evolution of bacterial pathogenesis

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  • CMLS, Cell. Mol. Life Sci. 56 (1999) 7197281420-682X:99:100719-10 $ 1.500.20:0 Birkhauser Verlag, Basel, 1999

    Evolution of bacterial pathogenesisW. Ziebuhra, K. Ohlsena, H. Karchb, T. Korhonenc and J. Hackera,*

    aInstitut fur Molekulare Infektionsbiologie, Rontgenring 11, D-97070 Wurzburg (Germany),Fax 49 931 31 2578, e-mail: j.hacker@mail.uni-wuerzburg.debInstitut fur Hygiene und Mikrobiologie, Josef-Schneider-Str. 2, D-97080 Wurzburg (Germany)cDivision of General Microbiolgy, University of Helsinki, PO Box 56, Viikinkaari 9, SF-00014 Helsinki(Finland)

    Abstract. The evolution of bacteria is associated with typic variation. They are often encoded on unstableDNA regions. Thus, they can be readily transferred tocontinuous generation of novel genetic variants. Thebacteria of the same species or even to non-relatedmajor driving forces in this process are point mutations,prokaryotes. This review article focuses on the maingenetic rearrangements, and horizontal gene transfer. Amechanisms of bacterial microevolution responsible forlarge number of human and animal bacterial pathogensthe rapid emergence of variants with novel virulencehave evolved the capacity to produce virulence factors

    that are directly involved in infection and disease. Addi- and resistance properties. In addition, processes oftionally, many bacteria express resistance traits against macroevolution are described with special emphasis onantibiotics. Both virulence factors and resistance deter- gene transfer and fixation of adaptive mutations in theminants are subject to intrastrain genetic and pheno- genome of pathogens.

    Key words. Evolution; pathogenesis; point mutation; pathogenicity islands; recombination; insertion sequences;gene transfer.


    Bacteria must conserve their genetic information fromone generation to the next. The maintenance of thecorrect genomic sequence is ensured by complex enzy-matic mechanisms managing the faithful replication andrepair of DNA [1, 2]. However, bacteria have to liveand survive under continuously changing environmentalconditions and are therefore compelled to adapt tothem. In addition to regulatory adaptive responses thatact at the level of gene expression, bacteria have alsoevolved strategies allowing the generation of geneticdiversity [3, 4]. Point mutations, recombination betweenhomologous DNA sites, and the action of transposablegenetic elements are major mechanisms by whichgenome flexibility is achieved. The capture and spreadof genes by horizontal gene transfer mechanisms involv-ing plasmids, phages and other mobile elements alsocontribute to this process. Finally, the clustering of

    genes on large genomic islands and their mobilizationenables bacteria to gain or lose huge amounts of DNAinvolved in the adaption to distinct ecological niches [5,6]. This mediates the very rapid development of newbacterial variants (within days or weeks), a process forwhich the term microevolution was coined. However,once successfully adapted, microorganisms tend to sta-bilize the newly generated genotype by adaptive muta-tions and they can maintain it for millions of years [7].Evolutionary processes that proceed over longer timeperiods are termed macroevolution. They lead to thedevelopment of completely new variants of organisms,to the generation of new species and even to the emer-gence of new genera. Both micro- and macroevolutionhave contributed to the impressive diversity of the mi-crobial world on earth.The general processes involved in the evolution of bac-teria also form the basis for the evolution of pathogens.Pathogenic bacteria often produce virulence or patho-genicity factors such as adhesins, capsules or toxinswhich enable them to cause infections in particular host* Corresponding author.

  • W. Ziebuhr et al. Evolution of pathogens720

    organisms. In addition, pathogenic bacteria are able toexpress resistance factors to overcome the action ofantibiotics used in human and veterinary medicine.Some of the pathogenic microorganisms are perfectlyadapted to one particular host species. For example, thehost spectrum of meningococci or gonococci is re-stricted to human beings. Other bacteria only causedisease when they are transferred to a new host organ-ism. Transmission can be mediated by vector organisms(e.g. fleas in the case of Yersinia pestis), food (e.g.enterohaemorrhagic Escherichia coli-EHEC), water(e.g. Vibrio cholerae) or by technical systems (e.g. Le-gionella pneumophila) [811]. Finally, bacteria belong-ing to the normal body flora or to the environment cancause disease when the host is immunocompromised orthe microorganisms are displaced to unusual body sites(e.g. uropathogenic E. coli, coagulase-negative staphylo-cocci) [12].This review describes genetic mechanisms of microevo-lution underlying the extraordinary capacity of patho-genic bacteria that gives rise to the continuousemergence of variants with novel virulence and resis-tance traits. In addition, the article provides insight intoprocesses of macroevolution with special emphasis ongene transfer and fixation of adaptive mutations inpathogen genomes.

    Point mutations, deletions and pathoadaptive mutationsare involved in micro- and macroevolution of pathogens

    Point mutations are considered as driving forces in slowevolutionary processes. However, in viruses, mutationsor small deletions can also contribute to the rapiddevelopment of structural genes [e.g. human im-munodeficiency virus (HIV) protease gene mutations,leading to protease-inhibitor-resistant HIV variants]

    [13]. In addition, particular genes of bacterial pathogensexhibit stretches of repeated DNA sequences in pro-moter regions and:or in the 5% end of virulence genes.During replication, point mutations can be generatedby slipped-strand mispairing, resulting in expression ornon-expression of particular genes. In gonococci,meningococci, Mycoplasma sp., and E. coli, phase andantigenic variation of surface-associated structures ismediated by these mechanisms [1417] (see table 1).Regulatory genes which control coordinated gene ex-pression under changing environmental conditions havealso been found to be subject to point mutations andsmall deletions. In many bacteria, the stress response isregulated by alternative sigma factors [18]. The mode ofaction of these factors has been extensively studied inBacillus subtilis, E. coli and Staphylococcus aureus [1923]. They are involved in sporulation (B. subtilis), sta-tionary and heat shock response (E. coli ) and also inthe expression of virulence genes (S. aureus, E. coli ).Mutations and deletions in such genes were demon-strated in Salmonella sp. and S. aureus and exhibited apleiotropic effect on gene expression which also influ-enced the virulence traits of these organisms [2426].Mutations in structural genes of putative virulence fac-tors can also modify or knock out the encoded proteinsand influence their function during pathogenesis. Manyof these mutations represent so-called pathoadaptivemutations which enable single bacterial clones to be-come more pathogenic without the acquisition of addi-tional genes. This mechanism is based on randommutagenesis which offers the bacterium a strong advan-tage under a selective pressure [7]. Pathoadaptive muta-tions are mainly observed in bacterial species that areopportunistic or non-primary pathogens (table 2). Thus,the type 1 fimbriae of enterobacteria (particular of E.coli ) were altered by pathoadaptive mutations leading

    Table 1. Genetic mechanisms involved in phase and antigenic variation contributing to microevolution in pathogenic bacteria.

    Genetic mechanism Bacterial species Functional effect

    Point mutations Neisseria meningitidis and phase variation of pili, capsules andN. gonorrhoeae lipopolysaccharide

    Deletions Haemophilus influenzae capsule variationEscherichia coli loss of P-fimbriae and haemolyisn

    loss of biofilm productionStaphylococcus epidermidis

    DNA modification E. coli phase variation of P, S, K99-fimbriae

    Homologous recombination N. gonorrhoeae antigenic variation of pili and surface proteinsMycoplasma pneumoniae antigenic variation of surface proteins

    Site-specific recombination E. coli phase variation of type-1 fimbriaeSalmonella spp. antigenic variation of flagellae

    phase variation of capsule productionInsertion sequence integration: N. meningititisexcision

    phase variation of biofilm formationS. epidermidis

  • CMLS, Cell. Mol. Life Sci. Vol. 56, 1999 721Multi-author Review Article

    Table 2. Examples of pathoadaptive mutations that confer altered bacterial pathogenicity according to Sokurenko et al. [7].

    Functional effectGene functionPre-existingBacterial species Adaptive advantage in virulencegene of mutation

    adhesion variation offimH increased tropism to uroepithelialE. coliamino acid and neural basement membranessequence

    hemB synthesis of electron transportS. aureus knockout intracellular persistence, and in-creased antibiotic resistancechain components

    S. aureus sigB alternative transcription factor, knockout increased activity of genes (e.g.toxins)regulation

    speB extracellular and cell surfaceGroup A variation of expansion of tissue tropism andStreptococcus amino acid inhibition of platelet aggregationprotease

    sequenceShigella, ompT surface protease knockout surface expression of actin-

    polymerization factorenteroinvasiveE. coli

    Shigella, cadA lysine decarboxylase knockout activation of endotoxinenteroinvasieE. coli

    bexA polysaccharide exportHaemophilus knockout of one increased capsule productionof two copiesinfluenzae

    downregulation of alginate produc-mucAPseudomonas knockout evasion of phagocytosistionaeruginosa

    Chlamydia omp1 adhesion, immune escape variation of expansion of tissue tropismamino acidtrachomatissequence

    to variants with incr


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