A central question in the biology of host–parasite interactions is how a balance between the costs and benefits to both is achieved. If the burden to the host is too high, the parasite will go extinct, and for this reason it is often postulated that parasites confer some benefit upon their hosts, thereby arriving at an equilibrium in the competition between parasite-free and infected host populations.
Bacterial viruses are parasitic. Roughly speaking, they either invade and kill the host or they invade and lie dormant, either integrated into the host genome or outside it as extrachromosomal elements [1
]. Phage that can exist in a dormant state are called temperate phage, and bacteria carrying temperate phage are said to be lysogenic. In the lysogenic state, viral functions needed for replication and packaging are shut down by a phage-encoded repressor. Occasionally, a temperate phage genome escapes repression, the virus begins to replicate, and soon the host cell lyses, producing a new generation of viral particles (A). The lysogenic state thus imposes a cost on the bacterium because every so often the viral genome (prophage) replicates and kills the host. This selective disadvantage is offset, however, in several important ways. Because prophage produce a repressor that keeps the prophage genes from being expressed, the host bacterium enjoys immunity from lytic infection by temperate family members. A second, and different, mechanism confers immunity to lytic phage, those phage that cannot exist in the host as prophage [2
]. Temperate phage may also confer fitness on a host by coding for genes that enhance host virulence and resistance to the immune system [4
], of which there are dozens of examples: the Shiga toxin produced by some strains of Escherichia coli;
the β toxin produced by Corynebacterium diptheriae,
the causative agent of diphtheria; endotoxin production by Clostridium botulinum;
staphylococcal endotoxins; and cholera toxin produced by Vibrio cholerae,
to name a few. Then too, prophage often code for functions that allow the lysogen to successfully colonize the animal host [4
], and in general, temperate phage increase horizontal gene flow in microbial populations [5
]. Thus there are several advantages to being a lysogen, and at least one big disadvantage: Occasionally the prophage replicates and kills the host.
The λ Life Cycle and Gene Organization
Of the many prophage that litter bacterial genomes, the best studied is λ. When it recombines into the E. coli
chromosome, phage multiplication is shut down by the phage-encoded repressor, cI, a critical element of the genetic switch. The continuous low-level production of cI protects the host against further infection by extracellular λ, while also regulating the levels of cI synthesis intracellularly (reviewed in [6
]). The phage also codes for genes required for replication, maintenance, integration, and escape from the host cytoplasm, as well as a series of genes not required for growth in the laboratory (B).
Most λ genes are repressed by cI, but there are several whose transcription is constitutive, their expression either dependent or independent of cI control. Two, the products of the rexA
genes, exclude productive infection by the unrelated lytic bacteriophage T2, T4, and T6 [2
]. The Rex proteins have also been reported to increase the advantage of lysogens in competition experiments [7
], but there are conflicting results in the literature on this point [8
]. Two other proteins, Bor and Lom, are found in the host outer membrane, and bor
lysogens are resistant to guinea pig serum [9
]. Each of the above examples illustrates how prophage-encoded λ genes increase lysogen fitness by coding for a protein that protects the host from invaders or from the humoral system.
Here we ask if the phage repressor directly or indirectly regulates host genes. There is indirect evidence that a streptococcal temperate phage may regulate a bacterial gene that protects cells against phagocytosis [11
], but there have been no systematic studies on this subject. By surveying both the host and phage genomes with microarrays, we have found several new and unexpected expression patterns in E. coli
lysogens, in addition to those viral genes known to be expressed. One in particular, a host gene partly responsible for gluconeogenesis, pckA,
is down-regulated many fold, and this leads to a growth disadvantage for the lysogen when grown on succinate, a common carbon and energy source. The DNA sequence lying upstream of the pckA
coding region contains sequences homologous to the DNA-binding site for cI, and, surprisingly, for the cI homologs of other temperate phage. Thus it appears that down-regulation of pckA
is part of an adaptive strategy for many different temperate phage.