Abstract

Bacteriophages typically may be grouped into two categories by their life cycle: lytic phages and lysogenic (temperate) phages. The five decades following the discovery of phages saw numerous investigations on the lytic phages of S. pyogenes, which included studies on host range, basic biology, and their ability to mediate general transduction. In contrast to lysogenic phages, lytic phages do not alter the phenotype of the host streptococcal cell during a long-term genetic relationship, but can shape the host population by eliminating susceptible cells in a population, or by facilitating genetic exchange by transduction. This chapter also presents a summary of information on the lysogenic phages of group A streptococci, their distribution and attachment sites, morphology and genome organization, and associated virulence genes. Additional areas of overview include the diversity of lysogenic phages and the horizontal transfer of genes from other species. Finally, there is a discussion of prophages as vectors for virulence genes, phage-like elements that carry antimicrobial resistance genes, and regulation of host gene expression.

Lytic phages of group A streptococci

Lysogenic phages of group A streptococci

Genome prophages, their distribution, and attachment sites

Lysogenic bacteriophages are defined by their ability to integrate their DNA into the host bacterium’s chromosome via site-specific recombination, becoming a stable genetic element that can be passed to daughter cells after cell division. Studies from the pre-genomics era suggested that lysogeny was common in S. pyogenes (Kjems E. , 1960; Krause, 1957; Chaussee, Liu, Stevens, & Ferretti, 1996; Hynes, Hancock, & Ferretti, 1995; Wannamaker, Skjold, & Maxted, 1970; Yu & Ferretti, 1989), but it was genome sequencing (starting with the first one completed and confirmed by almost every subsequent one) that demonstrated that toxin-carrying prophages were not only common, but were prominent genetic features that shaped the fundamental biology of this bacterial pathogen (Table 1). The number of lambdoid prophages or phage-like chromosomal islands found in a given genome strain has ranged from a low of one (MGAS15252) to as many as eight (MGAS10394), with three to four elements being most common. These prophages are found to be integrated into multiple sites on the S. pyogenes genome, and can be found in each quadrant (Figure 1 and Table 2). The majority of the genome prophages (72%) are found to be integrated into genes encoded on the lagging strand (relative to oriC). No prophages have been found to target genes in the hypervariable regions, which include the M-protein (emm) or the streptococcal pilus. Some sites are frequent targets for prophage integration; the genes for DNA binding protein HU, tmRNA, and the DNA mismatch repair (MMR) protein MutL are very commonly occupied by a prophage or prophage-like chromosomal island.

Table 1.

Assembled and annotated genomes of S. pyogenes that are hosts to prophages.

Figure 1.

Prophage attachment sites in the S. pyogenes genome. The locations of the genome prophages are shown as a generalized chromosome backbone based upon the SF370 M1 genome; each diamond represents a genome prophage that was identified at that site. The M-type (more...)

Table 2.

Prophages of S. pyogenes, and their integration sites and associated virulence genes.

The integration of prophages occurs via a homologous exchange between sequences shared between the phage and host chromosomes (attP and attB, respectively); this process is mediated by a phage-encoded integrase. These duplications between the phage and host DNA can be as few as a few nucleotides to over 100 bp, and can often include the coding regions of the bacterial genome (Campbell, 1992; Groth & Calos, 2004; Fouts, 2006). In S. pyogenes, the identifiable duplications between attB and attP range from 12 bp (MGAS10394.1) to 96 bp (T12). An extensive survey of bacterial genome prophages found that prophages usually integrate into a gene ORF (69% of identified prophages) while integration into an intragenic region, such as that seen in coliphage Lambda, is less common and accounts for only 31% of prophages (Fouts, 2006). Gene targets included tRNA genes (33%), tmRNA (8%), and various other genes (28%). Examples of each target site can be observed in the S. pyogenes genome prophages (Table 2). Most commonly, the duplication occurs between the phage and the 3’ end of the host gene, and integration leaves the open reading frame intact via the duplicated sequence (Fouts, 2006; McShan & Ferretti, 2007). However, in S. pyogenes, the 5’ end of genes are frequently targeted for integration, which could potentially lead to an altered expression of the host gene (Table 2). The best characterized system of an altered host gene expression is the control of MMR in strain SF370 by SpyCIM1 (S. pyogenes chromosomal island, serotype M1) where the expression of genes for MMR, multidrug efflux, Holliday junction resolution, and base excision repair are controlled by this phage-like chromosomal island, in response to growth (McShan & Ferretti, 2007; Nguyen & McShan, 2014; Scott, Nguyen, Hendrickson, King, & McShan, 2012; Scott, Thompson-Mayberry, Lahmamsi, King, & McShan, 2008). Similarly, the phage-like transposon MGAS10394.4 (also known as Tn1207.3 (D'Ercole, et al., 2005)) separates the DNA translocation machinery channel protein ComEC operon proteins 2 and 3, which potentially creates a polar mutation that silences protein 3. A number of other streptococcal genes are targeted at their 5’ ends by prophages, including genes that encode the recombination protein RecX, a HAD-like hydrolase, and DNA-binding protein HU (Table 2). Other prophages integrate into the promoter region that precedes the ORF in dipeptidase Spy0713, yesN and a gamma-glutamyl kinase. In the case of dipeptidase Spy0713 that is targeted by members of the SF370.1 family, integration separates the ORF from the predicted native promoter and may replace it with a phage-encoded promoter found immediately upstream of the coding region following integration (Figure 2). This phage-encoded promoter is preceded by a canonical CinA box (Claverys & Martin, 1998), which suggests that this putative alternate promoter may also change the transcriptional program of the gene. In another example, two serotype M3 prophages were found to be integrated into a CRISPR type II system direct repeat; remarkably, this event may have led to the loss of CRISPR function in these cells. In all of these examples, the integration of a phage or phage-like element into the 5’ end of a gene has the potential to alter streptococcal gene expression by blocking transcription or providing an alternative promoter, and the frequency of such transcription-altering prophages may be an important regulatory strategy in S. pyogenes.

Figure 2.

Integration of prophage SF370.1 may provide an alternate promoter for dipeptidase Spy0713. In strains that lack an integrated prophage at this site, the native promoter for dipeptidase Spy0713 is downstream from the uncharacterized gene Spy0654; the predicted (more...)

Not all S. pyogenes prophages inactivate host genes following integration. Those that integrate into the 3’ end of genes typically preserve gene function through the shared DNA sequence between the DNA molecules, and a number of examples can be found in the genome prophages (Table 2). Bacteriophage T12 integrates by site-specific recombination into what was initially identified as a gene for a serine tRNA (McShan, Tang, & Ferretti, 1997), but was correctly identified as a tmRNA gene after the completion of genome sequencing. Genes that encode tmRNA are frequently used as bacterial attachment sites (attB) for prophages that infect a range of bacterial species, including Escherichia coli, Vibrio cholerae, and Dichelobacter nodosus (Fouts, 2006; Williams, 2002). Besides the tmRNA gene, other 3' gene targets used by genome prophages include the histone-like protein HU, dTDP-glucose-4,6-dehydratase, a putative SNF helicase, and recombination protein recO.

Morphology and genome organization

Tailed phages with dsDNA genomes (Caudovirales) are abundant in the biosphere, and are perhaps the most frequently found form of life on Earth (Brüssow & Hendrix, 2002). Of the Caudovirales, the phage subset Siphoviridae (icosahedral heads with long, non-contractile tails) comprise about 60% of the total (Ackermann, 2005). A bacteriophage survey from the pre-genomics era found that 92% of phages of the genus Streptococcus were Siphoviridae by current classification (Ackermann & DuBow, 1987), and the few early electron micrographs published reflect this prevalence (Kjems, 1958; Malke, 1970; Zabriskie, Read, & Fischetti, 1972; Malke, 1972). Figure 3 shows the typical Siphoviridae morphology of two well-studied S. pyogenes phages, SF370.1 and T12. The tail fibers of SF370.1, which contain the hyaluronidase (hyaluronate lyase) used for capsule penetration during phage infection (Smith, et al., 2005), can be seen in the micrograph. The lytic transducing phage A25 also has typical Siphoviridae morphology (Malke, 1970; Malke, 1972). While lysogenic phages may be found to be mostly members of the Siphoviridae, given their probable common pool of genetic modules (see below), other phage morphotypes may be found in the lytic phages, such as the Podoviridae C1 phage of the related group C streptococci (Nelson, Schuch, Zhu, Tscherne, & Fischetti, 2003). The coliphage Lambda has been the prototype for lysogenic prophages, and the genetic organization of most group A streptococcal genome prophages follows a similar general plan (Desiere, McShan, van Sinderen, Ferretti, & Brüssow, 2001; Canchaya, et al., 2002), as they have identifiable genetic modules for integration and lysogeny, replication, regulation, head morphogenesis, head-tail joining, tail and tail fiber genes, lysis, and virulence (Figure 4).

Figure 3.

Morphology of streptococcal lysogenic phages. Prophages SF370.1 (A) and T12 (B) release typical Siphoviridae virions, following induction. In this micrograph, the SF370.1 head is about 55nm across and the tail is 168nm in length. In this image, the tail (more...)

Figure 4.

The genetic structure of streptococcal prophages and phage-like chromosomal islands. The prophages found in the genomes of S. pyogenes follow a typical lambdoid pattern in their organization with genetic modules for lysogeny, DNA replication, regulation, (more...)

Lysogeny module

Temperate phages are defined by their carriage of genes that establish and maintain a stable condition within a host cell, usually via site-specific integration. Minimally, lysogeny requires genes that encode an integrase (recombinase) and excisionase to mediate prophage DNA integration and excision, as well as genes that encode repressor and antirepressor proteins to direct and control this process, following the pattern seen in coliphage Lambda (Ptashne, 2004). Phage integrases typically mediate a recombination event between an identical sequence shared between the circular form of the prophage genome (attP) and the bacterial chromosome (attB), and the recognition of these DNA sequences is inherent in a given integrase protein (Groth & Calos, 2004; Campbell, del-Campillo-Campbell, & Ginsberg, 2002; Argos, et al., 1986). Most lambdoid phages usually have integrases that belong to the tyrosine integrase family, and the integrases of S. pyogenes prophages belong to this group. The excisionase gene in Lambda and many other Gram-negative host phages is positioned upstream of integrase; however, in the lactic acid bacteria and other Gram-positives, its genome location is variable (Bruttin, Desiere, Lucchini, Foley, & Brüssow, 1997; Breüner, Brøndsted, & Hammer, 1999). Indeed, since excisionase proteins often show little conservation (Lewis & Hatfull, 2001), it is often difficult to identify the correct ORF in a given prophage. Some excisionase genes may be provisionally identified in the S. pyogenes genome prophages by their homology to other phages (Desiere, McShan, van Sinderen, Ferretti, & Brüssow, 2001); however, to date, none have been experimentally confirmed.

DNA replication and modification

A region that shows considerable diversity between individual prophages, and which encodes genes involving DNA replication and modification, follows the lysogeny module. Homologs of DNA polymerases, replisome organizer, restriction-modification systems, and primase genes are present in these regions, as well as potential sequences that may function as the origins of phage DNA replication (Desiere, McShan, van Sinderen, Ferretti, & Brüssow, 2001; Canchaya, et al., 2002). Inspection of the genome annotations of these regions also shows that while many genes are unique to S. pyogenes phages, others have close homologs to phages from other streptococcal species such as Streptococcus thermophilus or Streptococcus equi, which suggests that a pool of genetic material is shared by a diverse group of phages (discussed below).

DNA packaging, capsid structural genes and host lysis genes

The next region of prophage genomes is dedicated to the genes that encode the proteins for the assembly of phage heads and tails, as well as the proteins needed to package the phage DNA into the heads and join this complex to the tails. The function of many of these genes has been inferred by homology to known phage proteins or sequences, or by presumption of function due to their relative order in the chromosome. However, with the exception of the hyaluronate lyase (hyaluronidase) gene found in some S. pyogenes phage tail fibers (Hynes, Hancock, & Ferretti, 1995; Smith, et al., 2005; Hynes & Ferretti, 1989), most of these genes have not been experimentally characterized, and as a result, these function assignments remain provisional. The typical holin-lysin genes that are employed at the end of the lytic phase to lyse the infected bacterial cell and release the newly formed phage particles follow the capsid genes.

Virulence genes

Finally, at the distal end of the phage chromosome are the genes for host conversion that encode a range of virulence factors; exotoxins that are often superantigens, as well as DNases like streptodornase, are prominent (Table 2). The biology of these virulence factors is covered in a separate chapter in this book. The origin of phage-encoded toxins remains unclear—but since these toxin genes play no known role in the replication of the phage, it suggests that such genes were acquired at some point late in the phage's evolutionary history. It has been proposed that virulence factors may be acquired by phages by imprecise excision events (Barksdale & Arden, 1974), but independently finding known phage-associated virulence genes on the bacterial chromosome has not been observed. Some superantigen genes are not associated with prophages (Proft, Sriskandan, Yang, & Fraser, 2003; Proft, Moffatt, Berkahn, & Fraser, 1999), but it remains unclear whether these genes are a genetic source of prophage superantigens. The lateral gene capture of virulence genes has undoubtedly been important in their dissemination (Ochman, Lawrence, & Groisman, 2000), and indeed, such exotoxins may have evolved de novo as elements to increase bacterial host cell fitness (Brüssow, Canchaya, & Hardt, 2004). Decayed prophage remnants with superantigen domains may be seen in the S. pyogenes genome (Canchaya, et al., 2002), and these regions may serve as a genetic reservoir for virulence genes. Similarly, host-range variants of phages from different bacterial species (or even genera) are another potential reservoir for toxin genes; for example, the speA gene of S. pyogenes and the enterotoxins B and C1 of Staphylococcus aureus show a significant degree of homology, and thus may share a common origin (Weeks & Ferretti, 1986).

Diversity of lysogenic phages

Structural genes dominate phylogenic relations

In a seminal 1980 paper, Botstein proposed that the product of bacteriophage evolution is not the individual virus but a pool of interchangeable genetic modules, each of which carries out a biological function in the phage lifecycle; therefore, natural selection acts at the level of these individual modules (functional units) (Botstein, 1980). Phylogenetic analysis of the Lambdoid S. pyogenes prophages predicts that several prominent groups exist (Figure 5). Within each branch, considerable group diversity may exist in terms of targeted bacterial attachment sites and encoded virulence factors (Table 2). Inspection of each group shows that phylogeny is driven by large shared blocks of genes encoding proteins for DNA packaging, heads and tails, and host lysis (Table 3); for example, see the analysis of the group of prophages that contain phage T12, where all members of the group minimally share these structural genes (Figure 6). However, other ones, such as the SF370.1 group, are much more clonal, with all prophages sharing the same virulence and lysogeny modules. Therefore, the phylogeny of individual functional modules (such as toxin genes) may be unrelated to other regions of the genome (such as the lysogeny module or capsid genes). The apparent shuffling of the individual modules may be driven by both homologous and non-homologous recombination (Desiere, McShan, van Sinderen, Ferretti, & Brüssow, 2001; Ford, Sarkis, Belanger, Hendrix, & Hatfull, 1998; Monod, Repoila, Kutateladze, Tétart, & Krisch, 1997; Juhala, et al., 2000). The actual driving force behind this engine of prophage diversity in S. pyogenes remains poorly understood, but some clues have emerged. In a survey of 21 toxin-carrying S. pyogenes strains, 18 were found to carry a highly conserved ORF adjacent to the toxin genes (Aziz, et al., 2005). This ORF, which was named paratox, may help promote homologous recombination between phages so that toxin genes may be exchanged, which would lead to phage diversity. Some genome phages or phage-like elements do not readily fall into any group: MGAS10394.2, HKU16.1, NZ131.1, m46.1, and MGAS10394.4 are phylogenetic outliers that have little commonality with other prophages. When the prophages are clustered by the M-type of their host cell, some patterns do emerge (Figure 7). There appears to be a pool of phages shared by M1 and M12 strains; for example, M3 strains have some phages that appear more frequently within this serotype, but the current sample size is too small to draw any definite conclusions. More genomic data will be required to obtain a clearer picture of prophage distribution by serotype.

Figure 5.

Phylogenetic relationships of S. pyogenes prophages. An unrooted phylogenetic tree was created by DNA alignment of the genome prophages. Prophages MGAS10394.2, HKU16.1, NZ131.1, m46.1, and MGAS10394.4 were so dissimilar from the other prophages that each (more...)

Table 3.

S. pyogenes prophages, grouped by shared structural modules.

Figure 6.

Shared genetic modules of the T12-related prophage family. The top line is the simplified genetic map of bacteriophage T12, colored by gene or genetic module for the integrase, repressor-antirepressor, DNA replication, DNA modification, DNA packaging, (more...)

Figure 7.

Identity matrix of genome prophages grouped by M-type. The identity matrix presents the Clustal-omega DNA alignment from Figure 5 as percentage identity between genome prophages, which are grouped by the M-type of their host streptococcus. The numbers (more...)

Prophage hyaluronidase (hyaluronate lyase)

A subset of genome prophages encode a hyaluronidase (hyaluronate lyase, hyaluronoglucosaminidase) gene (Table 3). Two alleles (hylP and hylP2) of this gene were originally identified (Hynes, Hancock, & Ferretti, 1995; Hynes & Ferretti, 1989), and subsequent studies show that this gene exists in multiple alleles that are mainly distinguished by SNPs and by collagen-like domain indels in some variants (Marciel, Kapur, & Musser, 1997; Mylvaganam, Bjorvatn, Hofstad, & Osland, 2000). The phage hyaluronidase gene found in the genome sequences also show considerable diversity that may have resulted from recombination (Hynes, Hancock, & Ferretti, 1995; Hynes & Ferretti, 1989; Marciel, Kapur, & Musser, 1997; Mylvaganam, Bjorvatn, Hofstad, & Osland, 2000). It had been suggested that phage hyaluronidase was a potential virulence factor; however, the crystallization and structural analysis of HylP1 from phage SF370.1 suggested that the function of this enzyme is to introduce widely spaced cuts in the bacterial hyaluronic acid to cause a local reduction in capsule viscosity and aid phage invasion during infection (Smith, et al., 2005). Similar structural properties were observed in the hyaluronidase proteins encoded by prophages SF370.2 and SF370.3 (Martinez-Fleites, Smith, Turkenburg, Black, & Taylor, 2009).

Horizontal transfer of genes from other species

One observation that comes from extensive genome sequencing is that the lysogenic phages of S. pyogenes share a gene pool with other streptococcal species, including those that are closely related (such as Streptococcus equi), as well as those that are more distant (S. pneumoniae). These shared genes include those that are essential to the basic phage life cycle, such as capsid proteins, as well as virulence genes, like exotoxins and superantigens. For example, Streptococcus equi prophages share many superantigens or virulence genes with S. pyogenes phages, including slaA, speL, speM, speH, and speI (Holden, et al., 2009). This study found that phage Seq.4 from S. equi strain Se4047 was very closely related at the DNA level to S. pyogenes Manfredo phage Man.3, including the two phage-encoded exotoxins. Similarly, Streptococcus agalactiae phage JX01, isolated in milk from cattle with mastitis, shares an extensive homology with S. pyogenes prophage MGAS315.2 in the modules that control DNA replication, tail, head-tail connector, head capsid, and DNA packaging, with over 97% amino acid identity between their terminase subunits; however, no virulence associated genes were identified in this phage (Bai, et al., 2013). The temperate phage MM1 of S. pneumoniae also draws from a common pool of structural genes, sharing the DNA packaging, head-to-tail joining, and tail genes with phage SF370.1 (Obregón, García, García, López, & García, 2003). Additionally, this phage and MGAS315.4 share tail and tape measure genes. Some of the oral streptococci also have phages that contribute to this common pool. The portal, terminase, major capsid protein, major tail protein, and tape measure protein of Streptococcus mitis phage SM1 share homology with prophage SF370.3 and a number of other phages of low-GC Gram-positive hosts (Siboo, Bensing, & Sullam, 2003). While acquisition of these phages structural genes from other streptococcal species may not directly impact virulence in the same way that a novel exotoxin would, these capsid genes may help to expand the host range within the group A organisms. The dairy species Lactococcus lactis also is included in this pool of shared phage genes, since prophage SF370.3 closely resembles the cos-site temperate phage r1t of L. lactis (Desiere, McShan, van Sinderen, Ferretti, & Brüssow, 2001; van Sinderen, et al., 1996).

Group A streptococcal prophages and the host phenotype

Phage-like element and regulation of host gene expression

A frequent mobile element found in S. pyogenes genomes are the phage-like SpyCI (Streptococcal pyogenes chromosomal islands) that integrate into the 5’ end of the MMR gene mutL (Nguyen & McShan, 2014; Scott, Nguyen, Hendrickson, King, & McShan, 2012; Scott, Thompson-Mayberry, Lahmamsi, King, & McShan, 2008). The SpyCI share integrase modules with related phage-like chromosomal islands from Streptococcus anginosus; Streptococcus canis; Streptococcus dysgalactiae, subsp. equisimilis; Streptococcus intermedius; and Streptococcus parauberis (Nguyen & McShan, 2014). The DNA replication module is even more widespread among other species, and in addition to the ones named above, is found in related chromosomal islands found in S. agalactiae, S. mitis, S. pneumoniae, Streptococcus pseudopneumoniae, Streptococcus suis, and Streptococcus thermophilus (Nguyen & McShan, 2014). The remarkable defining characteristic of SpyCI is how they regulate MMR and the other genes in the operon (major facilitator family efflux pump lmrP, Holliday junction resolvase ruvA, and base excision repair glycosylase tag). The best studied member of this family, SpyCIM1 from strain SF370, is a dynamic element that excises from the bacterial chromosome during early logarithmic growth and replicates as a circular episome (Scott, Thompson-Mayberry, Lahmamsi, King, & McShan, 2008). As the bacterial population reaches the end of the logarithmic phase and enters the stationary phase, SpyCIM1 re-integrates into the unique attachment site at the beginning of mutL ORF (Figure 8). The result of this cycle is that SpyCIM1 acts as a growth-dependent molecular switch to control the expression of MMR, which causes SF370 to alternate between a mutator and wild-type phenotype in response to growth. During rapid cell division and DNA replication, the integrity of the genome is maintained by an active MMR system; during periods of infrequent cell division, mutations may accumulate at a higher rate (Scott, Nguyen, Hendrickson, King, & McShan, 2012; Scott, Thompson-Mayberry, Lahmamsi, King, & McShan, 2008). Preliminary studies suggest that the SpyCI, which lacks identifiable structural genes, may employ a helper prophage for packaging and dissemination, in a fashion similar to the well-characterized Staphylococcus aureus pathogenicity islands (SaPI) (Novick, Christie, & Penadés, 2010). Further, the impact of this genetic regulatory switch upon S. pyogenes gene expression beyond the MMR operon needs to be characterized.

Figure 8.

A. SpyCIM1 regulation of the MMR operon through dynamic site-specific excision and integration. The MMR operon of S. pyogenes groups the genes that encode DNA mismatch repair (mutS and mutL), multidrug efflux (lmrP), Holliday-junction resolvase (ruvA (more...)

Conclusions

The association of S. pyogenes with its bacteriophages is a major factor in the biology of this human pathogen, which influences the distribution of virulence genes, the spread of antibiotic resistance, the horizontal transfer of host genes, and the population distribution of cells. These relationships can range from simple predator-prey models to complex symbiotic associations that promote the evolutionary success of both cell and phage. Furthermore, in prophages, the choice of integration site into the bacterial chromosome may alter the streptococcal genotype through either gene inactivation or the replacement of normal promoter elements with phage-encoded ones. The similarity that prophages have to pathogenicity islands can hardly be overlooked, and the range of prophage-mediated characteristics that add to host survival or virulence can be easily predicted to increase as new research is conducted. Genome sequencing has greatly contributed to our understanding of prophage distribution and genetic composition, and this bank of knowledge has been and will be an important foundation for future biological studies on the interactions of S. pyogenes and its phages that will be certain to reveal many novel—and perhaps surprising—relationships.

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