The human immunodeficiency virus (HIV) as a newly evolving pathogen.
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Animals↗
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Bordetella species are distinguished by patterns of substantial gene loss and host adaptation.
Pathogens of the bacterial genus Bordetella cause respiratory disease in humans and animals. Although virulence and host specificity vary across the genus, the genetic determinants of this diversity remain unidentified. To identify genes that may underlie key phenotypic differences between these species and clarify their evolutionary relationships, we performed a comparative analysis of genome content in 42 Bordetella strains by hybridization of genomic DNA to a microarray representing the genomes of three Bordetella species and by subtractive hybridization. Here we show that B. pertussis and B. parapertussis are predominantly differentiated from B. bronchiseptica by large, species-specific regions of difference, many of which encode or direct synthesis of surface structures, including lipopolysaccharide O antigen, which may be important determinants of host specificity. The species also exhibit sequence diversity at a number of surface protein-encoding loci, including the fimbrial major subunit gene, fim2. Gene loss, rather than gene acquisition, accompanied by the proliferation of transposons, has played a fundamental role in the evolution of the pathogenic bordetellae and may represent a conserved evolutionary mechanism among other groups of microbial pathogens.
Animals↗
Evolution of enterohemorrhagic Escherichia coli hemolysin plasmids and the locus for enterocyte effacement in shiga toxin-producing E. coli.
This study assessed the diversity of the enterohemorrhagic Escherichia coli (EHEC) hemolysin gene (ehxA) in a variety of Shiga toxin-producing E. coli (STEC) serotypes and the relationship between ehxA types and virulence markers on the locus for enterocyte effacement (LEE). Restriction fragment length polymorphism of the ehxA gene and flanking sequences and of the E. coli attaching and effacing (eae) gene was determined for 79 EHEC hemolysin-positive STEC isolates of 37 serotypes. Two main groups of EHEC hemolysin sequences and associated plasmids, which corresponded to the eae-positive and the eae-negative isolates, were delineated. Comparisons of the ehxA gene sequences of representative isolates of each group showed that this gene and the rest of the EHEC hemolysin operon are highly conserved. Digestion of an ehxA PCR product with the restriction endonuclease TaqI showed a unique restriction pattern for eae-negative isolates and another one for isolates of serotypes O157:H7 and O157:NM. A conserved fragment of 5.6 kb with four potential open reading frames was identified on the EHEC hemolysin plasmid of eae-positive STEC. Phylogenetic analysis of a subset of 27 STEC isolates, one enteropathogenic E. coli isolate, and a K-12 reference isolate showed that eae-positive STEC isolates all belong to a single evolutionary lineage and that the EHEC hemolysin plasmid and the ehxA gene evolved within this lineage without recent horizontal transfer. However, the eae gene and the LEE appear to have been transferred horizontally within this STEC lineage on several occasions. The reasons for the lack of transfer or maintenance of the LEE in other STEC lineages are not clear and require further study.
Adhesins, Bacterial↗
Pathogenic diversity of Escherichia coli and the emergence of 'exotic' islands in the gene stream.
Escherichia coli is a highly adaptive bacterial species that is both a member of the commensal intestinal flora and a versatile pathogen associated with numerous types of intestinal and systemic infections in humans and other animals. The spectrum of diseases caused by E. coli is due to the acquisition of specific virulence genes harbored on plasmids, bacteriophages, or within distinct DNA segments termed pathogenicity islands (PAIs) that are absent from the genomes of commensal E. coli strains. PAIs are likely to have been transferred horizontally and may have integrated into the E. coli chromosome through bacteriophage or plasmid integration or transposition. The contribution of intergenic inheritance to the adaptation and evolution of E. coli, types of PAIs associated with different groups of pathogenic E. coli and approaches to identify unique sequence islands (USIs), some of which might confer pathogenicity, in E. coli and other bacteria are presented.
Animals↗
Experimental canine leishmaniasis: evolution of infection following re-challenge with Leishmania infantum.
The aim of the study was to assess the clinical, parasitological and immunological effect of a second inoculation of amastigotes in dogs previously inoculated with Leishmania infantum. Three dogs primarily inoculated with amastigotes (Group I) and four with cultured virulent stationary phase promastigotes (Group II) were afterwards re-inoculated with 2x10(9) amastigotes per kg. Three other groups of dogs were used as controls: Group III was infected only once with amastigotes, Group IV only once with promastigotes and Group V was non infected. The animals were followed up by clinical and parasitological examinations, hematological and serum protein analysis, anti-leishmanial antibody levels and proliferative assays of specific peripheral blood mononuclear cells over a period up to 50 months. Parasites were isolated from lymph node of three animals during primary amastigote infection and in five animals (Group I and II) after re-challenge. Group I dogs presented a strong increase of the humoral immune response while Group II animals displayed no significant or significantly low antileishmanial antibodies titres, after re-challenge. The detection, only after challenge, of positive specific lymphoproliferation in two animals of Group II that had the longest primary infection interval (more than 26 months), indicates the requirement of a long time interval to obtain specific lymphocyte sensitization. A previous exposure to virulent cultured L. infantum promastigotes seems to confer some degree of resistance against an amastigote infection.
Animals↗
The recent emergence of plague: a process of felonious evolution.
Yersinia pestis, the causative agent of bubonic plague, evolved from closely related Yersinia pseudotuberculosis within the past 20,000 years, an event that corresponds to the end of the last ice age and distribution of Homo sapiens throughout the world. Y. pseudotuberculosis causes chronic but generally mild enteropathogenic infections whereas plague is the most devastating acute disease experienced by mankind. The very recent evolution of plague from its progenitor assures close genomic homogeneity between the two species and thus high probability that disparities in DNA sequence mediate dramatic differences in symptoms of infection. The purpose of this minireview is to define salient distinctions between the genomes of Y. pestis and Y. pseudotuberculosis and to equate unique functions to respective acute and chronic mechanisms of virulence. The significance of these processes is then related to the procedures the organisms use to survive when between hosts (i.e., the flea vector colonized by Y. pestis and natural environments including soil and water in the case of Y. pseudotuberculosis). Next, an attempt is made to order the various mutational events that caused the recent emergence of Y. pestis as a distinct species. Finally, selective pressures such as predatory soil nematodes are considered that possibly influenced the early evolution of those yersiniae now pathogenic to humans.
Animals↗
Restricted structural gene polymorphism in the Mycobacterium tuberculosis complex indicates evolutionarily recent global dissemination.
One-third of humans are infected with Mycobacterium tuberculosis, the causative agent of tuberculosis. Sequence analysis of two megabases in 26 structural genes or loci in strains recovered globally discovered a striking reduction of silent nucleotide substitutions compared with other human bacterial pathogens. The lack of neutral mutations in structural genes indicates that M. tuberculosis is evolutionarily young and has recently spread globally. Species diversity is largely caused by rapidly evolving insertion sequences, which means that mobile element movement is a fundamental process generating genomic variation in this pathogen. Three genetic groups of M. tuberculosis were identified based on two polymorphisms that occur at high frequency in the genes encoding catalase-peroxidase and the A subunit of gyrase. Group 1 organisms are evolutionarily old and allied with M. bovis, the cause of bovine tuberculosis. A subset of several distinct insertion sequence IS6110 subtypes of this genetic group have IS6110 integrated at the identical chromosomal insertion site, located between dnaA and dnaN in the region containing the origin of replication. Remarkably, study of approximately 6,000 isolates from patients in Houston and the New York City area discovered that 47 of 48 relatively large case clusters were caused by genotypic group 1 and 2 but not group 3 organisms. The observation that the newly emergent group 3 organisms are associated with sporadic rather than clustered cases suggests that the pathogen is evolving toward a state of reduced transmissability or virulence.
Alleles↗
Probing genomic diversity and evolution of Escherichia coli O157 by single nucleotide polymorphisms.
Infections by Shiga toxin-producing Escherichia coli O157:H7 (STEC O157) are the predominant cause of bloody diarrhea and hemolytic uremic syndrome in the United States. In silico comparison of the two complete STEC O157 genomes (Sakai and EDL933) revealed a strikingly high level of sequence identity in orthologous protein-coding genes, limiting the use of nucleotide sequences to study the evolution and epidemiology of this bacterial pathogen. To systematically examine single nucleotide polymorphisms (SNPs) at a genome scale, we designed comparative genome sequencing microarrays and analyzed 1199 chromosomal genes (a total of 1,167,948 bp) and 92,721 bp of the large virulence plasmid (pO157) of eleven outbreak-associated STEC O157 strains. We discovered 906 SNPs in 523 chromosomal genes and observed a high level of DNA polymorphisms among the pO157 plasmids. Based on a uniform rate of synonymous substitution for Escherichia coli and Salmonella enterica (4.7x10(-9) per site per year), we estimate that the most recent common ancestor of the contemporary beta-glucuronidase-negative, non-sorbitolfermenting STEC O157 strains existed ca. 40 thousand years ago. The phylogeny of the STEC O157 strains based on the informative synonymous SNPs was compared to the maximum parsimony trees inferred from pulsed-field gel electrophoresis and multilocus variable numbers of tandem repeats analysis. The topological discrepancies indicate that, in contrast to the synonymous mutations, parts of STEC O157 genomes have evolved through different mechanisms with highly variable divergence rates. The SNP loci reported here will provide useful genetic markers for developing high-throughput methods for fine-resolution genotyping of STEC O157. Functional characterization of nucleotide polymorphisms should shed new insights on the evolution, epidemiology, and pathogenesis of STEC O157 and related pathogens.
Chromosome Mapping↗
Sarcocystosis of chital-dhole: conditions for evolutionary stability of a predator parasite mutualism.
BACKGROUND: For parasites with a predator-prey life cycle, the completion of the life cycle often depends on consumption of parasitized prey by the predator. In the case of such parasite species the predator and the parasite have common interests and therefore a mutualistic relationship is possible. Some evidence of a predator-parasite mutualism was reported from spotted deer or chital (Axix axis) as a prey species, dhole or Indian wild-dog (Cuon alpinus) as the predator and a protozoan (Sarcocystis axicuonis) as the parasite. We examine here, with the help of a model, the ecological conditions necessary for the evolution and stability of such a mutualistic relationship. A two - level game theory model was designed in which the payoff of a parasite is decided not only by alternative parasite strategies but also by alternative host strategies and vice versa. Conditions for ESS were examined. RESULTS: A tolerant predator strategy and a low or moderately virulent parasite strategy which together constitute mutualism are stable only at a high frequency of recycling of parasite and a substantial prey - capture benefit to the predator. Unlike the preliminary expectation, parasite will not evolve towards reduced virulence, but reach an optimum moderate level of virulence. CONCLUSION: The available data on the behavioral ecology of dhole and chital suggest that they are likely to meet the stability criteria and therefore a predator-parasite mutualism can be stable in this system. The model also points out the gaps in the current data and could help directing further empirical work.
Animals↗
Countermeasures to the bioterrorist threat of smallpox.
Variola, the agent of smallpox, is a bioterrorist threat, as is monkeypox virus, which also occurs naturally in Africa. Development of countermeasures, in the form of improved vaccines, antiviral drugs, and other therapeutic strategies are a high priority. Recent advances in molecular biology and in animal model development have provided fresh insight into the virulence determinants for smallpox and the pathophysiology of disease. The complex replication cycle for orthopoxviruses, and the pivotal role for viral-specific immunomodulatory proteins which contribute to escape from immunologic surveillance, provide many unique targets for therapeutic intervention. The "toxemia" of smallpox has been elucidated in part by variola-infected primate studies which revealed the central role of apoptosis and the evolution of a cytokine storm leading to hemorrhagic diathesis, resembling fulminent "black" smallpox. This suggests a potential role for therapeutic strategies developed for septic shock, in treatment of smallpox. Drugs licensed for other viruses which share molecular targets with orthopoxviruses (e.g. Cidofovir) or cancer drugs (e.g. Gleevec and other tyrosine kinase inhibitors) have immediate application for treatment of smallpox and monkeypox and provide leads for second generation drugs with higher therapeutic indices. Recent advances in identification of virulence determinants and immune evasion genes facilitate the design of alternative vaccines to replace live vaccinia strains that are unsuitable for a large proportion of individuals in a mass immunization campaign.
Animals↗
Illuminating the evolutionary history of chlamydiae.
Chlamydiae are the major cause of preventable blindness and sexually transmitted disease. Genome analysis of a chlamydia-related symbiont of free-living amoebae revealed that it is twice as large as any of the pathogenic chlamydiae and had few signs of recent lateral gene acquisition. We showed that about 700 million years ago the last common ancestor of pathogenic and symbiotic chlamydiae was already adapted to intracellular survival in early eukaryotes and contained many virulence factors found in modern pathogenic chlamydiae, including a type III secretion system. Ancient chlamydiae appear to be the originators of mechanisms for the exploitation of eukaryotic cells.
Acanthamoeba↗
Some problems of molecular biology of poliovirus infection relevant to pathogenesis, viral spread and evolution.
Molecular mechanisms of poliovirus reproduction in the human gut remain largely unexplored. Nevertheless, there are grounds to believe that the virus spreads from cell to cell, like that from person to person during natural circulation, and involves a relatively small proportion of the highly heterogeneous viral population generated by the previous host. This mechanism of random sampling is responsible for the majority of fixed mutations, and contributes to the maintenance of a certain level of viral fitness (virulence). In the long term, random sampling may lead to the decrease in fitness and even to extinction of some viral evolutionary branches, explaining cases of self-limiting poliovirus infection in immunodeficient patients. A low propensity of the Sabin viruses for natural circulation may also be a related phenomenon. The trend to decrease in fitness may be interrupted by the appearance of rare, fitter (more virulent) variants, which may be responsible for poliomyelitis outbreaks caused by wild type virus, and for the development of paralytic disease in chronic carriers of the Sabin vaccine. All these evolutionary events are largely stochastic and hence are unpredictable in principle.
Digestive System↗
DNA sequence-based subtyping and evolutionary analysis of selected Salmonella enterica serotypes.
While serotyping and phage typing have been used widely to characterize Salmonella isolates, sensitive subtyping methods that allow for evolutionary analyses are essential for examining Salmonella transmission, ecology, and evolution. A set of 25 Salmonella enterica isolates, representing five clinically relevant serotypes (serotypes Agona, Heidelberg, Schwarzengrund, Typhimurium, and Typhimurium var. Copenhagen) was initially used to develop a multilocus sequence typing (MLST) scheme for Salmonella targeting seven housekeeping and virulence genes (panB, fimA, aceK, mdh, icdA, manB, and spaN). A total of eight MLST types were found among the 25 isolates sequenced. A good correlation between MLST types and Salmonella serotypes was observed; only one serotype Typhimurium var. Copenhagen isolate displayed an MLST type otherwise typical for serotype Typhimurium isolates. Since manB, fimA, and mdh allowed for the highest subtype discrimination among the initial 25 isolates, we chose these three genes to perform DNA sequencing of an additional 41 Salmonella isolates representing a larger diversity of serotypes. This "three-gene sequence typing scheme" allowed discrimination of 25 sequence types (STs) among a total of 66 isolates; STs correlated well with serotypes and allowed within-serotype differentiation for 9 of the 12 serotypes characterized. Phylogenetic analyses showed that serotypes Kentucky and Newport could each be separated into two distinct, statistically well supported evolutionary lineages. Our results show that a three-gene sequence typing scheme allows for accurate serotype prediction and for limited subtype discrimination among clinically relevant serotypes of Salmonella. Three-gene sequence typing also supports the notion that Salmonella serotypes represent both monophyletic and polyphyletic lineages.
Bacterial Typing Techniques↗
Quorum sensing: dynamic response of Pseudomonas aeruginosa to external signals.
A recent study suggests that the opportunistic pathogen Pseudomonas aeruginosa can actively monitor the host immune system. The P. aeruginosa outer membrane protein OprF was found to bind specifically to the cytokine interferon-gamma (IFN-gamma), and this interaction upregulated production of virulence factors through a cell-cell communication system known as quorum sensing (QS). Taken together with previous findings that P. aeruginosa QS can alter the host immune response (e.g. by activation of IFN-gamma), these data illustrate an exciting new element of bacteria-host interactions in which the P. aeruginosa quorum-sensing system both senses and modulates the host immune state.
Evolution, Molecular↗
Whole-genome analysis of two-component signal transduction genes in fungal pathogens.
Two-component phosphorelay systems are minimally comprised of a histidine kinase (HK) component, which autophosphorylates in response to an environmental stimulus, and a response regulator (RR) component, which transmits the signal, resulting in an output such as activation of transcription, or of a mitogen-activated protein kinase cascade. The genomes of the yeasts Saccharomyces cerevisiae, Schizosaccharomyces pombe, and Candida albicans encode one, three, and three HKs, respectively. In contrast, the genome sequences of the filamentous ascomycetes Neurospora crassa, Cochliobolus heterostrophus (Bipolaris maydis), Gibberella moniliformis (Fusarium verticillioides), and Botryotinia fuckeliana (Botrytis cinerea) encode an extensive family of two-component signaling proteins. The putative HKs fall into 11 classes. Most of these classes are represented in each filamentous ascomycete species examined. A few of these classes are significantly more prevalent in the fungal pathogens than in the saprobe N. crassa, suggesting that these groups contain paralogs required for virulence. Despite the larger numbers of HKs in filamentous ascomycetes than in yeasts, all of the ascomycetes contain virtually the same downstream histidine phosphotransfer proteins and RR proteins, suggesting extensive cross talk or redundancy among HKs.
Amino Acid Sequence↗
Human monkeypox and smallpox viruses: genomic comparison.
Monkeypox virus (MPV) causes a human disease which resembles smallpox but with a lower person-to-person transmission rate. To determine the genetic relationship between the orthopoxviruses causing these two diseases, we sequenced the 197-kb genome of MPV isolated from a patient during a large human monkeypox outbreak in Zaire in 1996. The nucleotide sequence within the central region of the MPV genome, which encodes essential enzymes and structural proteins, was 96.3% identical with that of variola (smallpox) virus (VAR). In contrast, there were considerable differences between MPV and VAR in the regions encoding virulence and host-range factors near the ends of the genome. Our data indicate that MPV is not the direct ancestor of VAR and is unlikely to naturally acquire all properties of VAR.
Amino Acid Sequence↗
Murine coronavirus evolution in vivo: functional compensation of a detrimental amino acid substitution in the receptor binding domain of the spike glycoprotein.
Murine coronavirus A59 strain causes mild to moderate hepatitis in mice. We have previously shown that mutants of A59, unable to induce hepatitis, may be selected by persistent infection of primary glial cells in vitro. These in vitro isolated mutants encoded two amino acids substitutions in the spike (S) gene: Q159L lies in the putative receptor binding domain of S, and H716D, within the cleavage signal of S. Here, we show that hepatotropic revertant variants may be selected from these in vitro isolated mutants (Q159L-H716D) by multiple passages in the mouse liver. One of these mutants, hr2, was chosen for more in-depth study based on a more hepatovirulent phenotype. The S gene of hr2 (Q159L-R654H-H716D-E1035D) differed from the in vitro isolates (Q159L-H716D) in only 2 amino acids (R654H and E1035D). Using targeted RNA recombination, we have constructed isogenic recombinant MHV-A59 viruses differing only in these specific amino acids in S (Q159L-R654H-H716D-E1035D). We demonstrate that specific amino acid substitutions within the spike gene of the hr2 isolate determine the ability of the virus to cause lethal hepatitis and replicate to significantly higher titers in the liver compared to wild-type A59. Our results provide compelling evidence of the ability of coronaviruses to rapidly evolve in vivo to highly virulent phenotypes by functional compensation of a detrimental amino acid substitution in the receptor binding domain of the spike glycoprotein.
Amino Acid Substitution↗
Inactivation of Rv2525c, a substrate of the twin arginine translocation (Tat) system of Mycobacterium tuberculosis, increases beta-lactam susceptibility and virulence.
The twin arginine translocation (Tat) system is used by many bacteria to export fully folded proteins containing cofactors. Here, we show genetically that this system is essential for Mycobacterium tuberculosis, as the tatAC operon and tatB genes could be inactivated only in partially diploid strains. Using comparative genomics, the rv2525c gene of M. tuberculosis was identified as encoding a histidine-rich protein, with a twin arginine signal peptide, and orthologous genes were shown to be present in several but not all actinobacterial species. Conservation of this gene by Mycobacterium leprae, which has undergone reductive evolution, suggested an important role for rv2525c. An rv2525c knockout mutant was constructed, and biochemical analysis indicated that the mature Rv2525c protein is secreted. Upon exposure to antituberculous drugs, rv2525c expression is significantly up-regulated together with those of other genes involved in cell wall biogenesis. Phenotypic comparison of the mutant with the parental strain revealed an increase in susceptibility to some beta-lactam antibiotics and, despite slower growth in vitro, enhanced virulence in both cellular and murine models of tuberculosis. The Tat system thus contributes in multiple ways to survival of the tubercle bacillus.
Amino Acid Sequence↗