v2i2-villafane

Review Article

Initiation of P22 Infection at the Phage Centennial

Joseph A. Ayariga1, Karthikeya Venkatesan1, Robert Ward1, Hongzuan Wu1, Doba Jackson2,

and Robert Villafane1,*

1Department of Biological Sciences, Alabama State University, Montgomery, Alabama 36104, USA; 2Department of Chemistry and Biochemistry, Huntingdon College, Montgomery, Alabama 36104, USA.

*Corresponding author, Robert Villafane, email: rvillafane@alasu.edu

Received 25 February 2018, revised 31 July 2018, accepted 1 August 2018

Publication Date (Web): August 1, 2018

Abstract

This review, written at the centennial of one of the two co-discoverers of phage (French Canadian, Dr d’Herelle), describes a short summary of phage with an emphasis on the initiation of phage infection as seen mainly through the phage P22 system. This phase in the phage lifecycle is likely to be important as a model for phage-host interaction studies and in the application of phages towards more accurate therapeutic strategies.

Keywords

Phages, Lipopolysaccharides, Receptors, TSP, Tailspike protein, Phage therapy

Introduction

Phages (or virions, bacteriophages) are bacterial viruses which can kill bacteria. Recently there is an intense steady flow of new useful applications of phages and their proteins and many use the Salmonella phage P22 as well as many other types of phages (Rohwer and Segall 2015; Switt et al 2015; O’Sullivan et al 2016; Salmond and Fineran 2016; Moineau and Tremblay 2017). The initial push for some of these phage studies evolved as a response to the emergence of antibiotic resistance in many bacteria making them harder to treat but even more devastating has been the fast rise of multi-drug resistant bacterial strains (Parisien et al 2015; Ventola CL 2015)

However, the study of phages and their proteins is of general interest to the broader scientific community because: 1) these phage systems are simple and elegant and the phage lifecycle is so fast that several complete generational studies can be carried out during the course of a single day; 2) the simple and elegant genetics can often be extended to eukaryotic systems (Baker et al 2005; Selvarajan et al 2013); 3) since these systems are monoploid, the effects of genetic changes can be readily observed and suppressors which can often denote interacting amino acids, can be more readily isolated; 4) This simple phage P22 genome is easily manipulated by most modern molecular genetics and biochemical technology; 5) proteins, the work molecule in any biochemical system, can readily be purified in bulk quantities in phage systems and analyzed; 6) often the functions of proteins determined in the prokaryotic background are helpful in determining function in the more complex eukaryotes. Sometimes, much more rarely, the eukaryotic protein homologs, help to determine structure and function in the prokaryotic system; 7) many useful technologies or avenues of investigation have been derived directly from phage studies and some are directly applicable to eukaryotic systems. Phage display is a technology that initially used a filamentous phage to which one can insert a non-phage DNA target gene or fragment within the coding sequence of a protein that is exposed on the phage surface (Smith 1985; Smith and Petrenko 1997; Qi et al 2012). The P22 TSP, a focal point of this review, has also been shown to be able to display peptide fragments on its surface (Carbonell and Villaverde 1996). 8) CRISPR, a primitive bacterial defense mechanism, components of which have recently been shown to serve as a means to correct genetics changes in eukaryotic human DNA, is a system designed to eliminate phage and other DNAs in a bacterial cell (Brounds et al 2008; Doudna and Charpentier 2014; Riordan et al 2015); 9) phage therapy is recently receiving intensive attention from American researchers, although such treatment has been studied and in practice in Europe for many years. There is considerable evidence in its use as a major clinical tool with the right conditions and precautions (Deresinski 2009; Loc-Carrillo and Abedon 2012; Lin et al 2017; Pirnay et al 2018). 10) On a global scale, bacteria control geochemical and geothermal cycles but these bacteria are themselves controlled by various phage species (Danovaro et al 2011). The use of phage has already been demonstrated to be important and beneficial in ecological management (Allen and Abedon 2014). 11) Phages have been shown to be important conduits to genetic exchange in other phages and bacterial strains (Canchaya et al 2003).

Phage have critical influences on the bacterium such as: phage influence in bacterial genome remodeling (Menouni et al 2014), bacteria biofilm formation, defense, bacterial motility, bacterial metabolism, bacterial quorum sensing, bacterial replication, bacterial sporulation, bacterial stress and bacterial toxicity (Hargreaves et al 2014). Phages are present in at least ten times greater numbers than bacteria, making phage the most abundant “living” organism on the planet (Clokie et al 2011). They also can be found in almost every ecological niche.

Phage studies cover four time periods since their discovery

It can be said that phages may have undergone four phage-time-periods. These time periods can be distinguished by a range of years: Range I: 1915 – 1939; Range II: 1940 – 1960; Range III: 1961-2000; and lastly Range IV: 2001-till today. The first period of time, 1915-1939, involved the discovery of phages in 1915 and 1917 (Twort 1915; d’Herelle 1917) as well at using these new viruses, which can lyse bacterial cells, as a bacterial therapy. These new phages could be grown in large quantities in liquid broth containing actively growing bacterial cultures. Phage treatment of bacterial disease was standard in both Europe and America in the period between the two world wars. This period of time was without serious bactericidal agents. However, a cursory understanding of the phage structure and function was still not available. Phage preparations, varied in caliber and efficiency even within commercial enterprises. These preparations were not standardized and phage contamination could not be ruled out. The first electron microscopic images of phage were not even available until 1940 (Ackermann 2011). By the end of this period of time, antibiotics started to become available essentially ending the use of phage as a therapy in Western countries especially the USA. Seminal studies on the nature of the genomic material were made during this time. An excellent review of this early phage period is available (Abedon et al 2011).

The second phage-time-period, from 1940 to 1960, saw substantial inroads in our knowledge of phage physiology and genetics as well as the establishment of DNA as the genetic material. Part of this success can be attributed to the fact that a group of research workers, called the Phage Group, headed by Max Delbruck and Salvador Luria, decided that the phages were too numerous and that to obtain insights into the function and structure of phages they had to agree to study a limited number of phages. This emphasis on a limited number of phages by many scientists who originally came from other scientific disciplines not only achieved its goal but also became the foundation for creation of the field of molecular biology (Cairns et al 2007). Many physiological studies were begun by the Phage Group members to study the characteristics of the phage particle itself (Delbruck 1940) with the resultant rise of molecular biology. The electron microscope and x-ray crystallography began to play significant roles in the analysis of phage and other biological materials. Phage studies played critical roles in the analysis of DNA and other basic life processes because of their small size and easy manipulation.

The third phage-time-period included the years 1960-2000. Phage structure and classification were studied intensely. The architecture of the head and tail structures and the type of genetic material that these phages carried were among some of the characteristics used in phage classification. Phages can infect individual bacterial strains. Since many phages are selective on what strains they will infect and form plaques, these phages were used to distinguish members of these and other bacterial species (Callow 1959; Chirakadze 2009). Electron microscopic studies began to be used to visually distinguish phages from each other and to classify them (Bradley 1967).

Significantly it was realized that the bacteria have developed resistances to antibiotics that had made such an important contribution to the general health of the entire global population and this has prompted the search for alternatives including the use of phage (phage therapy) (Weinbauer 2004; Nikaido 2009; Lin et al 2017). During this period of time important advances were made in technology allowing study and characterization of individual proteins and also of multi-subunit complexes. During this time, such important technology as DNA sequencing, polymerase chain reaction [PCR], Northern blot, Southern blot and protein blot were developed and many biophysical and biochemical techniques were applied to phage and bacterial structure. Molecular genetics tools were developed during this time and are now part of almost any laboratory. Phage therapy was revived especially in the USA and other places during this time.

The current and fourth phage-time-period includes the years after 2001. During this time many different types of microscopy have been very useful in determining phage structural elements and in further helping phage classification. These include: electron microscopy, atomic microscopy, cryo-electron tomography and especially cryo-electron microscopy (Ackermann 2009; Johnson 2010; Hryc et al 2011; Kuznetsov and McPherson 2011; Ranson and Stockley 2011; Johnson 2013; Guerrero-Ferreira and Wright 2013). Cryo-electron microscopic studies are now almost at atomic resolution (Hryc et al 2011). The importance of cryo-electron microscopy has been recognized by the 2017 Nobel Prize in Chemistry.These microscopies have led to a grouping of phages by a number of properties including physical appearance into a limited number of structural classes (Figure 1, Ackermann 2006; Ackermann 2011a). Even though the phage _ and P22 have similar gene arrangements and can form genetic hybrids, by this structural classification, the familiar E. coli phage _ and Salmonella phage P22 belong to the siphoviridae and podoviridae families, respectively (Ackermann 2006; Ackermann 2011a). Figure 1 shows the similar structural features of e34 and P22 phage which cannot infect the other phage’s host cell (Greenberg et al 1995). Classification of phages has undergone many iterations and includes many different considerations including type and similarities of genetic material, architectural similarities including tail morphologies, genomic arrangements of genes and related functions and protein homologies.

This current period of time has seen intensive studies of phage therapy and it has seen totally unexpected applications of phage and their products. It has also seen a stunning increase in the rise of multidrug resistant bacteria. Some of the antibiotic resistant strains do not respond to any of the currently available antibiotics. The discovery or creation of other bactericidal reagents has lagged significantly, forecasting a serious clinical outcome in the near future.

The extremely large number of phages in the biosphere has only recently been realized. Only a tiny fraction of these phages has been analyzed in any detail. Many phages infect a limited number of bacterial hosts which signifies that these phages have a limited host range (Kutter 2009). Phage that can infect a number of different bacterial strains are called broad host range phages and many have been shown to contain several different RBPs encoded within the same phage particle (Schwarzer et al 2012; Ross et al 2016). Phages are generally assayed (measured) by the number of circular clear areas (plaques) that appear on a petri dish containing solid nutrient surface seeded with bacteria (Villafane 2009).

We review some phages with an eye to similarities to phage P22. However, phages have made and continue to make major contributions to the clinical remedy of antibiotic resistant bacteria and an important part of that contribution will be based on knowledge of how a phage recognizes and interacts with its receptor on the bacterial cell surface. For this reason, we have emphasized the Salmonella phage P22 and initial interaction with its host cell and how the phage P22 (Figure 1, left panel, Greenberg et al 1995, Villafane et al 2008) infects a Salmonella typhimurium host cell and carries out its lifecycle. Since the development of new phage uses, cited previously, including phage therapy, is grounded in the knowledge of the phage lifecycle this also mandates a more detailed description of phage P22 lifecycle since it is a major model for many recent phage application developments. Where appropriate, other phages and bacteria are also discussed. Partially overlapping reviews have recently been published (Freire-Moran et al 2011; Salmond and Fineran 2015; Pires et al 2016; Moineau and Tremblay 2017). Phages, as a natural nanomachine, can make and have already made extraordinary scientific contributions to the basic and applied aspects of biology. Some of the phage accomplishments can be seen in the timeline in Figure 2.

Figure 1. Electron micrograph of P22 (left) and e34 phages (Permission granted; Greenberg et al 1995). Note the striking physical appearances of these two phages which infect mutually exclusive Salmonella strains: P22 infects Salmonella typhimurium while e34infects Salmonella Newington. These phages have homology, especially in the proteins of the tailmachines (Greenberg et al 1995; Zayas and Villafane 2007; Villafane et al 2008). These phages have much sequence identities within the first 108 aa of the P22 TSP.

Bacteria

Broadly, the bacteria can be divided into the Gram positive and the Gram negative bacterial cells. These bacterial cells are surrounded by a set of complex protective structural layers. Both contain a phospholipid bilayer (inner membrane) which immediately surrounds and protects the cellular cytoplasm and both contain a layer that surrounds the phospholipid layer in the form of a rigid peptidoglycan layer with the Gram positive cells containing a thick layer while the Gram negative contains a thin layer. The Gram negative cell envelope is more complicated by being surrounded by a distal outer membrane which contains a lipid bilayer (Esko et al 2009; Silhavy et al 2010; Lombard 2014). In addition the Gram negative outer membrane contains proteins (such as outer membrane proteins [OMPs] and lipopolysaccharide, LPS (Figure 3A and 3B). The role of these membrane structures in phage infection will be described below.

Although not emphasized in this review, much information has been obtained about the interaction of phage and their respective Gram positive host cells. Much of the research has been promoted by studies in Bacillus subtilis, Lactobacillus lactis, Lactococci, Lactic acid bacteria (LAB), Tuberculosis and their phages. Lactococci and lactobacillus are used as starter cultures for food fermentation for the production of yogurt and cheese, hence phage infections and bacterial lysis are not desirable outcomes (Chapot-Chartier 2014). Since the cell wall is a thick peptidoglycan (PG) layer, initial interaction may involve a peptidoglycan hydrolase (PGH). The phage might bore a hole through the thick peptidoglycan (endolysin activity) to get to the surface where it will inject its genetic material such as seen in Figure 4. High resolution studies of PG-tail protein interactions in these Gram positive strains are now allowing detailed analysis of phage-receptor interaction. Phage therapy is an important consideration for the analysis of pathogenic bacteria such as the intensive studies with the tuberculosis phage (Guo and Ao 2012).

Phage in general use their tails or tailspike proteins as the receptor-binding protein and many use the lipopolysaccharide, LPS and many different types of proteins as their major cell surface receptor (Lindberg 1973; Steinbacher et al 1996; Rakhuba et al 2010; Casjens and Molineaux 2012). The protein receptors for phages can vary from the tip of external host protein, such as bacterial fimbrae protein or the F-pilus to various transport proteins, enzymes, _b-barrel proteins, porins, membrane proteins such as maltodextrin receptor and outer membrane proteins (OMPs). Since we have studied only a tiny fraction of the available phage, in reality almost any moiety on the bacterial cell surface may suffice for the phage receptor.

For the P22 phage, its receptor-binding protein is its TSP whose structure is shown in Figure 5. The protein domain involved in this function is labeled the b-helix domain, described in more detail in another section below. Since virus-surface contact initiates the infection and since this interaction is currently the intense focus of many laboratories, it will be described briefly now; however, it will also be described in a more specific manner when the interaction of the P22 phage with the Salmonella surface is discussed.

Figure 2. Timeline of some major phage studies. Some major phage accomplishments during the first 100 years of phage research.

I: 1915-1939 Discovery of phage and some crude attempts are phage therapy

II: 1940-1960 Phage physiology and molecular genetics; antibiotics replace phage therapy

III: 1961-2000 Phage applications and earnest efforts at phage therapy

IV: 2001-cur Intense phage therapy applications and vast unexpected applications

Lifecycle

Most bacteriophages consist of two parts - a head or capsid structure and a tail structure (Bradley 1967; Ackermann 2006). The overwhelming number of phages that have been studied have tails and belong to the order Caudovirales (more than 95%, Ackermann 2011). Therefore, this order predominates in the scientific literature and will be emphasized in this review. The phage lifecycle described briefly here is that as it occurs in the P22 phage and then with some variations in many other phages. Phage lifecycles are normally very short. An infection, starting from initial interaction with a bacterial cell and complete lysis of the bacterial cell culture can be accomplished in less than one hour. For this reason, phages have become models for highly regulated expression of their life functions. Because phages are small (common phages in use being roughly 50,000 base pairs long) they must confiscate bacterial proteins and biosynthetic machineries for their intracellular survival, multiplication and cell lysis and phage liberation. Learning about phage systems has opened up detailed windows on the phage life functions. Many phages are directed to the lysis of bacterial cell host; however, the P22 phage is a temperate phage and is able to either infect a bacterial cell in a lytic mode or alternatively to infect in a manner in which the host cell survives and forms what is called a lysogen. Lysogenic bacterial cells generally contain a phage whose genome is integrated into the host genome under conditions where a phage-coded protein inhibits the phage lytic functions including excision from the host chromosome. Although Salmonella tailed phage P22 (caudovirales, podoviridae family) is emphasized in this review, it is important to note that some phages themselves, once stably established within a bacterium (lysogenic form) can impart pathogenic characteristics to the infected cell, generally by bringing to them toxigenic agents which agents are located within the same phage genome (Casas and Maloy 2011; Hulo et al 2011).

Figure 3A. Gram negative cell envelope (with permission) From Essentials of Glycobiology, 2nd Edition 2009 CSH Press. The lipopolysaccharide (LPS) can be seen protruding from the lipid bilayer in the outer membrane. The membrane bound lipidA part of the LPS (endotoxin) provides the stability for the entire LPS. Transmembrane proteins including porins and peripherally bound proteins such as lipoproteins are visible as well in this figure. Separating the two parts of the envelope is a thin rigid layer of the peptidoglycan which surrounds the entire cell and is located in the compartment periplasm. Finally the remaining compartment the inner or cytoplasmic membrane contains the phospholipid bilayer.

The general phage lifecycle can be divided into several steps: 1) Adsorption by a cell-surface interaction by the phage tail (or receptor binding protein, RBP) with its host cell receptor, in P22, the receptor-recognizing protein is the tailspike protein (TSP, Figure 5) and its initial receptor is the host lipopolysaccharide (LPS) receptor. After this interaction, a more stable and irreversible interaction with LPS. In M13 phage infection its receptor is the F-pilus. In others phages such as _ phage, its receptor is the LamB surface protein (Chatterjee and Rothenberg 2012). 2) Phage genome internalization and in some phages subsequent genomic circularization follows adsorption. The form of the genetic material can be linear or circular and RNA or DNA. 3) Transcription and protein production follow. At this point in the phage pathway, depending on a number of factors and conditions, the temperate phage makes a decision whether the transcription will favor a lytic outcome for the phage or a lysogenic one. If the transcription favors the non-lytic pathway, often the lytic phage genes are repressed by a phage encoded repressor protein and the phage genome is very often incorporated into the bacterial genome by recombination of those two DNAs. If the phage genome becomes part of the bacterial genome, it may reverse this process and follow the lytic pathway often by the bacterial cell experiencing harsh environmental conditions which are enough to set the integrated phage genome onto a lytic pathway 4) Genomes of normal lytic phages go into the cell cytoplasm and transcribe and replicate their genomes. They produce the proteins involved in the lytic functions in a highly regulated manner. Phage replication is quick and regulated and occurs by several common mechanisms such as sigma, theta replication. Linear and double stranded replication occur in phages (Weigele and Steitz 2006). Some of these mechanisms have shed enormous light on bacterial replication, especially from small phages with limited genomes that rely heavily on bacterial replication proteins and processes to replicate their own genomes. 5) Assembly of the phage particle for the lytic pathway occurs from assembly and about the same time some phage encoded proteins weaken or destroy the bacterial cell wall or membrane to help the fully assembled phage escape from the bacterial cells.

Figure 3B. Gram positive cell envelope (with permission) From Essentials of Glycobiology, 2nd Edition 2009 CSH Press. This comprises of a thick covering of peptidoglycan with teichoic acid variants (LTA).

All members of this podoviridae family use their tails or tailspike proteins as the receptor-binding protein and many use the LPS as their major cell surface receptor (Lindberg 1973; Rakhuba et al 2010; Casjens and Molineaux 2012). The first stable contact between the P22 phage and the host cell surface involves the b-helix domain, BHD of the P22 TSP. A brief review of this general process including the structure of the P22 tailspike protein (TSP) and LPS is warranted (Casjens and Molineaux 2012).

Adsorption and DNA Entry into the Host Cell

Figure 4. Phage penetration of host cell capsule. Electron micrograph of K49 phage on its host cell capsule. This figure shows a dominant form of host cell capsule degradation by the phage particle with the final result that the phage is at the surface of the bacterial cell for actual infection and penetration by the phage DNA (with permission, Bayer et al 1979).

Studies have indicated that adsorption is a complex multistep process (Lindberg 1973; Israel 1976; Lindberg 1977; Venza Colon et al 2004; Andres et el 2010; Rakhuba et al 2010; Casjens and Molineaux 2012). Such a process may involve steps such as reversible binding of phage tails, followed by irreversible binding, DNA ejection from the phage particle and DNA entrance into the cell (Steinbacher et al 1994; Rakhuba et al 2010; Casjens and Molineaux 2012). Although the P22 TSP enzymatic activity uses the O-antigen, the most distal part of the LPS, as its substrate, phages can use almost any part of the LPS and most of the cell surface constituents as a receptor (Lindberg 1973; Lindberg 1977; Rakhuba et al 2010; Simoliunas et al 2015).

There are at least two models for the adsorption of phage to the cell surface (Storms and Sauvageau 2015). The first is the one in which the phage undergoes a reversible attachment to the host cell surface, then it undergoes an irreversible interaction. This first model is called the sequential model while the other model is called the adsorption efficiency model where the reversibly interacting species occur but favor the irreversible attachment to the cell surface. This second model is called the adsorption efficiency model. Both models have received experimental support. Initial (reversible) interaction confers some specificity to the phage-host interaction; and it reduces the search space and time for the irreversible interaction to occur. Excellent reviews of all matters dealing with adsorption have been published (Steinbacher et al 1996; Rakhuba et al 2010; Casjens and Molineaux 2012).

Initial reversible receptor binding does not trigger DNA release from the phage particle structure because this stage is responsible for reducing the 3D search for its main receptor to a 2D search. Initial binding of the phage particle to the cell surface uses a phage tail, tail fiber, tailspike or a small specialized part of the phage as its RBP for a very brief interaction with the bacterial cell surface where phage might completely desorb from the cell surface. Since the phage is already close to the cell surface, the RBP search time and space is significantly reduced. The Gram negative membrane system is complicated and fluid. Much of the surface is covered with lipopolysaccharide (LPS). A number of the LPS components serve as receptors. Once a tail interacts with LPS initial receptor, it may become laterally mobile in its initial reversible interaction moving from LPS moiety to LPS in search of a secondary receptor as suggested by in vitro studies (Baxa et al 1996). Phages that use LPS as a receptor can sometimes be inhibited by purified host cell O-antigen (van der Ley et al 1986; Scholl et al 2005). This might be thought of as the reversible phase of attachment. It has been shown that the interaction of P22 TSP with the LPS affects the DNA ejection (Andres et al 2010). The role of the primary receptor is likely to find and speed up the search for the secondary and permanent receptor site.

Figure 5. Tailspike protein structure (accession number 2xc1). Rasmol representation of the trimeric tailspike protein which is divided into three domains which are labeled in this figure. The first domain, the N-terminal domain, is dome-shaped, and is involved in the last step of the phage assembly path. The second domain is involved in the attachment of the phage to the host cell surface via its LPS. The third and last domain is the trimerization domain.

Phage RBPs interacting with Gram negative bacteria which receptor is protein may have a more difficult time to attach to a surface localized protein host cell receptor since navigating through host cell capsule (Figure 4 Bayer et al 1979). Orientation may also play an important in producing a successful primary and secondary cell surface interaction because only a small part of a RBP is often used initially for a productive interaction which may result in a productive secondary host cell receptor interaction. For historical reasons our emphasis will remain in phages that infect Gram negative bacteria. Phage can use more than one host cell receptor. Most of these studies have optimized RBP-host cell interaction under laboratory conditions, only recently has a large concerted effort been made to understand this interaction in more natural settings.

Salmonella Phage Particle-Host Cell Interaction

Phages can bind many different types of host cell receptors. Twenty-five phages were isolated and shown to bind to a random Tn5 transposon treated Salmonella typhimurium strains which were used in a small study to describe the receptor diversity of Salmonella typhimurium phages (Bayer et al 1979). These phages were shown to bind to three different receptors: flagella, BtuB and O-antigen. But only two classes of phages bound to these host cell receptors, siphoviridae and podoviridae.

The structure of the P22 receptor, LPS

The structure of the LPS, the TSP_b-helix substrate, consists of three segments: 1) The LPS structure closest to the cell membrane is the Lipid A which is hydrophobic and contains some fatty acid chains. It is actually embedded in the outer membrane of the Gram negative cell wall. There are phages which use some portions of this Lipid A as the receptor and this part of the LPS is associated with its endotoxin activity. 2) The second structural element is called the Core polysaccharides and contains more complex polysaccharides. 3) The third and most distal part of the LPS is the O-antigen (Wang and Quinn 2010). The latter structure is the substrate for the phage P22 TSP and many other phages, (Venza-Colon et al 2004; Rakhuba et al 2010; Casjens and Mollineux 2012;). This O-antigen consists of a repeating unit of three disaccharides (rhamnose, mannose and galactose) although the identity of these disaccharides in the LPS may vary with bacterial strain, it can be as long as 40 repeat units long. (Whitfield and Trent 2014; Maldonado et al 2016). Two of these repeat units can be seen in Figure 6 as the red bulbous mass in the center of the TSP structure (colored green). This figure shows that a crevice is created by the Dorsal Fin on the right (colored blue) and three looped regions in the left (colored pink) and it is there that the LPS sits. The active site residues are located on the inside and back of the crevice which binds the LPS (Baxa et al 1996; Steinbacher et al 1996). Other sites have been recently found to affect binding and/ or catalysis (R Villafane, unpublished data).

Figure 6. Tailspike protein structure with 2 O-antigen repeating units. This figure from the crystal structure shows part of the b-helix containing two units of O-antigen (bulbous red mass) nestled within a cavity created on the left by three ridges and on the right by the blue-colored Dorsal Fin loop (Steinbacher et al 1994).

The same molecule LPS probably serves as the primary receptor. Previous studies had shown that the average phage particle, which contains 6 TSPs, must have three of those six TPs in a complex with LPS molecules for that phage to be infectious (Israel 1976). All other interactions may lead to a reversible interaction. This requirement may serve to transform the phage from the reversible to the irreversible attachment stage. Another study has shown that DNA ejection does not need a secondary receptor since it can be triggered in vitro (Israel 1976) more recent studies do not support this hypothesis (Bohm et al 2018). The subsequent steps in this attachment process such as a needle-like protein penetrating the outer membrane and the periplasm, are more speculative than not and are well described (Casjens and Molineux 2011, Bhardwaj et al 2014).

Because the P22 TSP BH domain can hydrolyze glycosidic bonds, it is a glycoside hydrolase (or glycosidase) which enzyme class can be grouped into many families. More specifically it is an endorhamnosidase, Some of these families have a preponderance of BH domain structures (Rigden and Franco 2002). Knowledge gained from P22 TSP catalysis may be important in elucidating glycosidase mechanism in general.

The P22 TSP structure

The P22 phage system is an extremely well characterized system: the phage genetics are very well defined, assembly pathways have been worked out, replication and the lysogenic pathways are likewise known very well (Botstein et a 1973; King et al 1973; Steinbacher et al 1994; Steinbacher et al 1997; Prevelige 2006; Rakhuba et al 2010; Casjens and Thurman-Commike 2012). The DNA and protein sequences of the tailspike protein have long been known as well as its 3D structure is known (Sauer et al 1982; Steinbacher et al 1994). It is a member of the beta-helical class of proteins (Jenkins et al 1998; Seckler 1998). Monoclonal antibodies are available to the P22 TSP NTD and its b-helix domains (Speed et al 1995; Jain et al 2005). Yet details and mechanisms of actions at the molecular level still need further study.

The P22 TSP is a homotrimer with three domains and contains 666aa (Figure 5). The native protein consists of three domains: the N-terminal domain (NTD), aa1-aa109, sometimes called the head-binding region; the b-helix domain (BHD), aa143-aa540; and the trimerization domain (TD), aa541-aa666 (Steinbacher et al 1994). The N-terminal domain is composed of a dome-like structure, formed non-covalently from the first 108aa of each of the three TSP chains with recent studies describing the stability of its dome-like structure (See Figure 5, top part of structure; Steinbacher et al 1994; Steinbacher et al 1997; Palmer et al 2014; Williams et al 2018). The b-helix domain is structurally composed of three identical polypeptide chains which interact non-covalently. Each separate chain consists of a beta-sheet structure which takes on a helical spatial arrangement encompassing aa143-aa540 (Steinbacher et al 1994; Steinbacher et al 1997; Steinbacher et al 1996; Jenkins et al 1998). One helical turn consists of 22aa and there are thirteen such helical rungs in this structure (Steinbacher et al 1994; Steinbacher et al 1997; Steinbacher et al 1996). This domain is thought to derive much of its stabilization energy from interchain interaction. The b-helix (BH) structure contains two functions: LPS-binding and LPS hydrolysis (Baxa et al 1996). The BH structure of the P22 TSP is used to start the infection by binding to the host cell LPS at its O-antigen sites (Figure 3A) and subsequently cleaving it. Generally, it could be shown that the infection process could be inhibited by the addition of LPS to the infection mixture by phages that use the LPS as a host cell receptor. The P22 TSP BH domain binds to the most distal part of the LPS from the cell surface, the O-antigen. The trimeric domain is mainly involved in formation of the protrimer folding intermediate and in its final trimer formation (Kreisberg et al 2000; Kreisberg et al 2002; Gage et al 2005; Weigel et al 2005).

The native form of the P22 TSP is that of a homotrimer (Figure 5). This trimeric TSP exhibits interesting properties: it is resistant to heat (Tm of ~ 88.4 °C), resistant to denaturation by SDS detergent (if is not heated), and it is resistant to proteases (Goldenberg et al 1982; Sturtevant et al 1989). These properties can be rationalized since the TSP must be rather rigid because of the hostile environments that the phage encounters and must overcome in the wild. The resistance to SDS is particularly useful since the TSP can be electrophoresed in an SDS-PAGE and will migrate as a trimer (since it is not denatured), as long as the sample itself is not heated.

At its simplest, the P22 phage particle can be thought of as consisting of two protein subassemblies: the capsid and the tail machine. The phage heads contains DNA spooled and three proteins called the ejection proteins (Gp7, Gp16, Gp20) inside the capsid under high internal pressure. These three proteins are thought to help in the ejection of the phage DNA into the host cell. These are the ejection proteins or the E proteins (Israel 1977). These E proteins have been visualized by a new Bubblegram Imaging technology within the capsid (Wu et al 2016). Studies have shown that these proteins are ejected from the phage particles before the genomic DNA, consistent with their proposed function (Jin et al 2015). Of the three E proteins only the Gp16 protein partitioned into the membrane fraction in DNA transport studies suggesting that this one protein may help to build a channel needed during P22 DNA transport into cells (Perez et al 2008).

The capsid or coat protein is generally the largest phage particle compartment and it consists of one or very few proteins which protein protects the linear DNA genomic material of the P22 phage of 41,724 bp (Pedulla et al 2003). As such it is generally the most abundant protein isolated from the phage particle. The other part of the phage particle is the tail machine (the lower part of both phage particles in Figure 1 and also Figure 7 (Lander et al 2006). The five proteins of the tail machine are listed (Hartwieg et al 1984; Tang et al 2005; Bhardwaj et al 2014). The tail machine can be seen in upper and lower panels of Figure 7 in two different forms (Chang et al 2006; Tang et al 2005). The bottom panel is the more clearly delineated with respect to the component proteins (Tang et al 2005). It consists in order (from top to bottom, also is order of assembly) of: gp1 (portal protein, DNA gateway protein), GP4 (tail accessory protein 4), GP10 (tail accessory protein 10), GP26 (needle or plug), and finally gp9 (TSP). The portal protein is present in only one vertex location in the phage capsid (Figure 1). It allows for an internal channel to be made in its structure for entry and exit of DNA for its entrance into the viral particle during the intracellular assembly process and its exit during the ejection process during the initiation of infection. Once this protein is in place, GP4 and GP10 follow sequentially to assemble the tail machine. These two proteins add in that order to the portal protein. Each protein leaves an internal cavity for the DNA exit at the initiation of P22 phage infection. The long plug is added which prevents DNA from exiting the phage particle (Bhardwaj et al 2014). In the last step in phage P22 assembly, the P22 TSP binds to the crevices formed by the GP4 and GP10 proteins (Figure 7, especially upper panel). The upper panel clearly shows that the NTD of the P22 TSP is what binds to the GP4-GP10 interface (Chang et al 2006). This figure also shows that there are at least two forms of the bound TSP that have been observed. One such form shows that the P22 TSP NTD binds to the GP4-GP10 crevice and that BHD also binds to the GP10 (Upper panel of Figure 7). The other TSP bound form only interacts with the phage particle at the NTD. This suggests conformational interactions that lead to these two stable TSP-phage particle interactions

An assay has been devised to select for phage receptor binding proteins (RBPs) and it has shown that the tailspike protein is highly likely to be the only RBP (Simpson et al 2016). However, the host cell receptor for the Salmonella phage P22 has been definitively determined to be LPS (Israel et al 1967; Steinbacher et al 1994; Baxa et al 1996). In vitro studies showed that the addition of LPS triggered the very slow release of P22 genomic DNA from the phage particles which suggested that there was no need for a cellular receptor (Andres et al 2010). Also important was the fact that the P22 TSP produced only two cleavage events per minutes at bacterial physiological temperatures (Baxa et al 1996). This latter report concluded that the TSP must spend a lot of time in the LPS before a cleavage event, happen, searching for its secondary and irreversible binding site. Its determined cleavage rate was not physiologically relevant.

Studies on another phage, Shigella phage Sf6, produced data very helpful for insight into the P22 system. The N-terminal domain of the Sf6 phage TSP contains a tailspike protein whose first 108 amino acids are very similar to that corresponding region on the P22 TSP (Zayas and Villafane 2007; Freiberg et al 2002; Muller et al 2008). Its 3D structure is similar to that of P22 TSP without amino acid similarity but the glycosidase enzymatic activity occurs between the monomer units of the trimeric Sf6 TSP as opposed to the P22 TSP in which every monomeric unit has enzymatic activity in and of itself (Muller et al 2008). For Sf6 phage it has been shown that both OmpA and OmpC proteins are required for infection (Parent et al 2014). During phage assembly DNA is spooled into the phage capsid, leaving the DNA-filled phage capsid under high internal pressure, using a clever in vitro assay with high molecular weight polyethylene glycol (“in vitro osmotic suppression system”), the release of the P22 DNA and the E proteins from the capsid was measured (Bhardwaj et al 2014, Jia et al 2015). Under these conditions of osmotic pressure induced by PEG, LPS alone was insufficient to release E proteins from the capsid under conditions that would not release the P22 genomic DNA from the capsid. However, under the same conditions of high pressure, the addition of LPS and OmpA (outer membrane protein A, a known receptor for Sf6 infection) to the assay, resulted in release of the E proteins.

The P22 phage adsorption process was shown to be temperature-independent and it was complete within five minutes after the start of infection process (Venza-Colon 2004). It is likely to involve only the P22 phage tailmachine structure (Figure 7 [phage proteins: Gp1, GP4, GP10, GP26 and Gp9]) P22 phage mutants have been isolated, in this laboratory by hydroxylamine mutagenesis that have characteristics of adsorption mutants (Venza-Colon 2004). Mutants obtained in this study were divided into two types: those that delayed adsorption and those that did not (Venza-Colon et al 2004). Thus, adsorption for the P22-Salmonella system is a multistage process (further studies are in progress). Further characterization of these mutants may provide insight into these complex processes and the proteins responsible for them as well as the possibility of secondary site receptors through suppressor analyses (R. Villafane, unpublished).

Figure 7. Cryoelectron Microscope of the P22 tailmachine. This figure contains two panels both cryoEM micrographs. Panel A is modified from Chang et al 2006 (with permission) and it clearly shows how the N-terminal domain of the P22 TSP is located in the crevice formed by the intersection of the GP4 and GP10 proteins. It shows one tail. It shows the phage plug that extends below the level of the P22 TSP and it indicates another secondary attachment site from the P22 TSP b-helix domain to the GP10 structure. The curved arrow at the left shows how the secondary site can lead to a squat splayed-out structure for the P22 TSP. (Chang et al 2006, with permission). The bottom panel shows the tailmachine with the relevant parts of the tailmachine labeled on the figure (Tang et al 2005, with permission). The bottom Panel B also show the channel available for the DNA to exit the phage particle.

A very recent and important study took advantage of individual reports of the generation of single gene and multiple gene deletion studies and other studies using transposons to identify genes involved in the infection process of the P22 phage into Salmonella typhimurium bacterium (Bohm et al 2018). The mutations generated showed that the corresponding proteins were non-essential to S typhimurium. One major result was the identification of an inner membrane protein essential for P22 phage infectivity. This protein, YajC, is a Sec translocase component. Although this protein is not essential for bacterial survival, it has been isolated in vitro as one of the components of the bacterial protein holotranslocase (Schulze et al 2014).

A speculative adsorption model for the interaction of the P22 and Salmonella typhimurium cell surface may entail the following. 1) Each phage particle consists of six tails of which each tail is composed of a trimer of the TSP. Theoretically each TSP is capable of binding one LPS molecule (actually the O-antigen part of the LPS). Each phage should be capable of binding 18 LPS molecules. 2) The phage interacts in a reversible manner with the host cell LPS. This can lead to lateral mobility of the P22 TSP on the LPS. 3) It had been determined that an interaction of three tails with LPS was necessary for infection. 4) Figure 7A shows that there are two TSP binding sites with other phage particle proteins. One interaction occurs between the P22 TSP NTD and a crevice at the interface between GP4 and GP10 while the other TSP binding site occurs between an area in the b-helix part of the TSP and GP10. 5) If the interaction between the b-helix part of the TSP and GP10 is real and functional, then this interaction might induce a conformational change in the TSP that could dissociate the TSP b-helix- GP10 interaction, this in turn might result in the “splay-out” conformation of the TSP where the TSP would be closer to being perpendicular to the main axis of the phage particle. This expanded form of the TSP might be likely to interact with LPS and thus cause the transition to the productive irreversible state of LPS binding. 6) If these interactions have functional significance, it is clear that a signal may be passed from b-helix structure or from the NTD to the b-helix structure. Alternatively, initial TSP-LPS interaction with the normal phage structure may cause conformational changes in the TSP which would accelerate TSP-LPS interaction (Andres et al 2010). 7) Enzymatic hydrolysis of the LPS ensues bringing both the TSP and the phage plug, GP26, closer to the cell surface. 8) As the GP26 protein (called plug or needle) reaches the membrane perhaps it interacts with the OmpA protein which has been shown to be a surface receptor for P22 phage as it accelerates the infection process (Jin et al 2015). 9) The hydrolysis of the LPS, may bring the GP26 .in contact with the cell surface (Figure 7). 10) Since the GP26 is long enough to interact with the inner membrane, it may interact directly with the YajC protein, a part of the Sec translocase, now Sec holotranslocon, HTL (Bohm et al 2018, Schulze et al 2014). 11) The YajC-GP26 interaction may cause a conformational change in the GP26 structure making it conformationally unstable and susceptible to proteolysis. 12) Since it has been shown that TSP and LPS interaction can result in DNA release from the capsid and it has been shown that the E-proteins are released before the genome during infection, then it is likely that the GP26 conformational change is transmitted to the TSP before proteolysis. That signal results in the release of the GP26 and subsequent release of the E-proteins from the capsid. 13) Proteolysis would result in a formation of “tunnel” into which the E-protein would drop. This would allow one of the E-proteins, GP16, to form a putative temporary intermembrane proteinaceous bridge for the subsequent passage of phage DNA into the cytoplasm (Perez et al 2008). Conformational changes are expected to drive many of these interactions.

Conclusion

The model described above points to the complexity of this simple process of phage infection initiation. Some of the complexity of this system can be handled by a genetic analysis of some of the steps. Many of the major steps of infection initiation involve analyzing complex conformational interactions in a multi-protein system which are the most interesting but are expected to be challenging for the near future.

This review presented a brief summary of phages, their lifecycle and the importance of phage infection studies with emphasis on the advances in studies related to the interaction of the Salmonella phage P22 with its host Salmonella typhimurium. Such studies are a prelude to a more mechanistic understanding of this interaction which is critical for its use as an agent for the elimination of its host through studies of phage therapy. The role of protein conformation will be essential for its use in an age of increasing appearance of multiply-antibiotic resistant bacterial strains. But currently there is a stark need for the application of other means to treat and eradicate the rise of the multi-antibiotic-resistant bacteria at a time when treatments for these bacteria have not kept up with this devastating trend. Very soon after the discovery of phages, attention was focused on the use of these phages as a bacterial treatment. The lack of standardization of the phage treatments and the development of antibiotics lead to a de-emphasis of phage treatment. Recently, phage therapy has now shown that both the phage particle and phage-encoded protein can be used to treat bacterial strains.

Only an intense and comprehensive study of phage-host interactions can lead to an understanding that will result in weaponizing the phage against the bacterial pathogens. For this reason, this review presented a summary of some of the data concerning interaction of this phage with the host cell membrane, using Salmonella phage P22 as a model system. This initial interaction is itself a target for phage and protein therapy of these pathogenic multiply drug resistant strains and yet opens up significant basic questions that are essential for phage interaction itself.

Acknowledgements

The author wishes to acknowledge Dr Jonathan King for introducing me to this wonderful and never-ending protein as well as Drs Jon King and Andrew Wright for encouragement in the early times. This area of study is replete with excellent workers who have contributed significantly such Drs Robert Seckler and Robert Huber, Peter Prevelige, Bentley Fane, Chris Bazinet, Sherwood Casjens, Andrew Kropinski, Mike McConnell, Cameron Haase-Pettingell, Vaidhi Sridhar, Celia Colon Venza and a large number of others which for time and page limitations I am unable to mention. Lastly I wish to thank members of my laboratory both past and current for their contributions and the Alabama State University and the College of Science, Mathematics and Technology for their continuous support.

References

Abedon ST, Kuhl SJ, Blasdel BG, Kutter EM. (2011) Phage treatment of human infections. Bacteriophage. 1, 66–85.

Ackermann H. (2006) 5500 Phages examined in the electron microscope. Arch Virol., 152, 227-243.

Ackermann H. (2009) Phage classification and characterization. Meth Mol. Biol., 501, 127-140.

Ackermann H. (2011) The first phage electron micrographs. Bacteriophage, 1, 225-227.

Ackermann H. (2011a) Bacteriophage Taxonomy. Microbiol. Austral., 32, 90-94.

Allen HK, and Abedon ST. (2014) Virus ecology and disturbances: Impact of environmental disruption on the viruses of microorganisms. Front. Microbiol., 5, 700.

Andres D, Hanke C, Baxa U, Seul A, Barbirz S, Seckler R. (2010) Tailspike interactions with lipopolysaccharide effect DNA ejection from phage P22 particles in vitro. J. Biol. Chem., 285, 36768-36775.

Baker M, Jiang W, Rixon F, and Chiu W. (2005). Common ancestry of Herpesviruses and tailed DNA bacteriophages. J. Virol., 79, 14967-14970.

Baxa U, Steinbacher S, Miller S, Weintraub A, Huber R. (1996) Interactions of phage P22 tails with their cellular receptor, Salmonella O-antigen polysaccharide. Biophys. J., 71, 2040-2048.

Bayer, M., Thurow, H., & Bayer, M. (1979). Penetration of the polysaccharide capsule of Escherichia coli (Bi161/42) by bacteriophage K29. Virology, 94, 95-118.

Bhardwaj A, Olia AS, Cingolani G (2014) Architecture of viral genome-delivery molecular machines. Curr. Opin.Struc.Biol., 25, 1–8

Bohm K, Porwollik S, Chu W, Dover JA, Gilcrease EB, Casjens SR, McClelland M, Parent K. (2018) Genes affecting progression of bacteriophage P22 infection in Salmonella identified by transposon and single gene deletion screens. Molec. Microbiol., 108, 288-305.

Botstein D, Waddell CH, King J. (1973) Mechanism of head assembly and DNA encapsulation in Salmonella phage P22. I. Genes, proteins, structures and DNA metabolism. J. Molec. Biol., 80, 669-695.

Bradley D. (1967) Ultrastructure of bacteriophages and bacteriocins. Bacteriol. Revs., 31(4), 230-314.

Brouns S, Jore M, Lundgren M, Westra E, Slijkhuis R, and Snijders A. et al. (2008). Small CRISPR RNAs guide antiviral defense in Prokaryotes. Science, 321, 960-964.

Bhardwaj A, Olia AS, Cingolani G (2014) Architecture of viral genome-delivery molecular machines. Curr. Opin.Struc.Biol., 25, 1–8

Cairns J, Stent G, and Watson J. (2007) Phage and the origins of molecular biology (1st ed.). Cold Spring Harbor: Cold Spring Harbor Laboratory Press.

Callow BR. (1959) A new phage-typing scheme for Salmonella typhimurium. J. Hyg., 57, 346–359.

Carbonell X, Villaverde A. (1996) Peptide display on functional tailspike protein of bacteriophage P22. Gene, 176, 225-229.

Casjens SR, Molineux IJ. (2012) Short noncontractile tail machines: adsorption and DNA delivery by podoviruses. Adv. Exp. Med. Biol., 726,143-179.

Casjens SR and Thuman-Commike PA. (2012) Evolution of mosaically related tailed bacteriophage genomes seen through the lens of phage P22 virion assembly. Virology, 411, 393-415.

Chapot-Chartier M-P (2014) Interactions of the cell-wall glycopolymers of lactic acid bacteria with their bacteriophaqes. Front. Microbiol., 5, 236

Chatterjee S and Rothenberg E (2012) Interaction of bacteriophage l with its E. coli receptor, LamB. Viruses, 4, 3162-3178.

Chirakadze, I., Perets, A., & Ahmed, R. (2009). Phage Typing. Meth. Molec. Biol., 501, 293-305.

Clokie, M. R.J., Millard, A. D., Letarov, A. V., Heaphy, S. (2011) Phages in nature. Bacteriophage 1, 31-45.

d'Herelle, F. (1917). Sur un microbe invisible antagoniste des bacilles dysenteriques. C. R. Acad. Sci. Ser. D., 165, 373-375.

Danovaro R, Corinaldesi C, Dell’Anno A, Fuhrman JA, Middelburg JJ., Noble RT, Suttle CA. (2011) Marine viruses and global climate change. FEMS Microbiol. Rev. 35, 993-1034.

Delbruck M. (1940) Adsorption of bacteriophage under various physiological conditions of the host. J. Gen. Physiol., 23, 631-642.

Deresinski S. (2009) Bacteriophage Therapy: Exploiting Smaller Fleas. Clin. Infect. Dis,. 48, 1096-1101.

Doudna J, and Charpentier E. (2014) The new frontier of genome engineering with CRISPR-Cas9. Science, 346, 1258096-1258096.

Esko JD, Doering TL, and Raetz CRH (2009) Eubacteria and Archaea in Essentials of Glycobaceria, (Varki et al editors, 2nd Edtion, Cold Spring Harbor, NY, Cold Spring Harbor Laboratory Press, 2009.

Freire-Moran, L., Aronsson, B., Manz, C., Gyssens, I., So, A., Monnet, D., & Cars, O. (2011) Critical shortage of new antibiotics in development against multidrug-resistant bacteria—Time to react is now. Drug Resistance Updates, 14, 118-124.

Gage MJ, Zak JL, Robinson AS (2005) Three amino acids that are critical to formation and stability of the P22 tailspike trimer. Protein Sci., 14, 2333-2343.

Goldenberg DP, Berget PB, King, J (1982) Maturation of the tail spike endorhamnosidase of Salmonella phage P22. J. Biol. Chem., 257, 7864-7871.

Greenberg M, Dunlap J, Villafane R. (1995) Identification of the tailspike protein from the Salmonella newington phage e34 and partial characterization of its phage associated properties. J. Struc. Biol., 115, 283-289.

Guerrero-Ferreira, R., & Wright, E. (2013). Cryo-electron tomography of bacterial viruses. Virology, 435, 179-186.

Guo S, and Ao Z (2012) Phage in the diagnosis and treatment of tuberculosis. Front. Biosci. 17, 2691-2697.

Hargreaves K, Kropinski, A, and Clokie M. (2014). Bacteriophage behavioral ecology. Bacteriophage, 4, e29866.

Israel V. (1976) Role of the bacteriophage P22 tail in the early stages of infection. J. Virol. 18, 361-364.

Jain M, Evans MS, King J, Clark PL (2005) Monoclonal antibody epitope mapping describes tailspike folding and aggregation intermediates. J. Biol. Chem., 280, 23032-23040.

Jenkins J, Mayans O, Pickersgill R. (1998) Structure and evolution of parallel b-helix proteins. J. Struc. Biol., 122, 236-246.

Jin Y, Sdao SM, Dover JA, Porcek NB, Knobler CM, Gelbart WM, Parent KN (2015) Bacteriophage P22 ejects all of its internal proteins before its genome. Virology, 485, 128-134.

Johnson J. (2010) Virus particle maturation: insights into elegantly programmed nanomachines. Curr. Opin. Struc. Biol. 20, 210-216.

Johnson J. (2013) Confessions of an icosahedral virus crystallographer. Microscopy, 62, 69-79.

King J, Lenk EV, Botstein D (1973) Mechanism of head assembly and DNA encapsulation in Salmonella phage P22. II. Morphogenetic pathway. J. Mol. Biol. 80, 697-731.

Kreisberg JF, Betts SD, King J (2000) b-helix core packing within the triple-stranded oligomerization domain of the P22 tailspike. Protein Sci. 9, 2338-2343.

Kreisberg JF, Betts SD, Haase-Pettingell C, King J. (2002) The interdigitated b-helix domain of the P22 tailspike protein acts as a molecular clamp in trimer stabilization. Protein Sci., 11, 820-830.

Kutter E. (2009) Phage host range and efficiency of plating. Meth. Mol. Biol., 501,141-149.

Kuznetsov, Y. & McPherson, A. (2011). Atomic force microscopy in imaging of viruses and virus-infected cells. Microbiol. Mol. Biol. Rev. 75, 268-285.

Lin D, Koskella B and Lin H (2017) Phage therapy: An alternative to antibiotics in the age of multi-drug resistance. World J. Gastrointest. Pharmacol. Ther., 8, 162-173.

Lindberg AA (1973) Bacteriophage receptors. Ann. Rev. Microbiol., 27, 205-241.

Lindberg, A. A. (1977) Bacterial surface carbohydrates and bacteriophage adsorption, p. 289-356. In I. W. Sutherland (ed.), Surface carbohydrates of the prokaryotic cell. Academic Press, Inc., New York.

Loc-Carrillo C. and Abedon ST. (2012) Pros and cons of phage therapy. Bacteriophage 1, 111-114.

Lombard J (2014) Once upon a time the cell membrane: 175 years of cell boundary research. Biology Direct, 9, 32,

Maldonado RF, Sa-Correia I, Valvano MA. (2016) Lipopolysaccharide modification in Gram-negative bacteria during chronic infection. FEMS Microbiol. Rev., 40, 480-493.

Menouni R, Hutinet G, Petit M, and Ansaldi M. (2014) Bacterial genome remodeling through bacteriophage recombination. FEMS Microbiol. Letts., 362, 1-10.

Moineau S, Tremblay DM (2017) Bacteriophage. Ref. Mod. Life Sci., 1-5.

Nikaido H. (2009). Multidrug Resistance in Bacteria. Annu. Rev. Biochem., 78, 119-146.

O'Sullivan L, Buttimer C, McAuliffe O, Bolton D, and Coffey A. (2016) Bacteriophage-based tools: recent advances and novel applications. F1000 Research, 5, 2782.

Parisien A, Allain B, Zhang J, Mandeville R, and Lan C. (2008) Novel alternatives to antibiotics: bacteriophages, bacterial cell wall hydrolases, and antimicrobial peptides. J. Appl. Microbiol., 103, 1-13.

Perez, G., Huynh, B., Slater, M., & Maloy, S. (2008). Transport of Phage P22 DNA across the Cytoplasmic Membrane. J. Bacteriol., 191, 135-140.

Pires, D., Cleto, S., Sillankorva, S., Azeredo, J. and Lu, T. (2016). Genetically engineered phages: A review of advances over the last decade. Microbiol. Mol. Biol. Rev., 80, 523-543.

Prevelige Jr, PE (2006) Bacteriophage P22, In: “The Bacteriophages,” R. Calendar, editor, 2nd Edition, pp. 457-468, Oxford University Press

Pirnay J-P, Verbeken G, Ceyssens P-J, Huys I, De Vos D, Ameloot C, Fauconnier A. (2018) The magistral phage. Viruses, 10, 64

Qi H, Lu H, Qiu H-J, Petrenko V, Liu A (2012) Phagemid vectors for phage display: Properties, characteristics and construction. J. Mol. Biol., 417, 129-143.

Rakhuba DV, Kolomiets EI, Dey ES, Novik GI (2010) Bacteriophage receptors, mechanisms of phage adsorption and penetration into host cell. Pol. J. Microbiol., 59, 145-155.

Ranson, NA, Stockley, PG. Cryo-electron microscopy of viruses. In: Stockley, PG, Twarock, editors. Emerging Topics in Physical Virology. London: Imperial College Press; 2010. pp. 1-34.

Rigden DJ, Franco OL. (2002) Beta-helical catalytic domains in glycoside hydrolase families 49, 55, and 87: domain architecture, modelling and assignment of catalytic residues. FEBS. Letts., 530, 225-232.

Riordan S, Heruth D, Zhang L, and Ye S. (2015). Application of CRISPR/Cas9 for biomedical discoveries. Cell Biosci, 5

Rohwer F, Segall A (2015) In retrospect: A century of phage lessons. Nature, 528, 46-48.

Ross A, Ward S, and Hyman P. (2016) More Is Better: Selecting for Broad Host Range Bacteriophages. Front Microbiol., 7.

Salmond G, Fineran P (2015). A century of the phage: past, present and future. Nat. Rev. Microbiol., 13, 777-786.

Sauer RT, Krovatin W, Poteete AR, Berget PB. (1982) Phage P22 tail protein: Gene and amino acid sequence. Biochemistry, 21, 5811-5815.

Schulze RJ, Komar J, Botte M, Allen WJ, Whitehouse S, Gold VAM, a Nijeholt JAL, Huard K, Berger I, Schaffitzel C, Collinson I. (2014) Membrane protein insertion and proton-motive-force-dependent secretion through the bacterial holo-translocon SecYEG-SecDF-YajC-YidC. Proc. Natl. Acad. Sci. USA., 111, 4844-4849.

Schwarzer D, Buettner F, Browning C, Nazarov S, Rabsch W, and Bethe A. et al. (2012) A multivalent adsorption apparatus explains the broad host range of phage phi92: A comprehensive genomic and structural analysis. J. Virol., 86, 10384-10398.

Seckler R. (1998) Folding and function of repetitive structure in the homotrimeric phage P22 tailspike protein. J. Struc. Biol., 122, 216-222.

Selvarajan S, Zhao H, Kamau Y, Baines J, and Tang L. (2013). The structure of the herpes simplex virus DNA-packaging terminase pul15 nuclease domain suggests an evolutionary lineage among eukaryotic and prokaryotic viruses. J. Virol., 87, 7140-7148.

Silhavy T, Kahne D, Walker S (2010) The bacterial cell envelope. CSH Perspectives in Biology ;2:a000414

Smith G. (1985) Filamentous fusion phage: novel expression vectors that display cloned antigens on the virion surface. Science, 228, 1315-1317.

Smith GP and Petrenko VA. (1997) Phage display. Chem. Rev., 97, 391-410.

Speed, MA, Wang DIC, King J. (1995) Multimeric intermediates in the pathway to the aggregated inclusion body state for P22 tailspike polypeptide chains. J. Protein Sci. 4, 900-908.

Steinbacher S, Baxa U, Miller S, Weintraub A, Seckler R et al (1996) Crystal structure of phage P22 tailspike protein complexed with Salmonella sp. O-antigen receptors. Proc. Natl. Acad. Sci. USA., 93, 10584-10588.

Steinbacher S, Miller S, Baxa U, Budisa N, Weintraub A et al. (1997) Phage P22 tailspike protein: Crystal structure of the head-binding domain at 2.3Å, fully refined structure of the endorhamnosidase at 1.56Å resolution, and the molecular basis of O-antigen recognition and cleavage. J. Mol. Biol. 267: 865-880.

Steinbacher S, Seckler R, Miller S, Streipe B, Huber R. et al. (1994) Crystal structure of the P22 tailspike protein: Interdigitated subunits in a thermostable trimers. Science, 265, 383-386.

Storms Z, and Sauvageau D (2015). Modeling tailed bacteriophage adsorption: Insight into mechanisms. Virology, 485, 355-362.

Sturtevant JM, Yu M-H, Haase-Pettingell C, King J (1989) Thermostability of temperature-sensitive folding mutants of the P22 tailspike protein. J. Biol. Chem., 254, 10693-10698.

Switt A, Sulakvelidze A, Wiedmann M, Kropinski A, Wishart D, Poppe C, Liang Y (2015) Salmonella phages and prophages: genomics, taxonomy, and applied aspects. Meth Mol. Biol., 1225, 237-287.

Ventola CL (2015) The antibiotic resistance crisis, Part I: Causes and threats. Pharm. Thera. 40, 277-283.

Venza CJC, Vazquez ALY, Villafane R (2004) Initial interaction of the P22 phage with the Salmonella typhimurium surface. PR Health Sci. J., 23, 95-101.

Villafane R, Zayas M, Gilcrease EB, Kropinski AM, Casjens SR (2008) Genomic analysis of bacteriophage e34 of Salmonella enterica serovar Anatum (15+). BMC Microbiol., 8, 227.

Villafane R (2009) Construction of phage mutants. Meth. Mol. Biol., 501, 223-238.

Wang X, Quinn PJ (2010) Lipopolysaccharide: Biosynthetic pathway and structure modification. Prog. Lipid Res., 49, 97-107.

Weigel C, and Seitz H (2006). Bacteriophage replication modules. FEMS Microbiol. Rev., 30, 321-381.

Weigele PR, Haase-Pettingell C, Campbell PG, Gossard DC, King J (2005) Stalled folding mutants in the triple b-helix domain of the phage P22 tailspike adhesion. J. Molec. Biol., 354, 1103-1117.

Weinbauer, M. (2004). Ecology of prokaryotic viruses. FEMS Microbiol. Rev, 28, 127-181.

Whitfield C, and Trent MS. (2014) Biosynthesis and export of bacterial lipopolysaccharides. Annu. Rev. Biochem., 83, 99–128.

Williams J, Venketesan K, Ayariga JA, Jackson D, Wu H, Villafane R (2018) An important hydrophobic interaction at the P22 TSP N-terminal domain. Arch Virol, accepted for publication.

Zayas M, and Villafane R. (2007) Identification of the Salmonella phage e34 tailspike gene. Gene, 386, 211-217.

Citation:

Joseph A. Ayariga, Karthikeya Venkatesan, Robert Ward, Hongzuan Wu, Doba Jackson, and Robert Villafane* (2018) Initiation of P22 Infection at the Phage Centennial, Frontiers in Science, Technology, Engineering and Mathematics, Volume 2, Issue 2, 64-81

Page updated

Report abuse