235) and Lb. acidophilus (phi y8), Lb. fermentum (064 and 0209) and Lb. salivarius (phi223). Interestingly, with one exception, all the Lb. delbrueckii phages described to date belong to the Siphoviridae family. Lb. plantarum siphophage B2 has the longest tail (500 nm) and the largest isometric capsid (110 nm in diameter) of any Lactobacillus phage isolated to date (54, 55). Lb. gasseri phage phiadh also has a long tail (about 400-460 nm in length (56, 57)), while Lb. sake phage PWH2 has a 81-nm diameter capsid (58). Lb. fermentum phages isolated from Chinese yogurt have the smallest capsid, surprisingly reported at 40 nm in diameter (40). Other morphological characteristics such as the presence or absence of a collar and a baseplate have not always been reported in the literature for Lactobacillus siphophages and are thus not discussed in the present review.
4. LACTOBACILLUS PHAGE MODELS
In the following sections, we will summarize the most relevant characteristics of the best-characterized phages that infect industrially relevant Lactobacillus species.
4.1. Lactobacillus delbrueckii phages
4.1.1. LL-H and others
Lactobacillus delbrueckii phages have been widely studied by the group of Alatossava in Finland. The siphophage LL-H, which infects subsp. lactis strains, has become one of the few Lactobacillus phages model. Two reviews on this phage have already been published (59, 60).
The Valio Finnish Co-operative Dairies Association isolated this virulent phage in 1972 at a local dairy. It has a 47 � 2 nm-diameter capsid and a 171 to 180-nm-long non-contractile tail (Table 2). The tail has approximately 45 cross-striations and a double-disk baseplate at the distal end. A 30-nm-long fiber appears to be attached to the lower baseplate structure (61-63). Like several other dairy phages, the lytic cycle of phage LL-H depends on the availability of divalent cations (Ca2+ and Mg2+) (64, 65). The genome of LL-H was the first Lactobacillus phage genome to be fully sequenced (66-68). It contains 34,659-bp with a G+C content of 47.8% (68). The revised NCBI sequence now points to 51 orfs on one strand and three on the other. The genome is organized into four general modules (DNA packaging, morphogenesis, cell lysis and DNA replication (Figure 1). Genes encoding for proteins with related putative functions are grouped together on the genome and are expressed on the same transcripts. Temporal gene expression analysis has revealed an early phase of approximately 20 min during which DNA replication is triggered. This early gene expression is followed by a late phase 30-40 min post-infection, which leads to transcription of genes encoding for phage structural components and cell lysis (68). The genome of LL-H is packaged (in a headful mechanism, pac-type) from a concatemer that can fill as many as six capsids (69).
Interestingly, the remnants of an integrase gene and an attP site have been found on the LL-H genome (70), which suggest that this virulent phage was derived from a temperate phage (59, 68). In support of this hypothesis, several homologous genes were found in the genome of Lb. delbrueckii subsp. bulgaricus temperate phage mv4 (66). This latter phage, also called 0448 (26), was one of the first prophages described for this Lactobacillus species (26, 28). Phage mv4 can also infect and integrate its genome into the chromosome of Lb. delbrueckii subsp. lactis LKT (30), a strain sensitive to virulent phage LL-H. Beside phages LL-H and the pac-type mv4, other Lactobacillus delbrueckii phages belong to the same DNA homology group (named "a", see Section 7) such as virulent phages LL-K and LL-S (previously called lv (25), or LL55 (71)), as well as the temperate phage lb539 (31). Phage lb539 was isolated with the host strain Lb. delbrueckii subsp. bulgaricus CRL539 but it can also infect Lb. lactis LKT (72).
Lb. delbrueckii phage JCL1032 is also reasonably well characterized, but, to our knowledge its complete genomic sequence is not yet available. Unlike LL-H, this Siphoviridae phage has a prolate capsid and packages its DNA via a cos site (73). It has been recently shown that JCL1032 can integrate its genome into two different sites in the chromosome of Lb. delbrueckii subsp. lactis ATCC 15808 (also a host strain for virulent phages LL-H and mv4), even though at low efficiency (73). JCL1032 is thus now considered a temperate phage. Interestingly, short genomic regions of JCL1032 are homologous to sequences found in the genomes of phages LL-K, mv4, and lb539 (73), but not in LL-H or LL-S (74). These observations reinforced the hypothesis that these phages share a common ancestor.
Many lactic acid bacteria phages have become models to study various aspects of phage biology. Lactobacillus phages are no exception. The first group I intron in a siphophage was found in the genome of phage LL-H (75). The intron (ORF168, Figure 1) is located in the terL gene that encodes the large terminase subunit (75) and contains an active endonuclease for self-splicing activity. Two similar introns have also been identified in phage JCL1032, one in the terL gene and the other in the gene encoding the putative tape measure protein (TMP). In JCL1032, both introns belong to the IA1 group, but they do not contain an endonuclease (76). The exact role of these introns in the phage replication cycle remains unclear.
4.2. Lactobacillus casei phages
The first phage infecting an Lb. casei (or paracasei) strain was isolated in Japan in 1965. Phage J-1 caused an abnormal fermentation of the Yakult beverage (fermented from skim milk) (77). Interestingly, the host strain was originally isolated from human feces ("Shirota" strain). Phage PL-1, which infects the same strain, was isolated two years later (78). Both siphophages have a long non-contractile tail ( about 290 nm in length for J-1 and about 265 to 280 nm for PL-1) and an icosahedral head (about 55 nm in diameter). PL-1 also has a fiber extending from the distal end of the baseplate.
4.2.1. A2
Phage A2 was isolated in Spain from a whey sample of a failed "Gamonedo" ("Gamoneu" in the Asturiaz dialect), a home-made blue cheese produced using Lb. casei 393 (79). The genome of this temperate phage of the Siphoviridae family can integrate into the genome of Lb. casei ATCC 27092 and is also spontaneously released from Lb. casei ATCC 393 (79). Its 42,411-bp genome has a G+C content of 44.8%, 61 orfs and cohesive ends (Table 4) (80, 81). Fifty-five orfs are oriented in one direction while six are transcribed in the opposite direction (80, 81) (Figure 1). Similar to other phage genomes with cohesive ends, phage A2 is organized in several modules that include in order packaging, head morphogenesis, head-tail joining, tail morphogenesis, lysis, integration, genetic switch region, and replication modules (82).
In the early-transcribed region, two promoters have been identified. While the promoter PL directs the expression of gene cI (lytic cycle repressor), PR mediates lytic functions and the transcription of the cro lysogenic repressor gene (82-84). The attP site is located between the lysis and lysogenic modules, close to orf20, which codes for the integrase (85). An interesting feature of this phage is the presence of two -1 frameshifts that are leading to the production of the major capsid and tail proteins (gp5 and gp10, respectively) as well as larger versions of these two proteins. The resulting four proteins were shown to be present in the virion structure (86, 87). Moreover, both forms of gp5 are essential for the phage progeny (86). Finally, on a global scale, the genomic comparisons showed similarities between A2 and S. thermophilus phage Sfi-21 and Staphylococcus aureus phage PVL (80), while its replication module shares homology with the corresponding module of Lb. gasseri phage phiadh (81) (Figure 1).
4.2.2. phiAT3
The complete genome sequence of Lb. casei temperate phage phiAT3, another cos-type siphophage, was reported in 2005 (88). The genome has 53 orfs and is organized into five functional clusters (DNA packaging, morphogenesis, lysis, lysogenic/lytic switch, and replication). The genes coding for the integrase, excisionase, and cI repressor are encoded on the complementary strand (Figure 1). A comparative analysis revealed that phiAT3 shares homology with Lb. casei phage A2, particularly in the replication region. As with phage A2, the attP locus of phage phiAT3 is located close to the 3' end of the integrase gene (88). However, the attB site of phage phiAT3 is located at the 3'end of the tRNAArg gene locus in Lb. casei ATCC393 (85), while the A2 integration site is in the tRNALeu gene locus. A distinctive feature of phiAT3 is the presence of an IS element (ISLC3) in a gene that encodes a putative structural protein (ORF14).
4.3. Lactobacillus rhamnosus phage Lc-Nu
Virulent phage Lc-Nu, a member of the Siphoviridae family, was isolated from a whey sample coming from a Finnish cheese plant (89) and can also infect an industrial probiotic Lb. rhamnosus strain (90). Of note, the host was originally identified as Lb. casei 1/3 (89, 91). Its 36,466-bp genome sequence has a 44.2% G+C content and 51 orfs (Table 4). Despite the absence of an attP site and an integrase gene, the genome contains the remnants of a repressor gene, suggesting a temperate origin for this phage (92). Several Lb. rhamnosus strains contain a number of phage-related DNA sequences (91, 93), although Lc-Nu cannot integrate in any of them (92). Other noticeable feature in this genome includes three putative methyltransferase genes that may be involved in methylation of newly synthesized DNA, likely to defend against host R/M systems. A signal peptide was also predicted in the endolysin-encoding gene suggesting exportation though a sec-dependent mechanism. Finally, Lc-Nu showed more homology with phiAT3 than with A2, mainly because over 90% identity was found in several structural proteins (Figure 1).
4.4. Lactobacillus plantarum phages
4.4.1. phig1e
This temperate pac-type siphophage lysogenizes Lb. plantarum G1e, which was isolated from plant materials in Japan (94). Its genome was the second Lactobacillus phage genome to be sequenced (95). Its 42,259-bp genome has a GC content of 43.1% and contains 62 orfs, 54 on the complementary strand and eight on the other strand (Table 4 and Figure 1). Putative functions were attributed to some ORFs. Ntp may be a terminase subunit while Hel is likely a putative DnaB-helicase involved in DNA replication. The major capsid protein (gpG, ORF32) was observed by SDS gel electrophoresis (94) while the major tail protein (gpP, ORF27) was confirmed by immunoelectron microscopy (96). The endolysin (97), holin (98, 99), and integrase proteins (100) were also purified and characterized for this phage. Among other orfs of particular interest, the cpg gene is expressed through the promoter PL and encodes a 132-aa protein similar to SOS-related repressors, while cng, under the control of the promoter PR oriented in the opposite direction, encodes a Cro-like repressor (88 aa). Both proteins can bind to operator-like GATAC boxes but in slightly different way (101, 102). As shown by footprint assays, Cng does not completely cover two of the seven boxes identified in the phig1e genome (namely Gb4 and Gb6). This difference could be involved in the lysogenic/lytic decision (103).
4.4.2. phiJL-1
The virulent Lb. plantarum siphophage phiJL-1 was isolated from a cucumber fermentation factory in the United States (104). It has a 36,700-bp linear, double-stranded DNA genome with a G+C content of 39.36% and 52 orfs (105). Seven functional modules have been proposed (DNA replication, transcription regulation, DNA packaging, head morphogenesis, head-tail joining, tail morphogenesis, and cell lysis) (105). On the 52 putative ORFs, five were experimentally determined to be part of the phage structure. Unlike other virulent Lactobacillus phages, no remnant of a lysogeny module was detected. Nonetheless, several deduced proteins (endonucleases, helicase, and a minor tail protein) are homologous with those of the cos-type temperate Lb. casei siphophage A2, and its genome organization is close to Lactobacillus phages phig1e (Lb. plantarum) and phiadh (Lb. gasseri) and to S. thermophilus temperate phage Sfi21 (105).
4.4.3. LP65
The virulent phage LP65 was isolated after a discoloration problem in a Spanish salami factory (106). Unlike other Lactobacillus phages for which the complete genome sequences are available, phage LP65 is a member of the Myoviridae family (Table 4). More specifically, it is included in the SPO1-like group of phages. LP65 has a very large genome of 131,573-bp with a G+C content of 37.3%, and 165 orfs (106). The genome was divided into three main regions. Region 1 contains orf5 to orf76, which code for the species-specific proteins ORF5 through ORF52 as well as ORF53 through ORF73, which are involved in DNA replication. Many tRNA are also found upstream from orf76. Region 2 contains orf88 through orf119, which code for structural genes. Lastly, region 3 contains orf120 through orf163, which do not correspond to any genes in databases, except for two intron-associated HNH endonucleases. No lysogenic module or remnants were found in the genome. More specifically, phage LP65 was compared to S. aureus phage K and Bacillus subtilis phage SPO1 because they share the same overall organization. In total, 32 orfs of LP65 share sequence identity with K and SP01. They also have the same morphology, except for the fact that LP65 has a longer tail and a tail fiber. Finally. DNA-DNA hybridization assays have also revealed that LP65 shares homology with phage fri, another Lb. plantarum myophage. Phage fri was isolated in 1983 from a commercial meat starter culture (36). Unlike most phages isolated from dairy fermentations, phage fri does not significantly impair fermentation as the infected host strain generates enough acid to produce an acceptable final product (107).
4.4.4. Y1
Lb. plantarum phage Y1 was isolated from a sauerkraut fermentation in Korea. To our knowledge, this is the only Lactobacillus phage that belongs to the Podoviridae family (short tail) (38, 108). Unfortunately, no further details are available.
4.5. Lactobacillus gasseri phage phiadh
Phage phiadh was isolated after inducing the strain Lb. acidophilus ADH (56), which was later renamed Lb. gasseri (109). This Lactobacillus strain is a human isolate that produces bacteriocins, is resistant to bile, and adheres to human fetal intestinal cells (110). Lb. gasseri NCK102, a prophage-cured derivative, is sensitive to phage phiadh (56).
Altermann et al. (1999) reported the complete genome sequence of phage phiadh (57). The genome of phiadh has cohesive ends (cos-type) flanking its 62 orfs (57), of which many are homologous with orfs of Lb. casei phage A2 (81) and, to a less extent, Lb. plantarum phage phiJL-1 (105). Based on transcriptional studies, the genome of phiadh has been divided into three groups (111). The early-expressed genes (mRNA expressed approximately 10 min after the beginning of infection) included those involved in the lytic/lysogenic module and in DNA replication. The middle-expressed class of transcripts appeared approximately 30 min after the infection and were probably involved in DNA packaging, while the late-expressed group of transcripts were transcribed 40 to 50 min after the infection and include the genes involved in morphogenesis and cell lysis (111). The integration and lysis systems of phiadh have also been characterized (112-114) (see section 6.3).
4.6. Lactobacillus crispatus phages
Another phage genome is available on the NCBI website, namely the Lb. crispatus temperate myophage kc5a (Table 4). This phage was isolated during a large study on vaginal biota in the United States and Turkey (15). It can be spontaneously released from strain Lb. crispatus KC5a by the addition of BPDE, a compound found in cigarette smoke (22). To our knowledge, its genome sequence has not been published. This small phage genome (38,239-bp) for a myophage contains 61 orfs, including orf45, which encodes a putative tail sheath protein.
5. LACTOBACILLUS PROPHAGES
Lysogeny, and even poly-lysogeny, is a common feature in several bacterial species (115) and Lactobacillus is no exception. At the time of writing this review, eleven Lactobacillus genome sequences were available on the NCBI web site (116). Prophage sequences are usually identified by the presence of an integrase gene as well as a seemingly morphogenesis module (117). Not all the genomes have been analyzed for the presence of prophages, but a few were retrieved from Lb. johnsonii, Lb. plantarum, Lb. salivarius subsp. salivarius, Lb. gasseri, and Lb. casei (118-122). Based on their genome organization, Lactobacillus prophages appear to belong to the Siphoviridae family, although many await confirmation. For example, two seemingly complete prophages (and one remnant) were detected in the genome of Lb. johnsonii NCC533 (123), but none of them can be induced with mitomycin C or UV (119). Prophage remnants as well as a few orfs showing similarities with phage genes have been identified in the genome of Lb. acidophilus NCFM (124). Similarly, one prophage remnant has been detected in the genome of Lb. sakei 23K, which was isolated from a sausage (125). Lb. salivarius UCC118 has two complete prophages (Sal1 and Sal2) as well as two remnants (Sal3 and Sal4) (126). An identical pattern was found in Lb. plantarum WCFS1 with two complete prophages (Lp1 and Lp2) and two remnants (R-Lp3 and R-Lp4) (118). Transcripts covering the lysogeny modules of Sal1 and Sal2 (120) and Lp1 (118) have been identified but none for Sal3 genes. Only a few genes of Sal4 are transcribed (120). Interestingly, a 10-kb circular DNA from Sal4 can observed following exposition of Lb. salivarius UCC118 to mitomycin C.
As mentioned previously, virulent phages can arise from prophages, particularly when the lysogeny module is inactivated (127). Virulent phages can also acquire new DNA from the gene pool available through prophages (128, 129). Indeed, the genome of the Lb. casei phage FSV contains extensive sequences also found in the temperate phage FSW (130, 131). Lb. delbrueckii subsp. lactis virulent phage LL-H is also related to temperate phage mv4 (66).
5.1. Lysogenic conversion genes
Prophages represent a significant part of the strain-specific DNA in many bacteria (23). Moreover, they carry genes that are expressed under lysogenic state and thus may provide a selective advantage to the host. These genes are often referred to lysogenic conversion genes when their presence change or provide a new characteristic/advantage to the host, but are not usually related to phage function. Candidates for lysogenic conversion genes have been found in the prophages of Lb. johnsonii NCC533 (119) and Lb. plantarum, both isolated from human oral cavity (132, 133), as well as in Lb. casei phage A2 and others. Those candidates were localized close to the prophage genome ends (121) either in the lysis or the lysogeny modules (118). For example, phage A2 genes possibly involved in lysogenic conversion are orf19 (located between the lysin and the integrase genes) and orf22 (upstream from the integrase gene) (Figure 1). The orf22 showed homology to a gene found in a pathogenic island of Clostridium difficile while the ORF19 presents similarity with a putative protein found in Listeria monocytogenes. In Lb. plantarum phage phig1e, four genes have been hypothesised to be lysogenic conversion genes (named 10 to 13 ; see Figure 1), mainly due to their localization and according with alignments with other prophages form various species (122). Further analyses and studies are still needed to determine if these genes indeed contribute to the fitness of Lactobacillus hosts.
6. OTHER CHARACTERISTICS OF LACTOBACILLUS PHAGES
6.1. Comparative genome analyses
As indicated previously, others have already reviewed in great details the genomic aspects of Lactobacillus phages (23). Comparative genome analyses have mainly focused on Lactobacillus siphophages because the genomes of only two Lactobacillus myophages are currently available (23). Here, we are providing an updated figure representing the comparative analyses of siphophage genomes (Figure 1). Considerable genetic polymorphism is found in the relatively small Lactobacillus phage genomes, which is in agreement with the diversity also found in their host genomes. However, the organization is similar with the general modules found in the same order in the genomes, including the lysogeny module when present (Figure 1). Interestingly, similarities are also found between cos- and pac-type Lactobacillus phages. Nonetheless, cos-type phages (Lb. casei phiAT3, Lb. rhamnosus Lc-Nu, Lb. casei A2, Lb. gasseri phiadh) are more related to each other than pac-type phages (Lb. plantarum phiJL-1, Lb. plantarum phig1e, Lb. delbruekii LL-H) (Figure 1). In particular, the morphogenesis module of Lb. rhamnosus phage Lc-Nu is highly similar to the one of Lb. casei phage phiAT3. Similarly, Lb. casei phage A2 is also related to Lb. casei phiAT3, suggesting a common ancestor. On the other hand, the two Lb. plantarum phage genomes suggest the presence of at least two lineages of siphophages in this species (Figure 1). The analyses of additional Lactobacillus phage genomes is certainly warranted to obtain in much better comprehensive dataset, which will eventually lead to a better understanding of their origin and evolution.
6.2. Identification of receptors
The first step in the tailed-phage infection process is the adsorption of the phage, through the receptor binding protein (RBP) located at the distal part of its tail, to the host cell surface receptor. The host recognition process is one of the most important in phage biology because mutation in either the phage RBP or the host receptors will prevent phage infection. It is thus not surprising that Lactobacillus phage adsorption and host-recognition processes have been investigated. The RBP protein of the virulent siphophage LL-H, which infects Lb. delbrueckii subsp. lactis strains, is encoded by gene g71. Amino acid changes in the C-terminal end of RBP affect adsorption. Moreover, most of the residues in the C-terminus of the protein are conserved in ORF474 of phage JCL1032, which infects the same host strain as phage LL-H. Since the N-terminal domain of the two proteins is different, the C-terminus is likely the protein interaction domain (134). The crystal structures of a few Lactococcus lactis phage RBPs have been solved and have confirmed that the C-terminal part (head domain) is responsible for host recognition (135-138).
The phage LL-H receptor on the host surface has also been investigated. Purified lipoteichoic acid (LTA) prevented the adsorption of phage LL-H to Lb. delbrueckii host cells, indicating that LTA is a component of the phage receptor (139). The degree of dealanylation of LTA also appears to play a role in phage adsorption (140). Interestingly, another study has suggested that Lb. delbrueckii subsp. lactis strains possess three types of phage receptors, two of which are recognized by phage LL-H and one by phage JCL1032 (134). LTA is not a component of Lb. delbrueckii phage LL-Ku and c5 receptors (140).
Rhamnose residues of the polysaccharide on the cell surface of Lb. casei have also been linked to the adsorption of phages PL-1 and J-1 (141-143). The virulent Lb. casei phage MLC-A, which has the same host range as J-1 and PL-1, likely uses the same receptor (144, 145), while Lb. delbrueckii phages YAB, lb3, and BYM attach to a cell surface polysaccharide-peptidoglycan complex (33). On the other hand, rhamnose (and several other sugars) have no effect on the adsorption of Lb. helveticus phages hv and ATCC 15807-B1 (146). The S-layer protein of various Lb. helveticus strains may also act as a receptor for phage adsorption (33, 147). Clearly, phage receptors are highly diverse in Lactobacillus and need to be studied on a case-by-case to better comprehend each phage-host system and to develop phage-resistant strains.
6.3. Endolysin studies
Cell lysis is another critical step in phage biology as it indicates the successful completion of the phage infection process. In most phages, the lytic process depends on the combined action of two proteins, namely the holin and the endolysin. The holin creates holes in the cell membrane to allow access of the endolysin to its substrate, the cell wall. One possible exception in Lactobacillus may be the endolysin of Lb. plantarum phig1e which possesses a signal peptide, suggesting secretion through a SecA-dependent mechanism (97, 148). Of the four main classes of bacterial endolysins, muramidase-like (also called lysozyme) and amidase-like endolysins have been found in Lactobacillus phages (149). While muramidase-like endolysins target the N-acetylmuramic acid backbone of the cell wall, amidase-like enzymes break down the peptidoglycan by acting on the amide bond linking a sugar to a peptide (148, 150). Lactobacillus phages LL-H, phiadh, and mv1 possess a muramidase-like endolysin (113, 151, 152), while phage PL-1 has an amidase-like endolysin (N-acetylmuramoyl-L-alanine amidase) (153). The endolysins of these phages have been expressed in E. coli, purified, and briefly characterized. Interestingly, the LL-H phage Mur protein has a broad activity as it hydrolyzes the cell walls of various Lactobacillus species and Pediococcus damnosus (151). Similarly, the endolysins of Lb. helveticus phage phi0303 (154) and Lb. gasseri phage phigaY are active against the cell walls of many Gram-positive bacteria (155). These cell-wall degrading enzymes have generally two domains. For example, the catalytic domain of phigaY endolysin is at the N-terminal, while the C-terminal domain binds to various Gram-positive bacteria (155). The catalytic domains of the LL-H and mv1 endolysin are also located at the N-terminal (151, 152). Phage endolysins are of particular interest for a better knowledge of the phage biology but also for biotechnological applications. Endolysin can be used to control flavor development (59, 156), to restrain various microflora (108) or used in molecular biology studies (157, 158).
6.4. Genetic tools developed from Lactobacillus phages
A number of genetic tools have been developed from Lactobacillus phages (reviewed in (159)). For example, the int gene from Lb. delbrueckii subsp. bulgaricus phage mv4 and its attP have been used to construct an integration vector (160). Interestingly, this vector can integrate into a conserved tRNASer gene found in the chromosome of Lb. delbrueckii subsp. bulgaricus strains as well as in Lb. plantarum, Lb. casei, Lactococcus lactis subsp. cremoris, Enterococcus faecalis, and Streptococcus pneumoniae strains (161). The characterization of the integrase gene and the attP site of the temperate Lb. gasseri phage phiadh (112) has also led to the construction of a site-specific integration vector (162-164). Similar studies have been performed with the integrases of Lb. casei phages A2 (85) and phiAT3, which were integrated into the chromosome of Lb. rhamnosus strains (88). Expression vectors have also been designed using Lactobacillus phage promoter and repressor (165, 166).
The analysis of the DNA replication module of Lb. casei temperate phage A2 DNA led to the construction of a vector containing the replication origin (ori) of A2. The presence of the vector into Lb. casei strains confers partial resistance to phage A2 (167). Origin-derived phage-encoded resistance (PER) is a system whereby multi-copies of phage ori sequences are supplied in trans on a plasmid carried by the host (168). Upon phage infection, the plasmid-based phage ori presumably segregates phage-encoded replication factors, thereby limiting phage development while leading to an increased plasmid replication. The same research group also constructed a food-grade Lb. casei strain resistant to phage A2 through the development of a "delivery and clearing" system using the A2 integrase, the attP site, and a cI-like repressor combined with a second vector containing a beta-resolvase gene to remove undesired DNA on the first vector such as an antibiotic resistance gene (169).
7. Towards a SPECIFIC classification scheme for Lactobacillus phages
Prior to the availability of genomic sequences, the classification of Lactobacillus phages was based mainly on morphological observations and DNA homology. Phages infecting Lb. delbrueckii strains were the first to be catalogued in the mid-1980s (26, 170). Phages classified within group "a" included phages LL-H, mv4, and LL-S (LL-55 or lv) because they shared homology in the morphogenesis and cell lysis genes as well as two major structural proteins (35 and 19 kDa). Group "b" included three virulent phages (lb4, c3, and c5) with two homologous structural proteins (23 and 31 kDa) (171), while Lb. delbrueckii group "c" included siphophages JCL1032 and 0235, which had a prolate capsid as compared to an isometric capsid for phages of groups "a" and "b". However, Forsman (1993) suggested that phage JCL1032 be classified in a different group because it still shared DNA homology with several phages from groups "a" and "b" (172). Finally, group "d" included only phage 0252, which possess a longer tail (20).
By the year 2000, complete genome sequences were available for five Lactobacillus siphophages. While they do not share significant DNA homology, the organization of their structural gene module was well conserved (173). This observation led to a proposed classification scheme for Siphoviridae phages (122) in which Lb. casei phage A2 and Lb. gasseri phage phiadh were assigned to the Sfi-21 supergroup whereas Lb. delbrueckii phages LL-H and mv4 as well as Lb. plantarum phage phig1e were classified within the Sfi11-like group (122). The genome organization of Lb. rhamnosus phage Lc-Nu was later shown to be similar to that of Sfi21-like phages (92).
This latter classification scheme has the merit of grouping several phages infecting distinct bacterial genera. For example, most Sfi-21-like phages possess a genome with cohesive ends and a characteristic capsid module, which includes a protease. Phages of the Sfi-11 group package their DNA via a headful mechanism and possess an additional gene coding for a capsid protein as well as a distinct scaffolding protein (122). Another proposal for phage classification was put forward and gave rise to the proteomic tree (174). This classification scheme also goes beyond host boundaries and is mainly based on the deduced proteome without taking into account the morphological characteristics. Finally, a classification system based on the presence of specific modules in phage genomes was also proposed (174). One particular phage could belong to several groups according to their module composition. A similar reticulate approach was also presented recently (175).
The mosaic nature of tailed phage genomes appear to be the main characteristic highlighted by many comparative studies (176). This mosaicism is likely reflecting lateral transfers that occurred (and are still occurring) between different phages (121). The polythetic nature of phages is obviously a problem when desiring to adopt a new classification system for phages (177). Another problem appears with the desire of grouping phages for which there is no possibility to get any morphological and host data, such as those from metagenomic studies (178). Finally, it is recognized that phylogenetic trees can be distorted by uneven representation. Dairy phages in general and Lactobacillus phages in particular are often under represented in these schemes. Therefore, it is our opinion that, at this time, such tree is currently not meaningful and certainly not practical. Much more data are needed before settling on a new phage classification. Similarly, the lack of standardized information on most Lactobacillus phages suggests that it is risky exercise to attempt to classify them by singling out one method.
8. OUTLOOK
Lactobacillus phage research has progressed significantly over the past decade. However, our knowledge of Lactobacillus phage biology is limited and certainly lags behind that of other phages. Phages with similar morphologies have been isolated from a wide variety of Lactobacillus species. From a practical standpoint, grouping Lactobacillus phages based on their host range and morphology is arguably the easiest way to currently classify them. Unlike phages from other lactic acid bacterial species such as Lactococcus lactis (179) and Streptococcus thermophilus (180), Lactobacillus phages are much more diverse, which is likely a reflection of the relatively high number of species in the Lactobacillus genus. It is valuable to observe, though, a relatively well-conserved genome organization (Figure 1).
Because of this diversity, the current gaps in our understanding of these phages and their ubiquity, the outlook for research on Lactobacillus phages is bright. It is likely that phage-associated fermentation/production difficulties will grow in the future, especially with the increased production of probiotic Lactobacillus strains. The on-going studied of the human Lactobacillus biota may also lead to the isolation of new phages. It remains to be seen which groups of phages will emerge with these new applications. A thorough characterization of these phages will be needed to shed light on their origins, evolution, and relationships with other phages (181).
9. ACKNOWLEDGEMENTS
We are very grateful to H.W. Ackermann and T. Alatossava for providing numerous articles on Lactobacillus phages. We also would like to thank Simon Labrie, Helene Deveau, and Genevieve Rousseau for their help and comments on the genomic analyses. This work was funded by the Natural Sciences and Engineering Research Council of Canada.
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Key Words Lactobacillus sp., Bacteriophage, Prophage, Lactococcus, Streptococcus, Genome, Review
Send correspondence to: Sylvain Moineau, Groupe de recherche en ecologie buccale, Faculte de medecine dentaire, 2420 rue de la Terrasse, Universite Laval, Quebec City, Quebec, Canada, G1V 0A6, Tel: 418-656-3712, Fax: 418-656-2861, E-mail:Sylvain.Moineau@bcm.ulaval.ca