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PubMed1999

Molecular characterization of equine isolates of Streptococcus pneumoniae: natural disruption of genes encoding the virulence factors pneumolysin and autolysin.

Although often considered a strict human pathogen, Streptococcus pneumoniae has been reported to infect and cause pneumonia in horses, although the pathology appears restricted compared to that of human infections. Here we report on the molecular characterization of a group of S. pneumoniae isolates obtained from horses in England and Ireland. Despite being obtained from geographically distinct locations, the isolates were found to represent a tight clonal group, virtually identical to each other but genetically distinguishable from more than 120 divergent isolates of human S. pneumoniae. A comprehensive analysis of known pneumococcal virulence determinants was undertaken in an attempt to understand the pathogenicity of equine pneumococci. Surprisingly, equine isolates appear to lack activities associated with both the hemolytic cytotoxin pneumolysin, often considered a major virulence factor of pneumococci, and the major autolysin gene lytA, also considered an important virulence factor. In support of phenotypic data, molecular studies demonstrated a deletion of parts of the coding sequences of both lytA and ply genes in equine pneumococci. The implications of these findings for the evolution and pathogenicity of equine S. pneumoniae are discussed.

Animals↗
PubMed2005

Evolutionary nursing: the case of infectious diseases.

AIM: The aim of this paper is to examine the effect of evolution on infectious diseases nursing, and propose a model that may help to increase understanding of how hosts and microorganisms co-exist and how humans can alter the delicate balance between them. BACKGROUND AND RATIONALE: Infectious diseases occur as the result of interactions between hosts and microorganisms. There is an increasing acceptance that the evolution of host and parasite is important in the development of infectious diseases. However, such views have made little impact in nursing, and the use of evolutionary interventions remains controversial. METHOD: The Medline database was searched from 1966 to present using the terms pathogen$, virulen$, evolution, bacteria, and all combinations of these. Additionally reference lists of text books and papers were hand searched for relevant papers. Papers were selected from a variety of disciplines, including infectious diseases, microbiology, evolutionary biology, and ecology. Recurrent themes from these papers were identified and a model of evolutionary nursing constructed. RESULTS: Microorganisms are plentiful, ubiquitous, and rapidly evolving by comparison with humans and other animals. As a result of this, attempts to 'outwit' them have been, and are, doomed to failure. However, through careful management of public and personal health, a balance encouraging co-existence may be possible. A number of specific interventions is proposed. CONCLUSIONS: There are a number of key interventions that may reduce the virulence of microorganisms. With an increasing world population, antibiotic resistance and international travel, such an approach may be one way of reducing the morbidity associated with infectious diseases.

Biological Evolution↗
PubMed2001

Type IV secretion: intercellular transfer of macromolecules by systems ancestrally related to conjugation machines.

Bacterial conjugation systems are highly promiscuous macromolecular transfer systems that impact human health significantly. In clinical settings, conjugation is exceptionally problematic, leading to the rapid dissemination of antibiotic resistance genes and other virulence traits among bacterial populations. Recent work has shown that several pathogens of plants and mammals - Agrobacterium tumefaciens, Bordetella pertussis, Helicobacter pylori and Legionella pneumophila - have evolved secretion pathways ancestrally related to conjugation systems for the purpose of delivering effector molecules to eukaryotic target cells. Each of these systems exports distinct DNA or protein substrates to effect a myriad of changes in host cell physiology during infection. Collectively, secretion pathways ancestrally related to bacterial conjugation systems are now referred to as the type IV secretion family. The list of putative type IV family members is increasing rapidly, suggesting that macromolecular transfer by these systems is a widespread phenomenon in nature.

Bacterial Proteins↗
PubMed1994

Gene sequence of recA+ and construction of recA mutants of Vibrio cholerae.

The recA+ gene of Vibrio cholerae O1 has been cloned, its nucleotide sequence determined and the product characterized. A deletion mutation was constructed in the recA gene and mutants showed the typical sensitivity to UV and to DNA-damaging agents, as well as an inability to mediate homologous DNA recombination. The chromosomal recA deletion mutants in V. cholerae do not show altered virulence in the infant mouse cholera model and are thus ideal strains for use in complementation studies.

Amino Acid Sequence↗
PubMed2025

Genomic characterisation of recurrent Mycobacterium avium isolates from chronically infected patients reveals patterns of within-host evolution.

BACKGROUND: Mycobacterium avium complex causes chronic and difficult-to-treat infection in vulnerable patient groups, and incidence is increasing worldwide. Whole genome sequencing has the potential to reveal new information about how M. avium persists over time in the human lung. METHODS: We analysed the genomes of 287 isolates of M. avium that were sampled longitudinally from 56 patients. Our dataset included 50 newly sequenced genomes from a cohort of 20 patients from Ireland who were sampled for up to 10 years, and we compared these to 237 published genomes from 2 pre-existing cohorts from Europe to evaluate strains from Ireland in a wider context. Additionally, we performed a combined analysis across the 3 cohorts to examine the changes that occurred over the course of infection. RESULTS: We identified 2 instances where strains from Ireland clustered with strains from Europe within a 13-SNP threshold, supporting previous observations that dominant circulating clones of M. avium are present internationally. Across the 3 cohorts, we found that the communities of M. avium evolved over time within individual hosts, and we report that acquisition of new strains is frequent. Importantly, our findings suggest that M. avium may adapt to the conditions that it faces in the host, with evidence of positive selection of 13 distinct mycobacterial genes. Notably, multiple virulence-associated genes were under selection, including genes that could confer resistance to antibiotics and host defence mechanisms. CONCLUSIONS: Whole genome sequencing provides novel insights into within-host evolution of M. avium and highlights potentially important mycobacterial strategies to enhance persistence that may provide new targets for therapeutic investigation.

Humans↗
PubMed1994

Mapping and genetic organization of pTiChry5, a novel Ti plasmid from a highly virulent Agrobacterium tumefaciens strain.

Agrobacterium tumefaciens Chry5, a wild-type strain originally isolated from chrysanthemum, is unusually tumorigenic, particularly on soybean. We have mapped the Chry5 Ti plasmid by genomic walking and restriction endonuclease analysis, and have located its virulence, T-DNA, plasmid incompatibility, and L,L-succinamopine utilization loci. Southern analysis has revealed that about 85% of the Chry5 Ti plasmid is highly homologous to another Ti plasmid, pTiBo542. Although all the functions that we have located on pTiChry5 are encoded by pTiBo542-homologous regions, the two Ti plasmids differ in their genetic organization. The overall patterns of restriction sites in the plasmids also differ, with the exception of an approximately 12 kb segment of the virulence region, where the BamHI sites appear to be conserved. Complementation analysis has shown that deletion of a DNA segment which flanks the oncogenic T-DNA results in severe attenuation of virulence. This region also contains a sequence that is repeated in the Chry5 genome outside the Ti plasmid, and that is widely distributed in the Rhizobiaceae.

Agrobacterium tumefaciens↗
PubMed1994

Unique lentivirus--host interactions: SIVsmmPBj14 infection of macaques.

The most virulent primate lentivirus identified to date, the simian virus SIVsmmPBj14 (SIV-PBj14), is unique not only because it causes acute disease and death within days instead of months or years, but also because of its replicative and cellular activation properties. The acute disease syndrome has many features in common with primary HIV-1 disease, but differences in the respective outcomes of these two acute lentiviral infections appear to be linked to the rapidity with which SIV-PBj14 replicates and the high titers of virus that subsequently accumulate in lymphoid tissues. The most prominent pathologic feature of SIV-PBj14 is extensive lymphoid hyperplasia of T-cell zones, especially in the gut-associated lymphoid tissue. These expanded T-cell zones contain a high proportion of lymphoblasts, activated macrophages and syncytial cells, which are positively correlated with high numbers of SIV antigen-positive cells. Replication of the virus to high titers, accompanied by extensive cellular activation and proliferation, leading to high levels of cytokines, such as interleukin-6 and tumor necrosis factor-alpha, are consistent with acute inflammatory disease. The pathogenesis of SIV-PBj14 also appears to correlate most directly with some of its unique biologic properties, such as the ability to replicate in resting peripheral blood mononuclear cells, to activate lymphocytes, and to induce lymphocyte proliferation. Biologically and molecularly cloned viruses derived from SIV-PBj14 and isolates obtained from macaque PBj at earlier times, are being used to identify viral determinants that influence biologic and pathogenic properties of SIV-PBj14. Further characterization of this virus should provide new insights into lentivirus-cell interactions and their contributions to disease.

Animals↗
PubMed2001

Identification and characterization of App: an immunogenic autotransporter protein of Neisseria meningitidis.

In a search for immunogenic virulence factors in Neisseria meningitidis, we have identified a gene encoding a predicted 160 kDa protein with homology to the autotransporter family of proteins. Members of this family are secreted or surface exposed and are often associated with virulence in Gram-negative bacterial pathogens. We named the gene adhesion and penetration protein (app), because of its extensive homology to the hap gene of Haemophilus influenzae. We reconstructed the gene with reference to genomic sequence data and cloned and expressed the protein in Escherichia coli. Rabbit antiserum raised against recombinant App reacted with proteins in all meningococcal isolates examined, which represented clonal groups responsible for the majority of meningococcal invasive disease. Antibodies to the protein were detected in the sera of patients convalescing from meningococcal infection. Purified App had strong stimulating activity for T cells isolated from a number of healthy donors and from one convalescent patient. We confirmed that App is surface localized, cleaved and secreted by N. meningitidis. Importantly, the rabbit anti-App serum killed the organism in the presence of complement. Thus, App is conserved among meningococci, immunogenic in humans and potentially involved in virulence. It therefore merits further investigation as a component of a future multivalent vaccine.

Antigens, Bacterial↗
PubMed2005

Enterohemorrhagic Escherichia coli in human infection: in vivo evolution of a bacterial pathogen.

BACKGROUND: Enterohemorrhagic Escherichia coli (EHEC) cause most cases of the hemolytic uremic syndrome (HUS) worldwide. To investigate genetic changes in EHEC during the course of human infection, we analyzed consecutive stool samples and shed isolates from patients with HUS, focusing on the genes encoding Shiga toxin (stx) and intimin (eae). METHODS: Sequential stool samples from 210 patients with HUS were investigated for the persistence of E. coli strains harboring stx and/or eae. Initial stool samples were collected during the acute phase of HUS, and subsequent stool samples were collected 3-16 days later (median interval, 8 days). RESULTS: Organisms that were stx and eae positive (stx+/eae+ strains; n=137) or stx negative and eae positive (stx-/eae+ strains; n=5) were detected in the initial stool samples from 142 patients. Subsequently, the proportion of those who shed stx+/eae+ strains decreased to 13 of 210 patients, whereas the proportion of those who shed strains that were stx-/eae+ increased to 12 of 210 patients. Seven patients who initially excreted strains that were stx+/eae+ shed, at second analysis, stx-/eae+ strains of the same serotypes; they had no free fecal Shiga toxin at follow-up. Comparison of the initial and follow-up isolates from these patients with use of molecular-epidemiological methods revealed loss of stx genes and genomic rearrangement. CONCLUSIONS: We demonstrate the loss of a critical bacterial virulence factor from pathogens during very brief intervals in the human host. These genetic changes have evolutionary, diagnostic, and clinical implications. Generation of stx- mutants might contribute to subclonal evolution and evolutionary success.

Enterotoxins↗
PubMed2001

Very large long-term effective population size in the virulent human malaria parasite Plasmodium falciparum.

It has been proposed that the virulent human malaria parasite Plasmodium falciparum underwent a recent severe population bottleneck. In order to test this hypothesis, we estimated the effective population size of this species from the patterns of nucleotide substitution at 23 nuclear protein-coding loci, using a variety of methods based on coalescent theory. Both simple methods and phylogenetically based maximum-likelihood methods yielded the conclusion that the effective population size of this species has been of the order of at least 10(5) for the past 300,000-400,000 years.

Alleles↗
PubMed2000

Functional implications of the beta-helical protein fold: differences in chemical and thermal stabilities of Erwinia chrysanthemi EC16 pectate lyases B, C, and E.

Colonization of plant tissue by the phytopathogen Erwinia chrysanthemi EC16 is aided by the activities of the pectate lyase isozymes (PLs), which depolymerize the polygalacturonic acid component (PGA) of plant cell walls. The bacterium secretes four pectate lyases (PLa, PLb, PLc, and PLe), two of which, PLc and PLe, have been shown to fold into a similar domain motif, the beta-helix. To understand the rationale behind the evolution and retention of these isoforms, the susceptibilities of pectate lyases B, C, and E to chemical and thermal denaturation and the resulting enzymatic inactivation were examined. With guanidine hydrochloride used as a denaturant, all three pectate lyases denatured with transition midpoint guanidine hydrochloride concentrations (Cm) of 1.3, 1.1, and 1.8 M for PLb, PLc, and PLe, respectively. Lyase activity decreased in direct response to loss of secondary structure in all enzymes. Pectate lyases B and C demonstrated increased enzymatic activity at temperatures above 30 degrees C, with maximal activity observed at 40 degrees C for PLb and 35 degrees C for PLc. Transition midpoints (Tm) as measured by circular dichroism were at 46.9 degrees C for PLb and 44.3 degrees C for PLc, indicating detectable conformational changes accompanying thermal inactivation. Decreased enzymatic activity of PLe was observed at all temperatures above 30 degrees C, and the enzyme was found to possess a Tm at 38.9 degrees C. The data demonstrate structural differences among these enzymes that may be the basis for different enzymatic efficiencies under the potential array of environmental conditions experienced by the bacterium. These differences, in turn, may play a part in the retention of these isozymes as virulence factors, allowing the successful colonization of susceptible plant hosts.

Bacterial Proteins↗
PubMed1988

Present state of lactic acid bacteria phage taxonomy.

Recent developments in molecular taxonomy of bacteriophages of lactobacilli and lactic streptococci are presented. DNA homology appears to be the most valid criterion in studying phage taxonomy. For each bacterial species, phages can be classified in a few families according to this criterion. A fair correspondence is observed between the groups differentiated by DNA-DNA hybridization and those differenciated by protein composition. In 2 bacterial species, a close relatedness between some virulent and temperate phages has been demonstrated. The presence of homologous sequences in the genome of various phages may play an important role in their evolution. For future taxonomic studies, some phages representative of DNA homology groups are proposed as reference phages.

Bacteriophages↗
PubMed2002

Genome analysis and strain comparison of correia repeats and correia repeat-enclosed elements in pathogenic Neisseria.

Whole genome sequences of Neisseria meningitidis strains Z2491 and MC58 and Neisseria gonorrhoeae FA1090 were analyzed for Correia repeats (CR) and CR-enclosed elements (CREE). A total of 533, 516, and 256 copies of CR and 270, 261, and 102 copies of CREE were found in these three genomes, respectively. The lengths of CREE range from 28 to 348 bp, and the lengths of multicopy CREE appear mainly in the ranges of 154 to 156 bp and 105 to 107 bp. The distribution of CREE lengths is similar between the two N. meningitidis genomes, with a greater number of 154- to 156-bp CREE (163 and 152 copies in N. meningitidis strain Z2491 and N. meningitidis strain MC58, respectively) than 105- to 107-bp CREE (72 and 77 copies). In the N. gonorrhoeae strain FA1090 genome there are relatively more 105- to 107-bp CREE (51 copies) than 154- to 156-bp CREE (36 copies). The genomic distribution of 107-bp CREE also shows similarity between the two N. meningitidis strains (15 copies share the same loci) and differences between N. meningitidis strains and N. gonorrhoeae FA1090 (only one copy is located in the same locus). Detailed sequence analysis showed that both the terminal inverted repeats and the core regions of CREE are composed of distinct basic sequence blocks. Direct TA dinucleotide repeats exist at the termini of all CREE. A survey of DNA sequence upstream of the sialyltransferase gene, lst, in several Neisseria isolates showed that 5 N. meningitidis strains contain a 107-bp CREE in this region but 25 N. gonorrhoeae strains show an exact absence of a 105-bp sequence block (i.e., the 107-bp CREE without a 5' TA dinucleotide) in the same region. Whole-genome sequence analysis confirmed that this 105-bp indel exists in many homologous 107-bp CREE loci. Thus, we postulate that all CREE are made of target TA with indels of various lengths. Analysis of 107-bp CREE revealed that they exist predominantly in intergenic regions and are often near virulence, metabolic, and transporter genes. The abundance of CREE in Neisseria genomes suggests that they may have played a role in genome organization, function, and evolution. Their differential distribution in different pathogenic Neisseria strains may contribute to the distinct behaviors of each Neisseria species.

Base Sequence↗
PubMed2006

Temporal and dose-dependent relationships between in vivo B cell receptor-targeted proliferation and deletion-induced by a microbial B cell toxin.

The effective functioning of the adaptive immune system requires careful clonal regulation within the B cell compartment. Some microbial pathogens produce virulence factors, like staphylococcal protein A, which interact at high frequencies with B lymphocyte through unconventional binding sites in BCR variable region frameworks conserved during evolution. We have characterized the in vivo effect of staphylococcal protein A treatment on peripheral B cells bearing susceptible BCR, and found a dose-dependent direct relationship over the range of 2 mg to <0.2 microg in the magnitude of induced BCR-targeted supraclonal cell death. Significantly, some level of targeted B cell proliferation was always detectable, with greatest interim supraclonal expansion demonstrated at 2 days after 20-microg treatment. Subsequently, this transient expansion always collapsed. In direct comparisons, i.p. treatment was more efficacious than i.v. treatment, although at higher doses this finding was less marked. These studies elucidate a general paradigm in which in vivo encounters with a B cell superantigen are uniformly associated with proliferative expansion followed by deletion that is more rapid and complete with higher doses, whereas lower doses lead to greater transient in vivo expansion with delayed deletion to levels at later times that are still quantitatively proportional to the dose. Our results document the potent in vivo B cell-targeted properties of a microbial B cell superantigen, even at submicrogram doses associated with great molar excess of circulating Ig, and clearly illustrate the intertwined relationships between targeted proliferative cycling and apoptotic death that is induced by a microbial B cell superantigen.

Animals↗
PubMed2001

Pattern of mutation in the genome of influenza A virus on adaptation to increased virulence in the mouse lung: identification of functional themes.

The genetic basis for virulence in influenza virus is largely unknown. To explore the mutational basis for increased virulence in the lung, the H3N2 prototype clinical isolate, A/HK/1/68, was adapted to the mouse. Genomic sequencing provided the first demonstration, to our knowledge, that a group of 11 mutations can convert an avirulent virus to a virulent variant that can kill at a minimal dose. Thirteen of the 14 amino acid substitutions (93%) detected among clonal isolates were likely instrumental in adaptation because of their positive selection, location in functional regions, and/or independent occurrence in other virulent influenza viruses. Mutations in virulent variants repeatedly involved nuclear localization signals and sites of protein and RNA interaction, implicating them as novel modulators of virulence. Mouse-adapted variants with the same hemagglutinin mutations possessed different pH optima of fusion, indicating that fusion activity of hemagglutinin can be modulated by other viral genes. Experimental adaptation resulted in the selection of three mutations that were in common with the virulent human H5N1 isolate A/HK/156/97 and that may be instrumental in its extreme virulence. Analysis of viral adaptation by serial passage appears to provide the identification of biologically relevant mutations.

Adaptation, Physiological↗
PubMed2000

[The niches and pathways of animal pathogens].

Infectious diseases are not a relict of the past but a topical phenomenon determined by complex evolution of the currently existing and constantly changing microbial agents and their hosts. With regard to abundance of species within the microbial kingdom and rate of its changes and development, it is difficult to predict the role of the microbial factor in mortality of humans and animals. The study and generalization of sequential similarities of microbial virulence factors after the completion of genome sequencing of principal pathogens can play a positive role in this direction. At present, molecular-genetic methods allow us to study the phylogenetic relationships of microbes and categorize them according to new criteria. The efficient control of diseases caused by microbes requires knowledge on their physiological and ecological niche from which they penetrate, in various ways, into the host organisms and, under suitable conditions, induce mass diseases. This process has several stages and, in the recent period, it is increasingly affected by human activities. The knowledge on all participants in this process, i.e. the microbe and its niche, factors of virulence and pathways of their dissemination, requires a scientifically based surveillance. Abundance and variability is characteristic for both microbial kingdom and microbial niche. Some identification of pathogenic properties of microorganisms and factors affecting their movement from their niche to the recipients results in activation of old classical diseases (e.g. plague, cholera, tuberculosis etc.) or emerging of new, so far unknown infections diseases ("emerging inf. disease"--EID), caused for example by lentiviruses, oncoviruses, filiviruses, bartonella, borrelia etc. This has provided the basis for establishment of new medical trends and approaches, such as "Emergency medicine" or "Travel medicine", expressing their purpose by their names. The control of existing or proposed infectious diseases in the 21st century (in which majority of factors such as urbanization, environmental factors, evolution of the microbial kingdom, will contribute to the persistence or "emergence" of new diseases) will be affected by the input of new knowledge in the field of molecular biology, such as introduction of biosensors, genetic tests, microchips, new generation of DNA vaccines, enteric vaccines and antibodies produced by transgenic animal bioreactors or plants, "customized" vaccines assessed for individual genetic profiles, etc. (Tab. 5, Ref. 21.)

Animals↗
PubMed2006

The origin of human pathogens: evaluating the role of agriculture and domestic animals in the evolution of human disease.

Many significant diseases of human civilization are thought to have arisen concurrently with the advent of agriculture in human society. It has been hypothesised that the food produced by farming increased population sizes to allow the maintenance of virulent pathogens, i.e. civilization pathogens, while domestic animals provided sources of disease to humans. To determine the relationship between pathogens in humans and domestic animals, I examined phylogenetic data for several human pathogens that are commonly evolutionarily linked to domestic animals: measles, pertussis, smallpox, tuberculosis, taenid worms, and falciparal malaria. The majority are civilization pathogens, although I have included others whose evolutionary origins have traditionally been ascribed to domestic animals. The strongest evidence for a domestic-animal origin exists for measles and pertussis, although the data do not exclude a non-domestic origin. As for the other pathogens, the evidence currently available makes it difficult to determine if the domestic-origin hypothesis is supported or refuted; in fact, intriguing data for tuberculosis and taenid worms suggests that transmission may occur as easily from humans to domestic animals. These findings do not abrogate the importance of agriculture in disease transmission; rather, if anything, they suggest an alternative, more complex series of effects than previously elucidated. Rather than domestication, the broader force for human pathogen evolution could be ecological change, namely anthropogenic modification of the environment. This is supported by evidence that many current emerging infectious diseases are associated with human modification of the environment. Agriculture may have changed the transmission ecology of pre-existing human pathogens, increased the success of pre-existing pathogen vectors, resulted in novel interactions between humans and wildlife, and, through the domestication of animals, provided a stable conduit for human infection by wildlife diseases.

Agriculture↗
PubMed2006

Multiple avirulence paralogues in cereal powdery mildew fungi may contribute to parasite fitness and defeat of plant resistance.

Powdery mildews, obligate biotrophic fungal parasites on a wide range of important crops, can be controlled by plant resistance (R) genes, but these are rapidly overcome by parasite mutants evading recognition. It is unknown how this rapid evolution occurs without apparent loss of parasite fitness. R proteins recognize avirulence (AVR) molecules from parasites in a gene-for-gene manner and trigger defense responses. We identify AVR(a10) and AVR(k1) of barley powdery mildew fungus, Blumeria graminis f sp hordei (Bgh), and show that they induce both cell death and inaccessibility when transiently expressed in Mla10 and Mlk1 barley (Hordeum vulgare) varieties, respectively. In contrast with other reported fungal AVR genes, AVR(a10) and AVR(k1) encode proteins that lack secretion signal peptides and enhance infection success on susceptible host plant cells. AVR(a10) and AVR(k1) belong to a large family with >30 paralogues in the genome of Bgh, and homologous sequences are present in other formae speciales of the fungus infecting other grasses. Our findings imply that the mildew fungus has a repertoire of AVR genes, which may function as effectors and contribute to parasite virulence. Multiple copies of related but distinct AVR effector paralogues might enable populations of Bgh to rapidly overcome host R genes while maintaining virulence.

Amino Acid Sequence↗