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Genomic islands are responsible for unique aspects of bacterial behavior such as symbiosis and pathogenicity. Photorhabdus luminescens is a pathogen of insects that spends part of its lifecycle in symbiosis with a nematode. Here, we describe novel genomic islands from Photorhabdus that are involved in symbiosis and pathogenicity, and discuss the inter-relationship between virulence factors used against invertebrates and vertebrates.
The plant pathogenic bacterium Pseudomonas syringae uses a type III secretion system to inject virulence proteins directly into the cytoplasm of its hosts. The P. syringae type III secretion apparatus is encoded, in part, by the HrpZ operon, which carries the hrpA gene encoding the pilin subunit of the pilus, various components of the structural apparatus, and the HrpZ harpin protein that is believed to produce pores in the host cell membrane. The pilus of the type III system comes into direct contact with the host cell and is, therefore, a likely target of the host's pathogen surveillance systems. We sequenced and analyzed 22 HrpZ operons from P. syringae strains spanning the diversity of the species. Selection analyses, including K(a)/K(s) tests and Tajima's D, revealed strong diversifying selection acting on the hrpA gene. This form of selection enables pathogens to maintain genetic diversity within their populations and is often driven by selection imposed by host defense systems. The HrpZ operon also revealed a single significant recombination event that dramatically changed the evolutionary relationships among P. syringae strains from 2 quite distinct phylogroups. This recombination event appears to have introduced genetic diversity into a clade of strains that may now be undergoing positive selection. The identification of diversifying selection acting on the Hrp pilus across the whole population sample and positive selection within one P. syringae lineage supports a trench warfare coevolutionary model between P. syringae and its plant hosts.
Malaria parasites cause much morbidity and mortality to their human hosts. From our evolutionary perspective, this is because virulence is positively associated with parasite transmission rate. Natural selection therefore drives virulence upwards, but only to the point where the cost to transmission caused by host death begins to outweigh the transmission benefits. In this review, we summarize data from the laboratory rodent malaria model, Plasmodium chabaudi, and field data on the human malaria parasite, P. falciparum, in relation to this virulence trade-off hypothesis. The data from both species show strong positive correlations between asexual multiplication, transmission rate, infection length, morbidity and mortality, and therefore support the underlying assumptions of the hypothesis. Moreover, the P. falciparum data show that expected total lifetime transmission of the parasite is maximized in young children in whom the fitness cost of host mortality balances the fitness benefits of higher transmission rates and slower clearance rates, thus exhibiting the hypothesized virulence trade-off. This evolutionary explanation of virulence appears to accord well with the clinical and molecular explanations of pathogenesis that involve cytoadherence, red cell invasion and immune evasion, although direct evidence of the fitness advantages of these mechanisms is scarce. One implication of this evolutionary view of virulence is that parasite populations are expected to evolve new levels of virulence in response to medical interventions such as vaccines and drugs.
A model of the interactions between populations of temperate and virulent bacteriophage with sensitive, lysogenic, and resistant bacteria is presented. In the analysis of the properties of this model, particular consideration is given to the conditions under which temperate bacteriophage can become established and will be maintained in bacterial populations. The effects of the presence of resistant bacteria and virulent phage on these "existence" conditions for temperate viruses are considered. It is demonstrated that under broad conditions temperate phage will be maintained in bacterial populations and will coexist with virulent phage. Extrapolating from this formal consideration of the population biology of temperate bacteriophage, a number of hypotheses for the conditions under which temperate, rather than virulent, modes of phage reproduction are to be anticipated and the nature of the selective pressures leading to the evolution and persistence of this "benign" type of bacterial virus are reviewed and critically evaluated. Two hypotheses for the "advantages of temperance" are championed: (1) As a consequence of the allelopathic effects of diffusing phage, in physically structured habitats, lysogenic colonies are able to sequester resources and, in that way, have an advantage when competing with sensitive nonlysogens. (2) Lysogeny is an adaptation for phage to maintain their populations in "hard times," when the host bacterial density oscillates below that necessary for phage to be maintained by lytic infection alone.
In this paper, we present a general selection-mutation model of evolution on a one-dimensional continuous fitness space. The formulation of our model includes both the classical diffusion approach to mutation process as well as an alternative approach based on an integral operator with a mutation kernel. We show that both approaches produce fundamentally equivalent results. To illustrate the suitability of our model, we focus its analytical study into its application to recent experimental studies of in vitro viral evolution. More specifically, these experiments were designed to test previous theoretical predictions regarding the effects of multiple infection dynamics (i.e., coinfection and superinfection) on the virulence of evolving viral populations. The results of these experiments, however, did not match with previous theory. By contrast, the model we present here helps to understand the underlying viral dynamics on these experiments and makes new testable predictions about the role of parameters such the time between successive infections and the growth rates of resident and invading populations.
The molecular basis of pathogen clone emergence is relatively poorly understood. Acquisition of a bacteriophage encoding a previously unknown secreted phospholipase A(2) (designated SlaA) has been implicated in the rapid emergence in the mid-1980s of a new hypervirulent clone of serotype M3 group A Streptococcus. Although several lines of circumstantial evidence suggest that SlaA is a virulence factor, this issue has not been addressed experimentally. We found that an isogenic DeltaslaA mutant strain was significantly impaired in ability to adhere to and kill human epithelial cells compared with the wild-type parental strain. The mutant strain was less virulent for mice than the wild-type strain, and immunization with purified SlaA significantly protected mice from invasive disease. Importantly, the mutant strain was significantly attenuated for colonization in a monkey model of pharyngitis. We conclude that transductional acquisition of the ability of a GAS strain to produce SlaA enhanced the spread and virulence of the serotype M3 precursor strain. Hence, these studies identified a crucial molecular event underlying the evolution, rapid emergence, and widespread dissemination of unusually severe human infections caused by a distinct bacterial clone.
The sex pheromone system of Enterococcus faecalis was discovered by observing a clumping reaction of E. faecalis strains during conjugative transfer of plasmids. It was found that only a special type of E. faecalis plasmids, the so-called sex pheromone plasmids, are transferred via this mechanism. Various experiments, especially by the group of D. B. Clewell, led to the formulation of a model describing how the sex pheromone system works. Small linear peptides, the so-called sex pheromones, are excreted by strains not possessing the corresponding sex pheromone plasmid. Donor strains harboring the plasmid do not produce the corresponding sex pheromone; they react to the presence of the peptide by production of a plasmid-encoded adhesin, the so-called aggregation substance. This adhesin allows contact between the non-motile mating partners; after conjugative transfer of the plasmid, the former recipient possesses and replicates the new plasmid. Thereby the population of E. faecalis strains is shifted to a high percentage of donor strains. This is especially true because a donor strain will still excrete sex pheromones corresponding to plasmids it does not harbor; therefore, such a strain can also function as recipient for other sex pheromone plasmids it does not possess. Various aspects of this unique plasmid collection mechanism have been studied during the last few years. The data indicate that, with the exception of pAM373, all sex pheromone plasmids possess one DNA region which is highly similar to and codes for the adhesin. It is also becoming more and more clear that regulatory functions/proteins are not conserved between different sex pheromone plasmids. Induction of adhesin synthesis needs the action of a regulatory cascade composed of unique features; at the moment we are just beginning to understand this cascade. By sequencing the first structural gene for one of those adhesins, we realized that the aggregation substance might act also as an adhesin for eucaryotic cells, probably by interaction with integrins. At least in the case of the in vitro cultured pig kidney tubulus cell line LLC-PK1 this idea could be verified. An interesting aspect of the sex pheromone system of E. faecalis is its evolution. I will discuss the idea that two different components, both of which well might contribute to virulence of the opportunistic pathogenic bacterium, were combined in the species E. faecalis to result in this unique plasmid collection system.
Deoxyribonucleic acid (DNA) and chemically defined media were used in transformation tests of 51 strains of Neisseria gonorrhoeae which exhibited various biosynthetic defects when isolated from patients. These auxotrophic gonococci had one or more nutritional requirements involving proline, methionine, arginine, hypoxanthine, uracil, and thiamine pyrophosphate (THPP). DNA from a clinical isolate which did not require these compounds for growth on defined medium transformed each of the auxotrophic markers of all 51 recipient populations. Ten isolates had defects involving the synthesis of THPP; four strains (designated Thp(-)) had a growth requirement that was satisfied only by THPP, whereas the requirement of six strains (designated Thi(-)) was satisfied by either thiamine or THPP. DNA from Thp(-) donors elicited transformation of Thp(-) as well as Thi(-) recipients. Reciprocally, DNA from a Thi(-) donor transformed both Thi(-) and Thp(-) recipients. Furthermore, DNA from other auxotrophic gonococci had transforming activity for some phenotypically similar auxotrophic recipients. The findings indicate the existence of various nonidentical genetic defects which block reactions in the biosynthesis of proline, methionine, arginine, hypoxanthine, and THPP. Routine cultures from patients with gonorrhea were the source of these auxotrophic strains of N. gonorrhoeae; the various nutritional requirements were identified by a recently described system of gonococcal auxotyping. The transformation test results verify the hereditary basis of the auxotypes, establish that many different mutations exist in potentially virulent gonococci, and illustrate the value of these auxotrophic mutants for studies of the genetic structure and evolution of natural populations of gonococci.
Over the last years, the emergence of resistance to antibiotics has complicated the management of streptococcal infections. The resistance of streptococci to antibiotics is increasing and seems to be linked to the consumption of antibiotics. Resistances to antibiotics have been noted in all species of streptococci and no family of antibiotics is unaffected by resistances. The incidence of resistance to antibiotics varies from one species to another and according to countries. Presently, even though no Streptococcus pyogenes has shown diminished susceptibility to betalactams, this phenomenon has been reported for some strains in the B, C, and G groups, and for up to 56 % of oral streptococci. As for the resistance to macrolides, it reaches as many as 41 % of Streptococcus pyogenes, 46 % of group B streptococci, and 63 % of oral streptococci responsible for severe infections. This evolution is worrying for all streptococci but particularly for oral streptococci which represent a potential reservoir of virulence genes, notably towards Streptococcus pneumoniae. New families of antibiotics as the ketolides or the oxazolidinones appear to be effective in the treatment of streptococcal infections, but it seems that only a policy of control of the consumption of antibiotics could globally decrease the occurrence of resistance.
Since diverging from a common ancestor some 120 million years, Escherichia coli and Salmonella typhimurium have accumulated numerous phenotypic characteristics which have traditionally been used to distinguish these enteric species. While most of the genetic differences between these species are due to the accumulation of point mutations, the majority of the observed variation in phenotypic characters is attributable to segments of the genome confined to only one of the species. We have analyzed the map positions, G+C contents, nucleotide sequences and functions of regions unique to the Salmonella chromosome in an attempt to determine the ancestry of species-specific sequences. Some of the Salmonella-specific regions had uncharacteristically low base compositions and contained open reading frames of atypical codon usage patterns suggesting that portions of the genome were acquired by horizontal transfer from distantly-related bacterial species. The role of these species-specific sequences was assayed by constructing mutant strains harboring deletions in the corresponding regions of the genome. Several functions were ascribed to these unique portions of the Salmonella chromosome, including one encoding proteins involved in virulence and invasion of host epithelial cells.
The epidemiological features of the H5N2 outbreak of influenza in poultry were studied by sequencing the HA genes of several viruses isolated during the epidemic. Comparison of the nucleotide sequences of the HA genes indicated there was a single introduction of virulent virus. The variation rate (silent mutations) in the HA gene of the virulent Ck/Penn virus was 9.0 or 14.4% per 10 years depending on the viruses compared and was similar to that in H3 HA gene of human influenza A virus. The virulent and avirulent viruses isolated after October 1983 were derived from a common ancestoral virus and the virulent virus did not supersede the avirulent virus, instead, the virulent and avirulent viruses coexisted and evolved separately during the course of the epidemic. The evolutionary changes in the HA of H5N2 viruses that occurred during the epidemic permitted us to establish that a virus (A/Chick/Washington/84) that was isolated 8 months after the last H5N2 virus had been isolated from poultry in Pennsylvania belonged to the family of potentially dangerous H5N2 viruses and was a direct descendent of the virus that spread to Maryland and Virginia. All of the virulent Ck/Penn viruses retained the amino acid changes at residues 13 and 69 in the HA.
Various Legionella isolates from different sources and origins were analysed by orthogonal field alternation gel electrophoresis of NotI cleaved genomic DNA. The genome of L. pneumophila Philadelphia I, the original isolate of the epidemics in 1976, exhibits only five NotI fragments. Two virulent derivatives, derived from L. pneumophila Philadelphia I, which were obtained by prolonged passage on artificial culture media, did not differ from their isogenic virulent strain according the NotI fragment pattern. By summing the lengths of the NotI fragments, the genome size of L. pneumophila Philadelphia I was calculated as approximately 3.9 Mb. Environmental L. pneumophila strains exhibited different NotI patterns, as did Legionella strains not belonging to the species pneumophila. The usefulness of DNA long range mapping of Legionella ssp. with NotI for epidemiology and evaluation of their evolutionary relationships is discussed.
Models for the diversity and evolution of pathogens have branched into two main directions: the adaptive dynamics of quantitative life-history traits (notably virulence) and the maintenance and invasion of multiple, antigenically diverse strains that interact with the host's immune memory. In a first attempt to reconcile these two approaches, we developed a simple modelling framework where two strains of pathogens, defined by a pair of life-history traits (infectious period and infectivity), interfere through a given level of cross-immunity. We used whooping cough as a potential example, but the framework proposed here could be applied to other acute infectious diseases. Specifically, we analysed the effects of these parameters on the invasion dynamics of one strain into a population, where the second strain is endemic. Whereas the deterministic version of the model converges towards stable coexistence of the two strains in most cases, stochastic simulations showed that transient epidemic dynamics can cause the extinction of either strain. Thus ecological dynamics, modulated by the immune parameters, eventually determine the adaptive value of different pathogen genotypes. We advocate an integrative view of pathogen dynamics at the crossroads of immunology, epidemiology and evolution, as a way towards efficient control of infectious diseases.
We determined the nucleotide sequences of two related isolates of simian immunodeficiency virus from the sooty mangabey monkey (SIVsmm) that exhibit dramatic differences in virulence. These isolates are separated by one experimental cross-species transmission, from sooty mangabey to pig-tailed macaque. The parental virus (SIVsmm9), nonpathogenic in the original host (sooty mangabeys), causes a chronic AIDS-like disease in macaques. In contrast, the variant virus (SIVsmmPBj14) induces an acute lethal disease in various macaque species and is also pathogenic for sooty mangabeys. The combination of necessary and sufficient mutations that determined the acutely lethal phenotype on the SIVsmm9 genetic background is included within a maximal set of 57 point mutations, plus two insertions located in the long terminal repeat (22 bp spanning an NF-kappa B-like enhancer element) and in the surface envelope glycoprotein (5 amino acids). Comparisons of synonymous and nonsynonymous nucleotide substitutions in the genome of SIVsmm indicated that selective pressures, probably due to the host immune response, favored amino acid changes in the envelope. This immunoevolutionary mechanism could explain the increase in diversity and the apparition of new virulent phenotypes after cross-species transmission.
While standard evolutionary algorithms employ a static, absolute fitness metric, coevolutionary algorithms assess individuals by their performance relative to populations of opponents that are themselves evolving. Although this arrangement offers the possibility of avoiding long-standing difficulties such as premature convergence, it suffers from its own unique problems, cycling, over-focusing and disengagement. Here, we introduce a novel technique for dealing with the third and least explored of these problems. Inspired by studies of natural host-parasite systems, we show that disengagement can be avoided by selecting for individuals that exhibit reduced levels of "virulence", rather than maximum ability to defeat coevolutionary adversaries. Experiments in both simple and complex domains are used to explain how this counterintuitive approach may be used to improve the success of coevolutionary algorithms.
The basic reproduction ratio R0 occupies a central position in the theory of host pathogen interactions. However, this quantity stresses the role of the pathogen. This paper proposes an additional, more host-centred char acterization using the basic depression ratio D0. This quantity is the number of host individuals per infected by which the infected host population is depressed below its uninfected level. This paper shows that a baseline criterion for the evolution of host resistance to microparasites is that resistance evolves to minimize D0. This parallels the result for pathogen virulence where R0 is maximized. The tension between these two criteria is noted. The framework established allows a discussion of trade-offs between aspects of the pathogen-free host biology and the host pathogen interaction. For certain linear and convex trade-offs it is shown that the strain with the lowest transmission parameter beta wins (despite the fact that it has the lowest intrinsic birth rate a). For corresponding concave trade-offs, either the strain with minimum beta and a or the strain with maximum beta and a wins. Finally the connection with the techniques of adaptive dynamics is made. Evolutionary singular points are shown to occur at extrema of D0. The evolutionary attainment of the results is discussed.
The hemolytic ability, the presence of cyl genes, and the diagnostic accuracy of cytolysin molecular detection were investigated in the genus Enterococcus by using 164 strains from 20 different species (26 reference strains, 42 clinical isolates from human and veterinary origin, and 96 isolates from ewe cheese and milk). Hemolysis was assayed with sheep and horse erythrocytes and under aerobic or anaerobic conditions. Screening of cytolysin genes (cylL(L), cylL(S), cylM, cylB, and cylA) was performed with new specific primers and the anaerobic assay of beta-hemolysis was used as the "gold standard" for the evaluation of cyl gene-based PCRs. Since beta-hemolysis and cyl genes were found in 10 and 14 species, respectively, the hemolytic ability seems to be spread throughout the genus ENTEROCOCCUS: Beta-hemolysis was observed in 6 of 26 (23%) reference strains, 14 of 42 (33%) clinical isolates, and 6 of 96 (6%) food isolates. The presence of cyl genes was detected in 15 of 26 (58%) reference strains, 37 of 42 (88%) clinical isolates, and 67 of 96 (70%) food isolates. These data indicate a virulence potential in food isolates, reinforcing the need of their safety assessment. Analysis of phenotypic-genotypic congruence suggests a divergent sequence evolution of cyl genes and the effect of environmental factors in the regulation of cytolysin expression. Evaluation of the diagnostic accuracy of cytolysin molecular detection points to cylL(L)-based PCR and cylL(L)L(S)MBA-based PCR as the most reliable approaches. Nevertheless, the low sensitivity (46%) and gene variability indicated by our study strongly recommend the phenotypic assay for the assessment of hemolytic ability in enterococci, followed by the molecular screening of cyl genes in nonhemolytic strains to evaluate their virulence potential.
The presence of genetic resistance to myxomatosis in a sample of wild rabbits from one area in England was reported in 1977. Rabbits from three other areas in Great Britain have been tested subsequently, and all cases showed similar resistance to a moderately virulent strain of myxoma virus. Rabbits from one area also showed a significant degree of resistance to a fully virulent strain of virus. It is concluded that genetic resistance to myxomatosis is widespread in wild rabbit populations in Britain. The implications of the results are discussed in relation to the co-evolution of the disease and its host.