Response from sokurenko and dykhuizen

Dr Tuomanen has provided insightful comments on pathoadaptive processes involved in bacterial virulence. We believe that the analogy between pathogens with virulence factors and soldiers with guns illustrates the concept very effectively.Soldiers are easy to recognize as those who carry guns. However, putting guns in the hands of civilians does not make them soldiers and soldiers without guns do not automatically become civilians. Similarly, in order to become a pathogen, a benign bacterial clone must do more than merely acquire specific virulence factors1xGroisman, E.A. and Ochman, H. Trends Microbiol. 1994; 2: 289–294Abstract | Full Text PDF | PubMed | Scopus (42)See all References1. Adapting the pre-existing genetic background (the soldier's basic training) will also play a major role in the survival and growth (living through war) of the bacterial cells in the alien and hostile environment of the virulence niche.The necessities of life can force peaceful peasants to beat their plowshares into swords and to become quite capable fighters. Similarly, commensals, which accidentally but regularly find themselves in forbidden host compartments, might adapt certain pre-existing traits into virulence-specialized determinants. For example, natural selection in the virulence niche could favor clonal variants or mutants with an adaptively modified adhesin specificity (e.g. the type I fimbriae in uropathogenic Escherichia coli2xSokurenko, E.V. et al. Proc. Natl. Acad. Sci. U. S. A. 1998; 95: 8922–8926Crossref | PubMed | Scopus (215)See all References2) or enzyme activity (e.g. the immunoglobulin A1-protease in the invasive Neisseria meningitidis3xVitovski, S., Read, R.C., and Sayers, J.R. FASEB J. 1999; 13: 331–337PubMedSee all References3). Interestingly, some traits found predominantly among the pathogens but rarely among the commensals (i.e. traits that are likely candidates for definition as specific virulence factors) might have evolved originally to maintain the bacteria in a rare commensal sub-niche of the species. For example, E. coli expressing P fimbriae, which were thought to be a specific virulence factor of pyelonephritis-causing isolates, can be found as a sub-dominant population of intestinal E. coli in up to one third of healthy individuals4xJohnson, J.R. et al. J. Infect. Dis. 1998; 177: 1120–1124Crossref | PubMedSee all References4. Similarly, the acquisition of chromosomal pathogenicity islands might play a role in the evolution of bacteria quite apart from their ability to cause disease5xBoyd, E.F. and Hartl, D.L. J. Bacteriol. 1998; 180: 1159–1165PubMedSee all References5.The question posed by Dr Tuomanen that is critically important to the study of bacterial pathogenesis is how to identify in the genome those background genes that make certain clones highly virulent. We think that, by using the comparative approach suggested by Dr Tuomanen, it will be possible to discover such genes in pathogens that cause disease by switching niches, and in microorganisms that establish chronic or recurring infection. In the multiniche species, the virulence-specific selection should leave a signature in the frequency distribution and phylogenetic relationships of the alleles of genes involved in pathoadaptation. Also, pathoadapted mutants could be caught red-handed by comparative genetic and functional analysis of the bacterial strains isolated from the same patient at different stages or sites of the infection6xLevin, B.R. Emerg. Infect. Dis. 1996; 2: 93–102Crossref | PubMedSee all References6. Development and use of the comparative mathematical tools of evolutionary genetics to discover pathoadapted genes will provide a novel approach for dissecting the molecular mechanisms of bacterial pathogenesis.