R EVIEWS TRENDS IN MICROBIOLOGY 191 VOL. 7 NO. 5 MAY 1999 0966-842X/99/$ - see front matter © 1999 Elsevier Science. All rights reserved. PII: S0966-842X(99)01493-6 D espite our monumental achievements in philos- ophy, technology and the arts, to bacteria humans are no more than an organic mass to be utilized for growth and reproduction. Thankfully, most bacterial inhabitants are, more or less, harmless com- mensals. Occasionally, how- ever, certain bacterial clones jeopardize the well-being of the individual and cause dis- ease. Some of the attributes that make certain bacterial lin- eages more pathogenic than others are provided by so-called specific virulence factors encod- ed by horizontally transferred genes of a foreign nature 1,2 . This review is intended to illustrate that the pathogenicity of a bacterial clone can also be enhanced via another mechanism: the mutational change (i.e. loss or modification of function) of pre-existing genes. Pathogenicity as a secondary property A variety of host conditions (e.g. genetic predis- position, immune status, integrity of the tissue barrier layers and protective microbiota) is critical to the sus- ceptibility of an individual to infectious diseases. However, given the same host conditions, only cer- tain bacterial lineages are pathogenic to humans. Sur- prisingly, pathogenic bacteria are usually members of a genus or species in which nonpathogenic or margin- ally pathogenic lineages predominate. Moreover, many pathogenic lineages share their primary habitat with benign relatives and only relatively rarely spread into distinct areas of the body where their growth will induce symptomatic disease (i.e. their ‘virulence niche’). Some pathogenic lineages are carried asympto- matically by humans as permanent or transient com- mensals (Table 1), whereas others primarily colonize non-human hosts or persist as free-living organisms whose association with humans is usually brief and nonpathogenic. Therefore, the greater virulence of pathogenic microorganisms frequently appears to be a secondary property, i.e. a recently acquired or purely accidental ability to adapt to an environment that is, from an evolutionary perspective, alien or novel. Two genetic mechanisms that enhance pathogenicity The phenotypic properties ac- quired during the evolution of pathogenic bacteria are traits that successfully provide strat- egies for: (1) tropism for tis- sues of a virulence niche, (2) mechanisms to consume avail- able nutrients and/or (3) mecha- nisms to evade or overcome antibacterial defenses. Theo- retically, bacterial evolution toward a more pathogenic phenotype could involve the acquisition of additional genes that encode for specific viru- lence factors (‘gain-of-func- tion’ mechanism) and/or an appropriate functional modifi- cation or loss of pre-existing genetic material (‘change-of-function’ mechanism). Some nonpathogenic or mildly pathogenic bacte- rial lineages might be capable of becoming successful pathogens if certain genes were to be horizontally transferred into the ‘commensal’ genome. The exist- ence of this gain-of-function mechanism is supported by epidemiological and experimental studies indicat- ing that many pathogenic lineages possess plasmids, phages or chromosomal ‘pathogenicity islands’ that are not common among their more benign relatives and that encode specific virulence factors 1,2 . This evo- lutionary pathway is expected to be important for microorganisms that are considered to be primary pathogens (i.e. organisms dependent on their ability to cause disease, at least occasionally, for their long- term persistence in nature). Alternatively, certain bac- terial clones might be capable of becoming more pathogenic if the functional modification or elimi- nation of an original gene(s) changed their phenotype appropriately. This change-of-function mechanism does not require the addition of new genes but de- pends on the occurrence of random (i.e. not pro- grammed or phase-variable) genetic mutations that confer a strong selective advantage upon the bacterial clone in the virulence niche. This type of mutation, which we call pathogenicity-adaptive (or patho- adaptive) 3 , can drive the adaptive evolution of both primary and opportunistic pathogens during their spread and growth in diverse host environments (see Box 1) 4 . However, in contrast to the gain-of-function Pathogenicity-adaptive, or pathoadaptive, mutations represent a genetic mechanism for enhancing bacterial virulence without horizontal transfer of specific virulence factors. Pathoadaptive evolution can be important within single infections and for defining the population structure of a pathogenic species. E.V. Sokurenko* is in the Dept of Microbiology, University of Washington, Seattle, WA 98195, USA; D.L. Hasty is in the Dept of Anatomy and Neurobiology, University of Tennessee, Memphis, TN 38163, USA, and is also in the Research Service (151), Dept of Veterans’ Affairs Medical Center, Memphis, TN 38104, USA; D.E. Dykhuizen is in the Dept of Ecology and Evolution, State University of New York, Stony Brook, NY 11794, USA. *tel: +1 206 543 1073, fax: +1 206 543 8297, e-mail: evs@u.washington.edu Pathoadaptive mutations: gene loss and variation in bacterial pathogens Evgeni V. Sokurenko, David L. Hasty and Daniel E. Dykhuizen