Immunity to bacteriophages

Bacteriophages are viruses comprising one type of nucleic acid, either DNA or RNA, and a capsid which protects the encapsided nucleic acid. After a random collision between the virion and the bacterial cell, the phage becomes specifically and irreversibly attached to a receptor located on the outer surface of the host cell. The phage DNA is then injected into the cytoplasm of the host. Two consequences of phage infection are possible: .1.) The bacteriophage replicates its DNA, produces the structural components of new phage particles, and packages the newly replicated DNA into the preheads. The progeny phages are released concomitant with lysis of the cell. This genetically well-regulated process is defined as the lytic cycle. 2) The phage structural proteins are not synthesized and the phage genetic material integrates into the bacterial chromosome and becomes dependent on the bacterial multiplication process. A cell that has integrated a phage DNA into its chromosome is referred to as a Ivsogen and the integrated phage DNA is termed a prophage. These two outcomes are possible for temperate phages, in contrast to the virulent phages which only-go through the lytic cycle. Immunity to phage is the refractory state of an infected bacteria to be reinfected by a phage of the same type. Immunity to superinfection proceeds differently with temperate phages and with virulent phages.

Virulent phages

After infection of cells with the virulent T4 bacteriophage, genetic markers from a superinfecting phage of the same or closely related type are not recovered. The superinfecting phage adsorbs to the cell surface but superinfection immunity prevents entry of the bacteriophage DNA into the cytoplasm of the bacteria. The DNA is ejected from the phage capsid into the intermembrane space of the bacteria where it is degraded by an endonuclease. Ghosts of phage T4 which lack DNA are also capable of killing nonin-fected bacteria. They provoke a depolarization of the cytoplasmic membrane but, in contrast to the action of intact T4 phages, the membrane is irreversibly depolarized. It is thought that transmembrane channels allow the penetration of phage DNA into the cytoplasm of the bacteria. On superinfection, binding of T4 to cells, tail-sheath contraction and penetration of the tail tube into the periplasm occur normally, but phage DNA is not liberated into the cytosol. An immunity mechanism causes the degradation of the ejected DNA.

The T4 bacteriophage immunity gene has been identified in the T4 genome. It encodes an immunity protein that acts 1-2 min after infection and which is responsible for most of the immunity to superinfection. The deduced amino acid sequence from the DNA sequence suggests that this protein has the structural features of an integral plasma membrane protein. The protein contains two hydrophobic segments which serve as membrane anchors. The action of the immunity protein specifically prevents superinfection by T-even phages. It is located at specific sites on the plasma membrane, bound to another protein, tt may act indirectly by changing the conformation of the bound protein to prevent DNA transfer (Figure 2). The immunity protein acts stoichio-metrically, therefore it must be located near the injection site or be able to diffuse very rapidly to this site since immunity develops in less than 2 min.

Temperate phages

Lysogenic bacteria are immune to infection by a phage of the carried type. Superinfecting phages of the same type as the integrated phage are unable to express their vegetative functions. This process is due to the expression of a prophage gene product called repressor which represses the expression of vegetat-

Adsorbed T4 phage

Superinfecting phage

Cellular component involved in the transfer of the phage genome into the cytoplasm

Phage genome injected into the cytoplasm

DNA retained In the phage head

Phage genome ejected into the periplasi

Phage genome ejected into the periplasi

Cellular component involved in the transfer of the phage genome into the cytoplasm

Outer membrane

Mu rein layer

Inner membrane

Inhibition of DNA transfer by the immunity protein

Phage genome injected into the cytoplasm

Figure 2 The immunity protein, probably bound to a plasma membrane protein, inhibits superinfecting phage DNA transfer. Its action may be indirect and remains poorly understood.

ive viral genes. The immunity thus depends on the synthesis of a repressor and on the sensitivity to this repressor, which is conferred by the repressor DNA binding sites. For the phage these flank the gene encoding the repressor. The region delimited by the repressor binding sites is referred to as the immunity region because it determines the type of superinfection immunity conferred by the prophage. Immunity of temperate bacteriophages is thus based on a pro-tein-DNA interaction which prevents the replication of the integrated phage and of superinfecting phages of the same type.

Immunity to bacteriophages Mu and PI is caused by a repressor which prevents transcription initiation at key promoters for lytic gene expression. Expression of the genes involved in the lytic cycle may also be prevented by the premature termination of transcription, as seen for phage P4. In this case, the trans-acting immunity factor is not a protein but a short RNA which causes transcription termination by pairing with complementary target sequences. For temperate bacteriophage PI, lysogenic bacteria do not carry the prophage integrated into the host chromosome, but the bacteriophage DNA remains as an autonomous plasmid in the cytoplasm of the host cell. Superinfection immunity is conferred by two repressors which prevent DNA replication associated to the lytic cycle: a protein repressor called CI negatively regulates the expression of the lytic genes and an antisense RNA (C4) inhibits the translation of an antirepressor whose product interferes with the activity of the CI repressor. Synthesis of only one repressor does nor render a PI lysogen immune to superinfection by PI unless the other repressor is also expressed. In addition to this double control of immunity, C1 repression is strengthened by an auxiliary repressor protein which enhances the binding of CI repressor to its operator sequence. These three components form a tripartite immunity system.

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