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PubMed2002

Pathogen population genetics, evolutionary potential, and durable resistance.

We hypothesize that the evolutionary potential of a pathogen population is reflected in its population genetic structure. Pathogen populations with a high evolutionary potential are more likely to overcome genetic resistance than pathogen populations with a low evolutionary potential. We propose a flexible framework to predict the evolutionary potential of pathogen populations based on analysis of their genetic structure. According to this framework, pathogens that pose the greatest risk of breaking down resistance genes have a mixed reproduction system, a high potential for genotype flow, large effective population sizes, and high mutation rates. The lowest risk pathogens are those with strict asexual reproduction, low potential for gene flow, small effective population sizes, and low mutation rates. We present examples of high-risk and low-risk pathogens. We propose general guidelines for a rational approach to breed durable resistance according to the evolutionary potential of the pathogen.

Bacteria↗
PubMed2006

Complete genome sequence of Shigella flexneri 5b and comparison with Shigella flexneri 2a.

BACKGROUND: Shigella bacteria cause dysentery, which remains a significant threat to public health. Shigella flexneri is the most common species in both developing and developed countries. Five Shigella genomes have been sequenced, revealing dynamic and diverse features. To investigate the intra-species diversity of S. flexneri genomes further, we have sequenced the complete genome of S. flexneri 5b strain 8401 (abbreviated Sf8401) and compared it with S. flexneri 2a (Sf301). RESULTS: The Sf8401 chromosome is 4.5-Mb in size, a little smaller than that of Sf301, mainly because the former lacks the SHI-1 pathogenicity island (PAI). Compared with Sf301, there are 6 inversions and one translocation in Sf8401, which are probably mediated by insertion sequences (IS). There are clear differences in the known PAIs between these two genomes. The bacteriophage SfV segment remaining in SHI-O of Sf8401 is clearly larger than the remnants of bacteriophage SfII in Sf301. SHI-1 is absent from Sf8401 but a specific related protein is found next to the pheV locus. SHI-2 is involved in one intra-replichore inversion near the origin of replication, which may change the expression of iut/iuc genes. Moreover, genes related to the glycine-betaine biosynthesis pathway are present only in Sf8401 among the known Shigella genomes. CONCLUSION: Our data show that the two S. flexneri genomes are very similar, which suggests a high level of structural and functional conservation between the two serotypes. The differences reflect different selection pressures during evolution. The ancestor of S. flexneri probably acquired SHI-1 and SHI-2 before SHI-O was integrated and the serotypes diverged. SHI-1 was subsequently deleted from the S. flexneri 5b genome by recombination, but stabilized in the S. flexneri 2a genome. These events may have contributed to the differences in pathogenicity and epidemicity between the two serotypes of S. flexneri.

Chromosome Aberrations↗
PubMed2003

Parasitism, the diversity of life, and paleoparasitology.

The parasite-host-environment system is dynamic, with several points of equilibrium. This makes it difficult to trace the thresholds between benefit and damage, and therefore, the definitions of commensalism, mutualism, and symbiosis become worthless. Therefore, the same concept of parasitism may encompass commensalism, mutualism, and symbiosis. Parasitism is essential for life. Life emerged as a consequence of parasitism at the molecular level, and intracellular parasitism created evolutive events that allowed species to diversify. An ecological and evolutive approach to the study of parasitism is presented here. Studies of the origin and evolution of parasitism have new perspectives with the development of molecular paleoparasitology, by which ancient parasite and host genomes can be recovered from disappeared populations. Molecular paleoparasitology points to host-parasite co-evolutive mechanisms of evolution traceable through genome retrospective studies.

Animals↗
PubMed2004

Avian coccidiosis: a disturbed host-parasite relationship to be restored.

The co-evolution of Eimeria and its host the domestic chicken has resulted in a delicate balance of mutual understanding and respect. This balance has been broken by the complete change of the environment in which the parasite was able to reproduce to such an extent that the host, stressed and weakened by heat, crowding and concurrent infections could not combat the shear numbers of organisms. The use of drugs to control the situation has been shown to only temporarily create relief. Resistance widely developed by the flexible genome of the parasite returned new drugs at a greater speed than they had been developed. Improved hygienic measures, better facility management and good understanding of epidemiology of the parasites spreading and proliferation seem the first and most promising set of tools to control the balance. Reduction of stock density may only provide any relief if this is done at a factor of 10 or higher and this is not a realistic measure in relation to the profit. Free-range chickens are an alternative if only animal welfare is at stake. However, in terms of prevalence of parasitic infections, such as coccidia, helminthes or ectoparasites, chickens do not seem to be better off (Permin et al., 2002). Immunological surveillance and the development of safe, effective and economical vaccines are further refinements that can be used to restore the relationship between parasite and host. Several live vaccines are effective and applied, but certainly have drawbacks in safety and production. New technology such as recombinant vectors together with a better understanding of the cell biology of the parasite from biological and genomic information should provide improved vaccines for the future. The strong genetically determined characteristics involved in the induction and maintenance of a sustainable protective immune response might turn out to be of decisive importance for the success of these strategies. The consequences for the physiology of the parasite remain to be understood.

Animals↗
PubMedDate not supplied

The dual role of wild phages for horizontal gene transfer among Salmonella strains.

Salmonella bacteriophages seem to mediate horizontal transfer of virulence functions among Salmonella strains in two different ways: by general transduction and also by lysogenic conversion. The majority of wild phages isolated from Salmonella strains belong to the P22 like phages and were able to transduce. Our data show that the lysogenic conversion is generally accompanied by changes in the susceptibility to the typing phages used for epidemiological purposes. Similar phage type conversions to S. Typhimurium DT104 could be detected upon lysogenization with two other S. Typhimurium strains. For some S. Typhimurium strains the typical phage pattern is actually associated with alterations of virulence characteristics. For example, all tested wild type isolates of phage types DT49 and DT204 were found to be SopE phi-lysogens. The Anderson typing phages interfere with the prophages and/or cryptic phages and so the complex genetic short-term evolution can be demonstrated in the lab. This is one reason for the successful application of phage typing in Salmonella epidemiology since the 50s.

Bacteriophage Typing↗
PubMedDate not supplied

Molecular mechanisms of bacterial virulence: type III secretion and pathogenicity islands.

Recently, two novel but widespread themes have emerged in the field of bacterial virulence: type III secretion systems and pathogenicity islands. Type III secretion systems, which are found in various gram-negative organisms, are specialized for the export of virulence factors delivered directly to host cells. These factors subvert normal host cell functions in ways that seem beneficial to invading bacteria. The genes encoding several type III secretion systems reside on pathogenicity islands, which are inserted DNA segments within the chromosome that confer upon the host bacterium a variety of virulence traits, such as the ability to acquire iron and to adhere to or enter host cells. Many of these segments of DNA appear to have been acquired in a single step from a foreign source. The ability to obtain complex virulence traits in one genetic event, rather than by undergoing natural selection for many generations, provides a mechanism for sudden radical changes in bacterial-host interactions. Type III secretion systems and pathogenicity islands must have played critical roles in the evolution of known pathogens and are likely to lead to the emergence of novel infectious diseases in the future.

Bacterial Proteins↗
PubMed1998

Secretion of proteins and assembly of bacterial surface organelles: shared pathways of extracellular protein targeting.

Extracellular or surface localization of virulence determinants is an important attribute of pathogenic microorganisms. The past decade has seen significant research advances in defining the steps and identifying the necessary machinery for protein secretion from bacterial cells. In Gram-negative pathogens, four distinct classes of secretion pathways have been identified that deliver virulence factors to their sites of action. These pathways are responsible for the delivery of soluble extracellular enzymes into the surrounding medium, or for specifically targeting proteins to the host cell. In several instances protein secretion pathways are similar to those involved in assembly of bacterial appendages. Combination of biochemical and genetic analyses has recently revealed that the pathways of protein secretion and surface localization of various organelles are mechanistically similar which was not apparent simply by comparing amino acid sequences of related proteins. The choice of the pathway that a protein will utilize may not be dictated only by the specific requirement of the secreted protein to traverse the cell envelope in the functional form, but also by the need to assure its delivery to the correct site of action outside the bacterial cell.

Bacterial Proteins↗
PubMed2001

Evolution of an autotransporter: domain shuffling and lateral transfer from pathogenic Haemophilus to Neisseria.

The genomes of pathogenic Haemophilus influenzae strains are larger than that of Rd KW20 (Rd), the nonpathogenic laboratory strain whose genome has been sequenced. To identify potential virulence genes, we examined genes possessed by Int1, an invasive nonencapsulated isolate from a meningitis patient, but absent from Rd. Int1 was found to have a novel gene termed lav, predicted to encode a member of the AIDA-I/VirG/PerT family of virulence-associated autotransporters (ATs). Associated with lav are multiple repeats of the tetranucleotide GCAA, implicated in translational phase variation of surface molecules. Laterally acquired by H. influenzae, lav is restricted in distribution to a few pathogenic strains, including H. influenzae biotype aegyptius and Brazilian purpuric fever isolates. The DNA sequence of lav is surprisingly similar to that of a gene previously described for Neisseria meningitidis. Sequence comparisons suggest that lav was transferred relatively recently from Haemophilus to Neisseria, shortly before the divergence of N. meningitidis and Neisseria gonorrhoeae. Segments of lav predicted to encode passenger and beta-domains differ sharply in G+C base content, supporting the idea that AT genes have evolved by fusing domains which originated in different genomes. Homology and base sequence comparisons suggest that a novel biotype aegyptius AT arose by swapping an unrelated sequence for the passenger domain of lav. The unusually mobile lav locus joins a growing list of genes transferred from H. influenzae to Neisseria. Frequent gene exchange suggests a common pool of hypervariable contingency genes and may help to explain the origin of invasiveness in certain respiratory pathogens.

Amino Acid Sequence↗
PubMed2004

The omptin family of enterobacterial surface proteases/adhesins: from housekeeping in Escherichia coli to systemic spread of Yersinia pestis.

The omptins are a family of enterobacterial surface proteases/adhesins that share high sequence identity and a conserved beta-barrel fold in the outer membrane. The omptins are multifunctional, and the individual omptins exhibit differing virulence-associated functions. The Pla plasminogen activator of Yersinia pestis contributes by several mechanisms to bacterial invasiveness and the systemic, uncontrolled proteolysis in plague. Pla proteolytically activates the human proenzyme plasminogen and inactivates the antiprotease alpha2-antiplasmin, and its binding to laminin localizes the uncontrolled plasmin activity onto basement membranes. These properties enhance bacterial migration through tissue barriers. Pla also degrades circulating complement proteins and functions in bacterial invasion into human epithelial cells. PgtE of Salmonella enterica and OmpT of Escherichia coli have been shown to degrade cationic antimicrobial peptides from epithelial cells or macrophages. PgtE and SopA of Shigella flexneri appear important in the intracellular phases of salmonellosis and shigellosis, whereas functions of OmpT have mainly been associated with protein degradation in E. coli cells. The differing virulence roles and functions have been attributed to minor sequence variations at the surface-exposed regions important for substrate recognition, to the dependence of omptin functions on lipopolysaccharide, and to the different regulation of omptin expression.

Adhesins, Bacterial↗
PubMed2005

Common evolutionary origin for the unstable virulence plasmid pMUM found in geographically diverse strains of Mycobacterium ulcerans.

The 174-kb virulence plasmid pMUM001 in Mycobacterium ulcerans epidemic strain Agy99 harbors three very large and homologous genes that encode giant polyketide synthases (PKS) responsible for the synthesis of the lipid toxin mycolactone. Deeper investigation of M. ulcerans Agy99 resulted in identification of two types of spontaneous deletion variants of pMUM001 within a population of cells that also contained the intact plasmid. These variants arose from recombination between two 8-kb sections of the same plasmid sequence, resulting in the loss of a 65-kb region bearing two of the three mycolactone PKS genes. Investigation of nine diverse M. ulcerans strains by using PCR and Southern hybridization for eight pMUM001 gene sequences confirmed the presence of pMUM001-like elements (collectively called pMUM) in all M. ulcerans strains. Physical mapping of these plasmids revealed that like M. ulcerans Agy99, three strains had undergone major deletions in their mycolactone PKS loci. Online liquid chromatography-sequential mass spectrometry analysis of lipid extracts confirmed that strains with PKS deletions were unable to produce mycolactone or any related cometabolites. Interstrain comparisons of the plasmid gene sequences revealed greater than 98% nucleotide identity, and the phylogeny inferred from these sequences closely mimicked the phylogeny from a previous multilocus sequence typing study in which chromosomally encoded loci were used, a result that is consistent with the hypothesis that M. ulcerans diverged from the closely related organism Mycobacterium marinum by acquiring pMUM. Our results suggest that pMUM is a defining characteristic of M. ulcerans but that in the absence of purifying selection, deletion of plasmid sequences and a corresponding loss of mycolactone production readily arise.

Amino Acid Sequence↗
PubMed1998

Myxoma virus in rabbits.

Myxoma virus in European rabbits (Oryctolagus cuniculus) is one of the best documented examples of host-virus co-evolution. In the natural hosts (Sylvilagus brasiliensis or S. bachmani rabbits in the Americas), myxoma virus causes a benign cutaneous fibroma. In European rabbits, however, myxoma virus causes the fulminant disease, myxomatosis. When introduced into wild European rabbit populations in Australia, Europe and Great Britain, the virus was initially highly lethal, killing in excess of 99% of infected rabbits. Development of resistance was encouraged by the emergence of attenuated virus strains which allowed the survival of moderately resistant rabbits. This may have occurred more rapidly in hot climates, as high ambient temperatures increase the survival rate of infected rabbits. Resistant rabbits are less effective transmitters of the virus and this may encourage the emergence of more virulent virus strains. Little is known of the mechanism of resistance. There have been suggestions of non-genetic resistance. However, these are yet to be confirmed experimentally.

Animals↗
PubMed2005

Evolutionary genetics of a new pathogenic Escherichia species: Escherichia albertii and related Shigella boydii strains.

A bacterium originally described as Hafnia alvei induces diarrhea in rabbits and causes epithelial damage similar to the attachment and effacement associated with enteropathogenic Escherichia coli. Subsequent studies identified similar H. alvei-like strains that are positive for an intimin gene (eae) probe and, based on DNA relatedness, are classified as a distinct Escherichia species, Escherichia albertii. We determined sequences for multiple housekeeping genes in five E. albertii strains and compared these sequences to those of strains representing the major groups of pathogenic E. coli and Shigella. A comparison of 2,484 codon positions in 14 genes revealed that E. albertii strains differ, on average, at approximately 7.4% of the nucleotide sites from pathogenic E. coli strains and at 15.7% from Salmonella enterica serotype Typhimurium. Interestingly, E. albertii strains were found to be closely related to strains of Shigella boydii serotype 13 (Shigella B13), a distant relative of E. coli representing a divergent lineage in the genus Escherichia. Analysis of homologues of intimin (eae) revealed that the central conserved domains are similar in E. albertii and Shigella B13 and distinct from those of eae variants found in pathogenic E. coli. Sequence analysis of the cytolethal distending toxin gene cluster (cdt) also disclosed three allelic groups corresponding to E. albertii, Shigella B13, and a nontypeable isolate serologically related to S. boydii serotype 7. Based on the synonymous substitution rate, the E. albertii-Shigella B13 lineage is estimated to have split from an E. coli-like ancestor approximately 28 million years ago and formed a distinct evolutionary branch of enteric pathogens that has radiated into groups with distinct virulence properties.

Adhesins, Bacterial↗
PubMed2000

Coevolution of host and virus: the pathogenesis of virulent and attenuated strains of myxoma virus in resistant and susceptible European rabbits.

Myxoma virus was introduced into the European rabbit population of Australia in 1950. Although the virus was initially highly lethal in rabbits, there was rapid selection for less virulent strains of virus and innately resistant rabbits. To investigate the basis of resistance to myxoma virus, we have compared the pathogensis of the virulent strain of myxoma virus originally released into Australia and an attenuated, naturally derived field strain of myxoma virus. This was done in laboratory rabbits, which have not been selected for resistance, and in wild rabbits that have developed significant resistance. Wild rabbits were able to recover from infection with virus that was always lethal in laboratory rabbits. Laboratory rabbits were able to control and recover from infection with attenuated virus. This virus caused a trivial disease in wild rabbits. There was little difference between laboratory and wild rabbits in titers of either virulent or attenuated virus in the skin at the inoculation site. However, resistant wild rabbits had a 10- to 100-fold lower titer of virulent virus within the lymph node draining the inoculation site and controlled virus replication in tissues distal to the draining lymph node. Replication of virus in lymphocytes or fibroblasts cultured from wild and laboratory rabbits demonstrated that resistance was not due to altered cellular permissivity for replication. Neutralizing antibodies were present in both susceptible and resistant rabbits, suggesting that these have no significant role in resistance. We hypothesise that resistance is due to an enhanced innate immune response that allows the rabbit to mount an effective cellular immune response.

Animals↗
PubMed1996

[Aspergillus fumigatus: from saprophytism to virulence. Phenotypic and genotypic biodiversity].

During the last two decades, deep changes have arised in aspergillosis. Thus, this fungal infection mainly due Aspergillus fumigatus is becoming a serious public health-hazard in the growing population of immunocompromised patients. From literature and their own experience, the authors present a synthesis of phenomenons promoting this evolution: the host predisposing factors, environment and potential contamination sources, then the fungus itself. Genetic research developed into the disease-causing organism could be of major interest in epidemiology of aspergillosis and to identify new targets of prophylaxis.

Aspergillosis↗
PubMed2005

Comparative genomic analysis of the pPT23A plasmid family of Pseudomonas syringae.

Members of the pPT23A plasmid family of Pseudomonas syringae play an important role in the interaction of this bacterial pathogen with host plants. Complete sequence analysis of several pPT23A family plasmids (PFPs) has provided a glimpse of the gene content and virulence function of these plasmids. We constructed a macroarray containing 161 genes to estimate and compare the gene contents of 23 newly analyzed and eight known PFPs from 12 pathovars of P. syringae, which belong to four genomospecies. Hybridization results revealed that PFPs could be distinguished by the type IV secretion system (T4SS) encoded and separated into four groups. Twelve PFPs along with pPSR1 from P. syringae pv. syringae, pPh1448B from P. syringae pv. phaseolicola, and pPMA4326A from P. syringae pv. maculicola encoded a type IVA T4SS (VirB-VirD4 conjugative system), whereas 10 PFPs along with pDC3000A and pDC3000B from P. syringae pv. tomato encoded a type IVB T4SS (tra system). Two plasmids encoded both T4SSs, whereas six other plasmids carried none or only a few genes of either the type IVA or type IVB secretion system. Most PFPs hybridized to more than one putative type III secretion system effector gene and to a variety of additional genes encoding known P. syringae virulence factors. The overall gene contents of individual PFPs were more similar among plasmids within each of the four groups based on T4SS genes; however, a number of genes, encoding plasmid-specific functions or hypothetical proteins, were shared among plasmids from different T4SS groups. The only gene shared by all PFPs in this study was the repA gene, which encoded sequences with 87 to 99% amino acid identityamong 25 sequences examined. We proposed a model to illustrate the evolution and gene acquisition of the pPT23A plasmid family. To our knowledge, this is the first such attempt to conduct a global genetic analysis of this important plasmid family.

DNA Helicases↗
PubMed1996

Characterization of the immunological memory state generated in mice susceptible to Leishmania major following exposure to low doses of L. major and resulting in resistance to a normally pathogenic challenge.

BALB/c mice are susceptible to a high-dose infection of the protozoan Leishmania major, which induces a parasite-specific antibody, Th2-like response, exclusive of a significant and protective cell-mediated Th1 component. We have shown, in contrast, that infection with a low number of parasites induces cell-mediated immunity exclusive of antibody production, and results in resistance to substantial subsequent high-dose infection. Low-dose exposure thus constitutes effective vaccination. In the present study, we analyze lymphokine production by parasite-specific T cells from those low-dose exposed, resistant mice and from normal, susceptible mice following high-dose infection. Two findings stand out. First, the parasite-specific T cells in mice rendered resistant appear not to be in an activated, effector state at the time of parasite challenge, as assessed by lack of lymphokine production on short-term stimulation with parasite antigens, but to be rather in a memory state. Second, the ratio of parasite antigen-dependent production of interferon-gamma to that of interleukin-4 by spleen cells of low-dose exposed and normal mice upon high-dose challenge takes a dramatically different course. This ratio is similar in both groups of mice shortly after challenge, but increases dramatically in the resistant and declines dramatically in the control mice over a period of weeks, such that these ratios differ by about 60-fold 12 weeks after the high-dose challenge. In addition, we show that a similar state of resistance occurs following low-dose infection with a more virulent strain of L. major. In toto, our observations suggest that resistance may be generally achievable by low-dose exposure and may be associated with a memory state which, when activated by parasite challenge, results in the evolution of the response over weeks such that the protective, Th1 component becomes ever more dominant over the Th2 component.

Animals↗