Over the last 10 years, genome sequencing has fundamentally changed microbiology. However, a genomic sequence is fundamentally static. True biological processes are defined by the dynamic interaction of biological systems. Phage and bacterium interaction is conceptually the simplest case of such genome interaction. The infection process provides a precise kinetics for this interaction. Microarray analysis of phage transcription throughout the infection cycle is still limited to phage T4-infected E. coli cells (43). In the next logical step, microarray analysis from the invading phage must be integrated with that of the infected bacterium, especially when it concerns such a well-investigated organism as E. coli.
Phage infection is a highly dynamic process, probably inducing bacterial gene expression. Some of these events might even be visible in thin-section electron microscopy (Fig. 4). If the genomes of both the phage and the bacterium were sequenced, transcription of both genomes could be analyzed on microarrays at different time points after phage infection. If this analysis is combined with thin-section immune electron microscopy and proteomics, one could combine cell biology with gene and protein expression studies to examine the consequences of two genomes confronting each other in a hostile encounter.
However, the analysis must not stop here, since this corresponds still to the test tube situation that has dominated phage biology in the past. The phage research community should immediately envision the next level of complexity with interacting systems. An attractive test system is provided by streptococcal lysogens. Many prophages from low-GC-content, gram-positive bacteria encode candidate lysogenic conversion genes located between the phage lysin gene and the right attachment site (4
). In lactic streptococci and in lactobacillus commensals, these prophage genes are expressed during broth culture (63
). In contrast, the expression level of the corresponding prophage genes in pathogenic streptococci is low. Interestingly, when Streptococcus pyogenes
comes in contact with pharyngeal cells (the natural target cells in streptococcal angina), the expression of the lysogenic conversion gene is upregulated (12
). Broudy and coworkers have identified a low-molecular-weight compound released by the pharyngeal cell that induces the expression of this prophage gene (13
). In this cell culture system, one has the chance to study by microarray analysis the interaction of a phage, a bacterium, and a human cell in a system that is directly relevant for the disease process. The mammalian host not only promotes prophage induction in S. pyogenes
, but it also favors the lysogenization of nontoxigenic bystander bacteria resulting in the generation of new toxin-producing cells (11
). Within the mammalian host, bacteria apparently alter not only their gene expression (46
) but their genomes themselves.
There are still other suitable model systems to study phage-host interaction in a relevant ecological context. A lysogenic avian E. coli pathogen, when injected into a chicken, showed an upregulation of prophage gene expression (22). This and similar whole-animal experimental systems allow the analysis of genome interactions at the next complexity level. As the data analysis for such complex genome interactions will represent a substantial challenge, the old virtue of phages, i.e., "small is beautiful," will again become an asset in the postgenomic era.