Phages and Pathogenicity

The tremendous impact of phages on the pathogenicity of their host has only recently become the focus of detailed research.

Phages can introduce new bacterial DNA into their host after infection. Although regulated, the normal packaging of phage DNA into capsids can in certain cases result in incorporation of host DNA into phage particles. This process is called transduction and occurs in two different forms. In specialized transduction, improper excision of phage DNA results in packaging of host genes immediately adjacent to the phage genome into infectious phage particles (Matsushiro 1963). This process is unlikely to have a large impact on the pathogenicity of bacteria which are infected by these particles, since only very small portions of host DNA are transduced, and these portions are always those adjacent to the phage integration sites. In generalized transduction, however, random host DNA roughly equal in size to a normal phage genome may be packaged into the empty phage heads. The resulting particles are identical to normal phage except for their information content, and they can perform the first two steps of the infectious process, attachment and injection of DNA (Ikeda and Tomizawa, 1965). A schematic overview of generalized transduction is shown in Figure 13.1. It is conceivable that such a more or less randomly selected stretch of host DNA may also contain virulence factors which can, upon recombination with the chromosome of the infected bacteria, influence the phenotype and pathogenicity of the recipient.

Ikeda Tomizawa Transduction

Figure 13.1. The principle of generalized transduction is shown here. In panel A, normal phage development is depicted. After rolling-circle replication of the phage DNA into multigenome concatemers, the genomes are individually packaged into empty heads (1). Phage particles are assembled (2), and progeny virions are released to infect new host cell (3). In panel B, host DNA is packaged into phage head particles (1). Particles containing bacterial DNA are normally assembled (2), and phage progeny is released. These pseudoinfective particles containing host DNA can inject the mistakenly packaged genetic material into susceptible host bacteria (3).

Figure 13.1. The principle of generalized transduction is shown here. In panel A, normal phage development is depicted. After rolling-circle replication of the phage DNA into multigenome concatemers, the genomes are individually packaged into empty heads (1). Phage particles are assembled (2), and progeny virions are released to infect new host cell (3). In panel B, host DNA is packaged into phage head particles (1). Particles containing bacterial DNA are normally assembled (2), and phage progeny is released. These pseudoinfective particles containing host DNA can inject the mistakenly packaged genetic material into susceptible host bacteria (3).

Evidence for this mechanism has been put forward, implicating phages in the distribution of a virulence-associated region in the genome of the animal pathogen Dichelobacter nodosus and various other bacteria (Cheetham and Katz 1995).

A phenomenon called lysogenic conversion is often involved in the modulation of host pathogenesis by phage. After incorporation of a temperate phage genome into the host chromosome, most prophage genes are silenced, especially those involved in virus morphogenesis and host cell lysis. In contrast, the genes needed to maintain the lysogenic state are normally expressed during lysogeny. However, bioinformatic analyses have demonstrated that many phage-encoded genes have unknown functions, and it is generally assumed that temperate phages can serve as vectors to introduce novel genetic information into their host that may enhance their fitness in certain environments. These coding sequences may themselves directly specify new properties or act by influencing the expression of existing genes. If this new environment happens to be the human body, the results can be dramatic. Table 13.1. shows several examples of pathogens, their prophages, and the toxins or virulence factors that are encoded by the phages. Such lysogenic conversion has also been reported for Mycoplasma, Staphylococcus, and Streptococcus (for a comprehensive overview of the state of research concerning these matters, the interested reader is referred to recent overviews on phage-related virulence of pathogens; Waldor et al. 2005).

Interestingly, the transcription promoter for the CTX cholera toxin from Vibrio cholerae (Table 13.1.), encoded by genes ctxA and ctxB, is not phage-regulated but controlled by the master V. cholerae virulence regulator, transcription factor ToxR (Skorupski and Taylor 1997). This is in contrast to another well-known example of lysogenic conversion: that of shiga-like toxin (stx) converting E. coli phages (Table 13.1.), where the transcription of stx genes is largely controlled by

Table 13.1. Examples of temperate phages encoding pathogenicity and/or virulence factors required for bacterial pathogenesis.

Host species Phages Genes Virulence factor Reference

Vibrio cholerae CTX$ ctxA/ctxB Cholera toxin CTX Waldor and Mekalanos

Escherichia coli H19-B stx1A/stx1Bstx2A/stx2 (STEC, EHEC) 933W

Shiga-like toxins Smith et al. (1983) and STX1 and STX2 O'Brien et al. (1984)

Salmonella enterica

Fels-1 nanH SopE$ sopE

Neuraminidase Hardt and Galan (1997)

Type III-translocated and Figueroa-Bossi et

G nucleotide al. (2001) exchange factor

Clostridium 1D

botulinum

Corynebacterium ß diphtheriae botD

Neurotoxin BoNT Eklund et al. (1971)

Freeman (1951)

late phage promoters, and the highest levels of STX transcription are observed during lysis of part of the bacterial population (Yee et al. 1993). Virulence modulation after phage induction has recently also been reported for Staphylococcus aureus (Goerke et al. 2006). The observations indicate that not only the phage per se, but also the highly specific interaction of both virus and host cell is responsible for full expression of the phenotype.

13.2. Listeria Phages

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