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PubMed2000

Micro-evolution and emergence of pathogens.

Changes in the epidemiology of infectious diseases are the direct result of ecological and evolutionary changes in hosts and parasites. Precisely what the causal processes are is rarely known in any particular case, and this hinders the design of appropriate control strategies. This is particularly so for emerging infections, as opportunity is rapidly lost to study the ecological parameters which might have affected initial emergence. However, molecular evolutionary studies of the pathogens can yield data which discriminate between possible causes. The current distribution of DNA sequence variation is important information which may reveal past and current changes in pathogen population structures, and can also identify adaptive changes in pathogen genes which have affected their evolution. Such studies have been quite intensively performed on particular viral and bacterial pathogens, and some of the successes of these are noted here. Approaches to understanding the recent evolution of eukaryotic pathogens are outlined, with particular reference to current problems of emerging zoonoses, and changes in virulence and drug resistance.

Animals↗
PubMed2001

Does clutch size evolve in response to parasites and immunocompetence?

Parasites have been argued to influence clutch size evolution, but past work and theory has largely focused on within-species optimization solutions rather than clearly addressing among-species variation. The effects of parasites on clutch size variation among species can be complex, however, because different parasites can induce age-specific differences in mortality that can cause clutch size to evolve in different directions. We provide a conceptual argument that differences in immunocompetence among species should integrate differences in overall levels of parasite-induced mortality to which a species is exposed. We test this assumption and show that mortality caused by parasites is positively correlated with immunocompetence measured by cell-mediated measures. Under life history theory, clutch size should increase with increased adult mortality and decrease with increased juvenile mortality. Using immunocompetence as a general assay of parasite-induced mortality, we tested these predictions by using data for 25 species. We found that clutch size increased strongly with adult immunocompetence. In contrast, clutch size decreased weakly with increased juvenile immunocompetence. But, immunocompetence of juveniles may be constrained by selection on adults, and, when we controlled for adult immunocompetence, clutch size decreased with juvenile immunocompetence. Thus, immunocompetence seems to reflect evolutionary differences in parasite virulence experienced by species, and differences in age-specific parasite virulence appears to exert opposite selection on clutch size evolution.

Animals↗
PubMed2006

Phenotypic switching and its implications for the pathogenesis of Cryptococcus neoformans.

Phenotypic switching has been described in several strains of Cryptococcus neoformans. It occurs in vivo during chronic infection and is associated with differential gene expression and changes in virulence. The switch involves changes in the polysaccharide capsule and cell wall that affect the yeast's ability to resist phagocytosis. In addition, the phenotypic switch variants elicit qualitatively different inflammatory responses in the host. The host's immune response ultimately affects selection of the switch variants in animal models of chronic cryptococcosis. The biological relevance of phenotypic switching is demonstrated in several murine infection models and further underlines the importance of phenotypic switching in the setting of human disease. This includes the association of switching and poor outcome in chronic infection, the ability of the mucoid variant of strain RC-2 (RC-2 MC) but not the smooth variant (RC-2 SM) to promote increased intracranial pressure in a rat model, and lastly the observation that antifungal interventions can promote the selection of more virulent switch variants during chronic murine infection.

Animals↗
PubMed2005

Host-derived pathogenicity islands in poxviruses.

BACKGROUND: Poxviruses are important both as pathogens and as vaccine vectors. Poxvirus genomes (150-350 kb) consist of a single linear dsDNA molecule; the two polynucleotide strands are joined by short hairpin loops. The genomes encode highly conserved proteins required for DNA replication and mRNA transcription as well as a variable set of virulence factors; transcription takes place within the cytoplasm of the host cell. We are interested in evolution of poxvirus genomes and especially how these viruses acquire host-derived genes that are believed to function as virulence factors. RESULTS: Using a variety of bioinformatics tools, we have identified regions in poxvirus genomes that have unusual nucleotide composition (higher or lower than average A+T content) compared to the genome as a whole; such regions may be several kilobases in length and contain a number of genes. Regions with unusual nucleotide composition may represent genes that have been recently acquired from the host genome. The study of these genomic regions with unusual nucleotide content will help elucidate evolutionary processes in poxviruses. CONCLUSION: We have found that dotplots of complete poxvirus genomes can be used to locate regions on the genome that differ significantly in A+T content to the genome as a whole. The genes in these regions may have been acquired relatively recently from the host genome or from another AT-rich poxvirus.

Amino Acid Sequence↗
PubMed2026

Perturbing H-NS function reveals roles in restricting virulence heterogeneity and pathogen adaptation.

Xenogeneic silencers, such as histone-like nucleoid structuring protein (H-NS), are critical for maintaining horizontally acquired genes in bacterial genomes and minimizing fitness costs associated with inappropriate expression. For bacterial pathogens, this has enabled the acquisition of costly virulence regulons, with H-NS balancing the need for tight silencing with rapid expression in host environments. For Salmonella enterica serovar Typhimurium (STm), survival in these environments relies on phenotypic heterogeneity in virulence gene expression and evolutionary adaptation. Although complete loss of hns is highly deleterious in STm, how subtle impairments to this global silencer disrupt heterogeneity in virulence gene expression and alter adaptation to host environments remains poorly understood. Here, we identify an STm hns hypomorph strain and find that its reduced H-NS DNA-binding affinity increases the proportion of virulence-expressing cells, resulting in enhanced epithelial cell infection in vitro. Furthermore, through experimental evolution in intracellular-like conditions in vitro, we demonstrate that both wild-type and mutant populations converge on disrupting the SPI-2 virulence regulon to improve fitness; however, the mutant population also acquires distinct adaptive mutations to resolve the underlying dysregulation in gene expression. These results suggest that H-NS sets single-cell virulence activation thresholds and that even minor disruptions to its silencing function impact pathogen adaptation, highlighting its role as a critical evolutionary buffer.

Salmonella typhimurium↗
PubMed1998

"Black holes" and bacterial pathogenicity: a large genomic deletion that enhances the virulence of Shigella spp. and enteroinvasive Escherichia coli.

Plasmids, bacteriophages, and pathogenicity islands are genomic additions that contribute to the evolution of bacterial pathogens. For example, Shigella spp., the causative agents of bacillary dysentery, differ from the closely related commensal Escherichia coli in the presence of a plasmid in Shigella that encodes virulence functions. However, pathogenic bacteria also may lack properties that are characteristic of nonpathogens. Lysine decarboxylase (LDC) activity is present in approximately 90% of E. coli strains but is uniformly absent in Shigella strains. When the gene for LDC, cadA, was introduced into Shigella flexneri 2a, virulence became attenuated, and enterotoxin activity was inhibited greatly. The enterotoxin inhibitor was identified as cadaverine, a product of the reaction catalyzed by LDC. Comparison of the S. flexneri 2a and laboratory E. coli K-12 genomes in the region of cadA revealed a large deletion in Shigella. Representative strains of Shigella spp. and enteroinvasive E. coli displayed similar deletions of cadA. Our results suggest that, as Shigella spp. evolved from E. coli to become pathogens, they not only acquired virulence genes on a plasmid but also shed genes via deletions. The formation of these "black holes," deletions of genes that are detrimental to a pathogenic lifestyle, provides an evolutionary pathway that enables a pathogen to enhance virulence. Furthermore, the demonstration that cadaverine can inhibit enterotoxin activity may lead to more general models about toxin activity or entry into cells and suggests an avenue for antitoxin therapy. Thus, understanding the role of black holes in pathogen evolution may yield clues to new treatments of infectious diseases.

Cadaverine↗
PubMed2025

Adaptation of the Cyst Nematode Globodera pallida to the Colinear Potato Resistant QTLs GpaVvrn and GpaVspl Involved Distinct Genomic Regions and Absence of Cross-Virulence.

The use of alternative methods to control cyst nematode populations has accelerated since the ban of chemical nematicides in Europe. The resistant QTL GpaVvrn, derived from the wild species Solanum vernei, is widely present in resistant European potato cultivars and provides strong protection against Globodera pallida populations although a risk of resistance breakdown has already been demonstrated in both experimental evolution studies and field populations. The wild relative S. sparsipilum, harbouring the resistant QTL GpaVspl, would be an interesting alternative source of resistance to control virulent G. pallida. The goal of the present study was to understand the genomics of adaptation of the nematode to these two colinear resistant QTLs. Starting with two natural populations, an experimental evolution approach allowed, after 10 generations on resistant potato genotypes, selecting independent nematode lineages adapted to each QTL. These virulent lineages were analysed through a combination of phenotyping and genome scans approaches. Phenotyping enabled the quantification of virulence levels and confirmed resistance breakdowns. Pool-Seq whole genome sequencing followed by genome scan analyses identified genomic regions under selection, potentially involved in the adaptive mechanisms to each resistance factor. Candidate genes within these regions provided insights into the genetic basis of adaptation, revealing effectors known to suppress plant immunity. As genome scans highlighted distinct genomic regions for the adaptation to both resistant factors, we were able to predict and phenotypically confirm the absence of cross-virulence between nematode lineages evolving on GpaVvrn and GpaVspl. These findings have significant implications for the design of effective and sustainable resistance management strategies.

Animals↗
PubMed2004

Intraspecific phylogeny and lineage group identification based on the prfA virulence gene cluster of Listeria monocytogenes.

Listeria monocytogenes is a serious food-borne pathogen that can cause invasive disease in humans and other animals and has been the leading cause of food recalls due to microbiological concerns in recent years. In order to test hypotheses regarding L. monocytogenes lineage composition, evolution, ecology, and taxonomy, a robust intraspecific phylogeny was developed based on prfA virulence gene cluster sequences from 113 L. monocytogenes isolates. The results of the multigene phylogenetic analyses confirm that L. monocytogenes comprises at least three evolutionary lineages, demonstrate that lineages most frequently (lineage 1) and least frequently (lineage 3) associated with human listeriosis are sister-groups, and reveal for the first time that the human epidemic associated serotype 4b is prevalent among strains from lineage 1 and lineage 3. In addition, a PCR-based test for lineage identification was developed and used in a survey of food products demonstrating that the low frequency of association between lineage 3 isolates and human listeriosis cases likely reflects rarity of exposure and not reduced virulence for humans as has been previously suggested. However, prevalence data do suggest lineage 3 isolates may be better adapted to the animal production environment than the food-processing environment. Finally, analyses of haplotype diversity indicate that lineage 1 has experienced a purge of genetic variation that was not observed in the other lineages, suggesting that the three L. monocytogenes lineages may represent distinct species within the framework of the cohesion species concept.

Animals↗
PubMed2004

The surface-mosaic model in host-parasite relationships.

The dynamics of protein adsorption to a microbial surface could be of significance in host-parasite relationships because non-defense proteins might interfere with the binding of defense proteins. A surface mosaic of defense and non-defense proteins formed on the microbial surface could activate one of the tissue reactivity programs via a binary code (help or silence) generated by the adsorbed proteins. Understanding the mechanisms of the mosaic formation and its evolution might help to identify evasion mechanisms used by virulent microorganisms. This also provides a conceptual framework to design new strategies to control the infectious diseases they cause.

Adsorption↗
PubMed2004

Within-host dynamics of a microsporidium with horizontal and vertical transmission: Octosporea bayeri in Daphnia magna.

The fresh-water crustacean Daphnia magna may acquire an infection with the microsporidium Octosporea bayeri either by ingesting spores from the water (horizontally), or directly from its mother (vertically). Due to differences in the time and mechanisms of transmission, horizontal and vertical infections may lead to differences in the growth of the parasite within the host. This may influence parasite virulence, transmission to new hosts, and, consequently, epidemiology and evolution. Here we describe the within-host dynamics of 3 spore-types of O. bayeri from infections that were acquired either horizontally or vertically. In all treatments the number of spores increased exponentially until spore density reached a plateau, suggesting density-dependent within-host growth. The spore types seen differ in their growth dynamics, suggesting different roles in the parasite life-cycle. Horizontally-infected hosts harboured significantly fewer spores than vertically-infected hosts. Further, host survival was affected by infection route, with mortality being higher in horizontal infections than in vertical infections. Our results suggest that different routes of infection have an immediate effect on within-host parasite growth and thus on parasite fitness and epidemiology.

Animals↗
PubMed2002

Escherichia coli as a cause of diarrhea.

Escherichia coli is the best-known member of the normal microbiota of the human intestine and a versatile gastrointestinal pathogen. The varieties of E. coli that cause diarrhea are classified into named pathotypes, including enterotoxigenic, enteroinvasive, enteropathogenic and enterohemorrhagic E. coli. Individual strains of each pathotype possess a distinct set of virulence-associated characteristics that determine the clinical, pathological and epidemiological features of the diseases they cause. In the present brief review, we summarize the key distinguishing features of the major pathotypes of diarrheagenic E. coli. Knowledge of the pathogenic mechanisms of these bacteria has led to the development of rational interventions for the treatment and prevention of E. coli-induced diarrhea. In addition, investigations into E. coli virulence are providing useful insights into the origins and evolution of bacterial pathogens more generally.

Diarrhea↗
PubMed2001

Molecular regulation of urothelial renewal and host defenses during infection with uropathogenic Escherichia coli.

Uropathogenic Escherichia coli (UPEC), the principal cause of urinary tract infection in women, attaches to the superficial facet cell layer of the bladder epithelium (urothelium) via its FimH adhesin. Attachment triggers exfoliation of bacteria-laden superficial facet cells, followed by rapid reconstitution of the urothelium through differentiation of underlying basal and intermediate cells. We have used DNA microarrays to define the molecular regulators of urothelial renewal and host defense expressed in adult C57Bl/6 female mice during the early phases of infection with isogenic virulent (FimH+) or avirulent (FimH-) UPEC strains. The temporal evolution and cellular origins of selected responses were then characterized by real time quantitative reverse transcriptase-PCR, in situ hybridization, and immunohistochemical analyses. Well before exfoliation is evident, FimH-mediated attachment suppresses transforming growth factor-beta (Bmp4) and Wnt5a/Ca(2+) signaling to promote subsequent differentiation of basal/intermediate cells. The early transcriptional responses to attachment also include induction of regulators of proliferation (e.g. epidermal growth factor family members), induction of the ETS transcription factor Elf3, which transactivates genes involved in epithelial differentiation and host defense (inducible nitric-oxide synthase), induction of modulators, and mediators of pro-inflammatory responses (e.g. Socs3, Cebp/delta, Bcl3, and CC/CXC chemokines), induction of modulators of apoptotic responses (A20), and induction of intermediate cell tight junction components (claudin-4). Both early and late phases of the host response exhibit remarkable specificity for the FimH+ strain and provide new insights about the molecular cascade mobilized to combat UPEC-associated urinary tract infection.

Adhesins, Bacterial↗
PubMedDate not supplied

A novel family of channel-forming, autotransporting, bacterial virulence factors.

Pathogenic bacteria produce virulence factors that cross the bacterial cell envelope from the cytoplasm to the extracellular milieu where they promote disease. The mechanisms of their export are poorly understood. We here characterize a family of autotransporter (AT) protein domains present at the C-termini of several nonhomologous Gram-negative bacterial virulence factors. The family consist of 18 sequenced protein domains, the functionally characterized members of which catalyze export of (1) proteases, (2) virulence-related cell adhesins, (3) mediators of actin-promoted bacterial motility, (4) cytotoxins and (5) tissue invasion proteins. We (1) establish that these AT domains are homologous, (2) multiply align their sequences, (3) derive an AT family-specific signature sequence, and (4) define the evolutionary relationships between members of the family. Secondary structural predictions as well as average hydropathy, average similarity and average amphipathicity plots have allowed us to propose a specific 14 beta-stranded barrel structural model that may be applicable to all protein members of the AT family. We suggest that the AT domains became associated with active virulence factor domains by interdomain fusion events that occurred during the evolution of these complex proteins.

Adhesins, Bacterial↗
PubMed2006

Genome sequence diversity and clues to the evolution of variola (smallpox) virus.

Comparative genomics of 45 epidemiologically varied variola virus isolates from the past 30 years of the smallpox era indicate low sequence diversity, suggesting that there is probably little difference in the isolates' functional gene content. Phylogenetic clustering inferred three clades coincident with their geographical origin and case-fatality rate; the latter implicated putative proteins that mediate viral virulence differences. Analysis of the viral linear DNA genome suggests that its evolution involved direct descent and DNA end-region recombination events. Knowing the sequences will help understand the viral proteome and improve diagnostic test precision, therapeutics, and systems for their assessment.

DNA, Viral↗
PubMed1983

Immune serum-mediated effects on brucellosis evolution in mice.

Immune serum injected into mice before a footpad challenge of virulent strain Brucella abortus 544 can prevent dissemination of infection to the spleen. Sera from mice infected with Brucella for at least 2 months or from mice vaccinated with a protein-bound cell wall peptidoglycan Brucella fraction completely stopped dissemination. Brucella lipopolysaccharide and polysaccharide cross-reacting Yersinia immune sera reduced dissemination. Both peptidoglycan and lipopolysaccharide immune sera injected simultaneously with an intravenous challenge caused a shift in Brucella from spleen to liver. When immune sera were injected simultaneously with an intravenous challenge, the kinetics of splenic infection showed two effects: an early one, optimally measured at day 7 postchallenge, showed reduced numbers in the spleen due to the shift of Brucella to the liver; a late effect, measured at day 21 postchallenge, showed reduced numbers in spleen and liver with nearly complete clearance by day 49 postchallenge. Brucella lipopolysaccharide and cross-reacting bacterial antisera induced the early effect only, whereas peptidoglycan and infected mouse sera induced both effects. When peptidoglycan immune serum was injected 2 or 7 days after intravenous challenge, the late effect was somewhat reduced. Hence, immune sera to protein and polysaccharide surface antigens can (i) prevent dissemination of systemic infection and (ii) help destroy intercellular bacteria (protein antigen only). These effects may represent a large part of vaccinal immunity.

Animals↗
PubMed2004

Cellular source of the poxviral N1R/p28 gene family.

Full-length poxvirus N1R/p28 orthologous proteins feature a prominent C-terminal RING zinc-finger motif. The RING moiety is conspicuously mutated in a number of vaccinia virus strains relative to variola virus. This, together with empirical data, suggests that N1R/p28 proteins promote virulence by suppressing apoptosis. Poxvirus N1R/p28 orthologues are strikingly similar to the RING motif of the cellular Makorin family of zinc-finger proteins, suggesting a homologous relationship connecting the viral and cellular genes. Recently identified avipox N1R/p28 orthologues further encode additional Makorin-like zinc-finger motifs, consistent with this suggestion. Phylogenetic analysis supports a model of poxviral capture of a MKRN cDNA and fusion with an existing viral gene. Establishing an evolutionary link between the viral and cellular genes will facilitate the elucidation of their respective cellular functions, and of how they interact in modulating virulence.

Animals↗
PubMed2001

Structural mimicry in bacterial virulence.

An important mechanism underlying the strategies used by microbial pathogens to manipulate cellular functions is that of functional mimicry of host activities. In some cases, mimicry is achieved through virulence factors that are direct homologues of host proteins. In others, convergent evolution has produced new effectors that, although having no obvious amino-acid sequence similarity to host factors, are revealed by structural studies to display mimicry at the molecular level.

Adhesins, Bacterial↗
PubMed1996

Host-symbiont conflict over the mixing of symbiotic lineages.

Host and symbiont often conflict over patterns of symbiont transmission. Symbionts favour dispersal out of the host to avoid competition with close relatives. Migration leads to competition among different symbiotic lineages, with potentially virulent side-effects on the host. The hosts are favoured to restrict symbiont migration and reduce the virulent tendencies of the symbionts. Reduced mixing of symbionts would, in many cases, lower symbiont virulence and increase the mean fitness of the host population. But a host modifier allele that reduced symbiont mixing increases only when directly associated with reduced virulence. The association between modifiers and reduced virulence depends on the particular details of symbiont biology. The importance of this direct association between modifier and virulence was first noted by Hoekstra (1987) when studying the evolution of uniparental inheritance of cytoplasmic elements. I apply Hoekstra's insight to a wide range of host-symbiont life histories, expanding the scope beyond cytoplasmic inheritance and genomic conflict. My comparison of differing symbiont life histories leads to a careful analysis of the conditions under which hosts are favoured to control mixing of their symbionts.

Alleles↗