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PubMed2006

Bile-induced curing of the virulence plasmid in Salmonella enterica serovar Typhimurium.

Exposure to bile induces curing of the virulence plasmid in Salmonella enterica serovar Typhimurium (pSLT). Disruption of the ccdB gene increases pSLT curing, both spontaneous and induced by bile, suggesting that the pSLT ccdAB genes may encode a homolog of the CcdAB addiction module previously described in the F sex factor. Unlike the F sex factor, synthesis of pSLT-encoded pili does not confer bile sensitivity. These observations may provide insights into the evolution of virulence plasmids in Salmonella subspecies I, as well as the causes of virulence plasmid loss in other Salmonella subspecies.

Arabidopsis Proteins↗

PubMed2001

Regulation of differentiation to the infective stage of the protozoan parasite Leishmania major by tetrahydrobiopterin.

A critical step in the infectious cycle of Leishmania is the differentiation of parasites within the sand fly vector to the highly infective metacyclic promastigote stage. Here, we establish tetrahydrobiopterin (H4B) levels as an important factor controlling the extent of metacyclogenesis. H4B levels decline substantially during normal development, and genetic or nutritional manipulations showed that low H4B caused elevated metacyclogenesis. Mutants lacking pteridine reductase 1 (PTR1) had low levels of H4B, remained infectious to mice, and induced larger cutaneous lesions (hypervirulence). Thus, the control of pteridine metabolism has relevance to the mechanism of Leishmania differentiation and the limitation of virulence during evolution.

Animals↗

PubMed2006

Host life-history strategy explains pathogen-induced sterility.

Virulence is often equated with pathogen-induced mortality, even though loss of fecundity is also common. But while the former may be understood as a simple consequence of lost host resources for the purposes of pathogen transmission, pathogen-induced sterility is often not associated with changes in host mortality. As a result, a separate literature has emerged to explain fecundity effects of parasitism that has not been integrated into general theories of the evolution of virulence. Here, I present a model of pathogen-induced sterility that is based on the assumption that hosts and pathogens vie for the same host resources for both reproduction and maintenance. Loss of host fecundity can then be explained by the host compensating for its future loss of resources, before infection. Such preinfection ;;fecundity compensation" may often cause preinfection investment in maintenance to be as low as postinfection levels, despite a loss of total host resources after infection. Thus, sterility is simply explained as a host life-history strategy in a system where the pathogen necessarily steals host resources for its own transmission. In certain circumstances, the pathogen may even be able to manipulate the host to redirect resources away from reproduction and toward maintenance through castration, causing gigantism.

Animals↗

PubMed2006

Interaction of MEQ protein and C-terminal-binding protein is critical for induction of lymphomas by Marek's disease virus.

Marek's disease virus (MDV) is an oncogenic herpesvirus that induces fatal T cell lymphomas in chickens. With more than 20 billion doses of vaccine used annually, vaccination constitutes the cornerstone of Marek's disease control. Despite the success of vaccination, evolution of virulence among MDV strains continues to threaten the effectiveness of the current Marek's disease vaccines. MDV-encoded protein MEQ (MDV EcoRI Q) probably acts as a transcription factor and is considered to be the major MDV oncoprotein. MEQ sequence shows a Pro-Leu-Asp-Leu-Ser (PLDLS) motif known to bind C-terminal-binding protein (CtBP), a highly conserved cellular transcriptional corepressor with roles in the regulation of development, proliferation, and apoptosis. Here we show that MEQ can physically and functionally interact with CtBP through this motif and that this interaction is critical for oncogenesis because mutations in the CtBP-interaction domain completely abolished oncogenicity. This direct role for MEQ-CtBP interaction in MDV oncogenicity highlights the convergent evolution of molecular mechanisms of neoplastic transformation by herpesviruses because Epstein-Barr virus oncoproteins EBNA 3A and 3C also interact with CtBP. We also demonstrate that the nononcogenic MDV generated by mutagenesis of the CtBP-interaction domain of MEQ has the potential to be an improved vaccine against virulent MDV infection. Engineering MDV with precisely defined attenuating mutations, therefore, represents an effective strategy for generating new vaccines against this major poultry disease.

Alcohol Oxidoreductases↗

PubMed1997

Rapid genomic evolution of a non-virulent coxsackievirus B3 in selenium-deficient mice.

Keshan disease, an endemic cardiomyopathy in China, can be prevented with selenium (Se) supplementation. However, the seasonal and annual nature of the disease suggests that an infectious co-factor is required along with a deficiency in Se. Using a murine model of coxsackievirus B3 (CVB3)-induced myocarditis, Se-deficient mice were shown to be more susceptible to the cardiopathologic effects of the virus. In addition, a normal benign strain of CVB3 becomes virulent in Se-deficient mice. This change in virulence was shown to be due to point mutations in the viral genome. Although the mechanism of the viral mutation is not known, the oxidative stress status of the Se-deficient host may play a role, either by directly affecting the virus and/or affecting host immune defenses.

Animals↗

PubMed2002

Complete genome sequence and comparative genomic analysis of an emerging human pathogen, serotype V Streptococcus agalactiae.

The 2,160,267 bp genome sequence of Streptococcus agalactiae, the leading cause of bacterial sepsis, pneumonia, and meningitis in neonates in the U.S. and Europe, is predicted to encode 2,175 genes. Genome comparisons among S. agalactiae, Streptococcus pneumoniae, Streptococcus pyogenes, and the other completely sequenced genomes identified genes specific to the streptococci and to S. agalactiae. These in silico analyses, combined with comparative genome hybridization experiments between the sequenced serotype V strain 2603 V/R and 19 S. agalactiae strains from several serotypes using whole-genome microarrays, revealed the genetic heterogeneity among S. agalactiae strains, even of the same serotype, and provided insights into the evolution of virulence mechanisms.

Amino Acid Sequence↗

PubMed1997

Synergistic effect of mutations in invA and lpfC on the ability of Salmonella typhimurium to cause murine typhoid.

Penetration of the intestinal mucosa at areas of Peyer's patches is an important first step for Salmonella typhimurium to produce lethal systemic disease in mice. However, mutations in genes that are important for intestinal invasion result in only moderately decreased virulence of S. typhimurium for mice. Here we report that combining mutations in invA and lpfC, two genes necessary for entry into Peyer's patches, results in a much stronger attenuation of S. typhimurium than inactivation of either of these genes alone. An S. typhimurium invA lpfC mutant was 150-fold attenuated by the oral route of infection but was fully virulent when the intestine was bypassed by intraperitoneal challenge of mice. During mixed-infection experiments, the S. typhimurium invA lpfC mutant showed a strong defect in colonizing Peyer's patches and mesenteric lymph nodes. These data suggest that mutations in invA and lpfC deactivate distinct pathways for intestinal penetration and colonization of Peyer's patches. While the inv-mediated pathway is widely distributed, the lpf operon is absent from many phylogenetic groups within the genus Salmonella. To investigate how acquisition of the lpf-mediated pathway for mucosal penetration contributed to evolution of virulence, we studied the relationship between the presence of the lpf operon and the pathogenicity for mice of 18 isolates representing 14 Salmonella serotypes. Only strains possessing the lpf operon were able to cause lethal infection in mice. These data show that both the invA- and lpfC-mediated pathways of intestinal perforation are conserved in mouse virulent Salmonella serotypes.

Animals↗

PubMed2002

Analysis of molecular markers genetically linked to the Leptosphaeria maculans avirulence gene AvrLm1 in field populations indicates a highly conserved event leading to virulence on Rlm1 genotypes.

Map-based cloning of the avirulence gene AvrLm1 of Leptosphaeria maculans was initiated utilizing a genetic map of the fungus and a BAC library constructed from an AvrLm1 isolate. Seven polymorphic DNA markers closely linked to AvrLm1 were identified. Of these, two were shown to border the locus on its 5' end and were present, with size polymorphism, in both the virulent and the avirulent isolates. In contrast, three markers, J19-1.1, J53-1.3 (in coupling phase with avirulence), and Vir1 (in repulsion phase with avirulence), cosegregated with AvrLm1 in 312 progeny from five in vitro crosses. J19-1.1 and J53-1.3 were never amplified in the virulent parents or progeny, whereas Vir1 was never amplified in the avirulent parents or progeny. J19-1.1 and J53-1.3 were shown to be separated by 40 kb within a 184-kb BAC contig. In addition, the 1.6-cM genetic distance between J53-1.3 and the nearest recombinant marker corresponded to a 121-kb physical distance. When analyzing a European Union-wide collection of 192 isolates, J53-1.3, J19-1.1, and Vir1 were found to be closely associated with the AvrLm1 locus. The results of polymerase chain reaction amplification with primers for the three markers were in accordance with the interaction phenotype for 92.2% (J53-1.3), 90.6% (J19-1.1), and 88.0% (Vir1) of the isolates. In addition, genome organization of the AvrLm1 region was highly conserved in field isolates, because 89.1% of the avirulent isolates and 79.0% of the virulent isolates showed the same association of markers as that of the parents of in vitro crosses. The large-scale analysis of field isolates with markers originating from the genetic map therefore confirms (i) the physical proximity between the markers and the target locus and (ii) that AvrLm1 is located in (or close to) a recombination-deficient genome region. As a consequence, map-based markers provided us with high-quality markers for an overview of the occurrence of race "AvrLm1" at the field scale. These data were used to propose hypotheses on evolution towards virulence in field isolates.

Ascomycota↗

PubMed2025

Isolation and characterization of bacteriophages from clinical enterohemorrhagic Escherichia coli strains.

Temperate bacteriophages play a pivotal role in the biology of their bacterial host. Of particular interest are bacteriophages infecting enterohemorrhagic E. coli (EHEC) due to their significant contribution to the pathogenicity of its host, most notably by encoding the key virulence factor of this pathogen, the Shiga toxin. To better understand the role of EHEC phages on the functionality of its host, we isolated eight temperate phages from clinical EHEC isolates and characterized their genomic composition, morphology, and receptor targeting. Morphological analysis identified one long-tailed siphophage, targeting the OmpC receptor for host recognition, whereas the other seven phages are short-tailed podophages and target the essential BamA protein. Genomic characterization revealed significant variations between the long- and short-tailed phages. Five of the eight isolated phages encode the potent Shiga toxin. Comparative analysis displays the typical lambdoid mosaicism, indicative of horizontal gene transfer driving evolution. These findings provide insights into the genetic and morphologic diversity and receptor specificity of EHEC phages, highlighting their role in the evolution and pathogenicity of clinical EHEC strains.IMPORTANCECharacterizing bacteriophages from clinical EHEC isolates is crucial in understanding the mechanisms underlying bacterial evolution and virulence. Despite the clinical relevance of EHEC bacteriophages, they remain underexplored, and particularly phage receptors are often not characterized. Studying temperate EHEC phages is essential in the development of strategies to address the global burden of these foodborne infections. Notably, identifying the phage receptors is critical in unraveling the specific interaction between phage and host. Knowledge of the phage receptors can provide insights into the mechanisms of phage infection, host range, and bacterial resistance and is fundamental in the design of targeted therapies like new antimicrobials, phage therapy, or prevention of those infections.

Humans↗

PubMed2007

Yersiniabactin is a virulence factor for Klebsiella pneumoniae during pulmonary infection.

Iron acquisition systems are essential for the in vivo growth of bacterial pathogens. Despite the epidemiological importance of Klebsiella pneumoniae, few experiments have examined the importance of siderophores in the pathogenesis of this species. A previously reported signature-tagged mutagenesis screen identified an attenuated strain that featured an insertional disruption in ybtQ, which encodes a transporter for the siderophore yersiniabactin. We used this finding as a starting point to evaluate the importance of siderophores in the physiology and pathogenesis of K. pneumoniae. Isogenic strains carrying in-frame deletions in genes required for the synthesis of either enterobactin or yersiniabactin were constructed, and the growth of these mutants was examined both in vitro and in vivo using an intranasal infection model. The results suggest divergent functions for each siderophore in different environments, with enterobactin being more important for growth in vitro under iron limitation than in vivo and the reverse being true for the yersiniabactin locus. These observations represent the first examination of isogenic mutants in iron acquisition systems for K. pneumoniae and may indicate that the acquisition of nonenterobactin siderophores is an important step in the evolution of virulent enterobacterial strains.

Animals↗

PubMed2001

Directional gene movement from human-pathogenic to commensal-like streptococci.

Group A streptococci (GAS) are highly pathogenic for humans, and their closest genetic relatives, group C and G streptococci (GCS and GGS, respectively), are generally regarded as commensals, although they can be found in association with human disease. As part of an effort to better understand the evolution of virulence, the phylogenetic relationships between GAS, GCS, and GGS were examined. The nucleotide sequence was determined for an internal portion of seven housekeeping (neutral) loci among >200 isolates of GAS and 34 isolates of GCS or GGS obtained from human subjects. Genotypic analysis failed to show support for the separation of GCS and GGS into two distinct populations. Unlike GAS, there was poor concordance between emm type and genetic relatedness among GCS and GGS. All housekeeping genes within GAS displayed relatively low levels of sequence diversity. In contrast, individual GCS and GGS strains had mosaic genomes, containing alleles at some loci that were similar or identical to GAS alleles, whereas the alleles at other loci were about 10 to 30% diverged. The data provide evidence for a history of recent interspecies transfer of neutral genes that exhibits a strong net directionality from GAS donors to GCS and GGS recipients. A model for the evolution of GAS and of GCS and GGS is described.

Base Sequence↗

PubMed2003

The evolution of immune defense and song complexity in birds.

There are three main hypotheses that explain how the evolution of parasite virulence could be linked to the evolution of secondary sexual traits, such as bird song. First, as Hamilton and Zuk proposed a role for parasites in sexual selection, female preference for healthy males in heavily parasitized species may result in extravagant trait expression. Second, a reverse causal mechanism may act, if sexual selection affects the coevolutionary dynamics of host-parasite interactions per se by selecting for increased virulence. Third, the immuno-suppressive effects of ornamentation by testosterone or limited resources may lead to increased susceptibility to parasites in species with elaborate songs. Assuming a coevolutionary relationship between parasite virulence and host investment in immune defense we used measures of immune function and song complexity to test these hypotheses in a comparative study of passerine birds. Under the first two hypotheses we predicted avian song complexity to be positively related to immune defense among species, whereas this relationship was expected to be negative if immuno-suppression was at work. We found that adult T-cell mediated immune response and the relative size of the bursa of Fabricius were independently positively correlated with a measure of song complexity, even when potentially confounding variables were held constant. Nestling T-cell response was not related to song complexity, probably reflecting age-dependent selective pressures on host immune defense. Our results are consistent with the hypotheses that predict a positive relationship between song complexity and immune function, thus indicating a role for parasites in sexual selection. Different components of the immune system may have been independently involved in this process.

Age Factors↗

PubMed2003

Pathogenic potential of environmental Vibrio cholerae strains carrying genetic variants of the toxin-coregulated pilus pathogenicity island.

The major virulence factors of toxigenic Vibrio cholerae are cholera toxin (CT), which is encoded by a lysogenic bacteriophage (CTXPhi), and toxin-coregulated pilus (TCP), an essential colonization factor which is also the receptor for CTXPhi. The genes for the biosynthesis of TCP are part of a larger genetic element known as the TCP pathogenicity island. To assess their pathogenic potential, we analyzed environmental strains of V. cholerae carrying genetic variants of the TCP pathogenicity island for colonization of infant mice, susceptibility to CTXPhi, and diarrheagenicity in adult rabbits. Analysis of 14 environmental strains, including 3 strains carrying a new allele of the tcpA gene, 9 strains carrying a new allele of the toxT gene, and 2 strains carrying conventional tcpA and toxT genes, showed that all strains colonized infant mice with various efficiencies in competition with a control El Tor biotype strain of V. cholerae O1. Five of the 14 strains were susceptible to CTXPhi, and these transductants produced CT and caused diarrhea in adult rabbits. These results suggested that the new alleles of the tcpA and toxT genes found in environmental strains of V. cholerae encode biologically active gene products. Detection of functional homologs of the TCP island genes in environmental strains may have implications for understanding the origin and evolution of virulence genes of V. cholerae.

Animals↗

PubMed1993

Evidence of natural recombination within the S1 gene of infectious bronchitis virus.

During an outbreak of severe respiratory disease, a field strain of infectious bronchitis virus (IBV), PP14, was isolated from a bird in a Texas flock that had been previously vaccinated with an attenuated Mass serotype virus. After cloning and sequencing the S1 gene from several IBV strains, it was found that the 5' end of the cDNA was 96% identical to the published sequences of Mass41 and 77% identical with Ark99. The following 402 bases which included the hypervariable regions (HVR) of the S1 gene were 94% homologous with Ark99 and only 69% with Mass41. In addition, the HVR in the 3' noncoding region of the genome, which is totally absent in Mass41, was 99% homologous with the Ark99 strain. This abrupt shift in identity of PP14 in the S1 strongly indicated that a recombination event had occurred about 98 bases from the beginning of the S1 gene between an Ark-like and a Mass-like virus. Downstream, 33 bases from the PP14 recombination junction, a second putative "cross-over" site was identified in the S1 of the SE17 strain where the 5'131 bases of the S1 gene of the Ark99 and SE17 were found to be 95% identical and the following 368 base sequence was only 78% homologous. In addition, a second shift in homology in the S1 of SE17 was identified between nucleotide 1112 and 1460 which shared 95% identity with Mass41. The putative recombination junctions which were downstream of the signal sequence and upstream of the S1 HVR may represent a "hot spot," but not an exclusive region, for exchanging genetic material between IBV strains. Genetic shifts are apparently not only common mechanisms for variation in nature, but vaccine strains may actually play a critical role in these events in the evolution of virulent strains of IBV.

Animals↗

PubMed2003

Cross-species infections.

Animals have always been a major source of human infectious disease. Some infections like rabies are recognized as primary zoonoses caused in each case by direct animal-to-human transmission, whereas others like measles become independently sustained within the human population so that the causative virus has diverged from its morbillivirus progenitor in ruminants. Recent examples of direct zoonoses are variant Creutzfeldt-Jakob disease arising from bovine spongiform encephalopathy, and the H5N1 avian influenza outbreak in Hong Kong. Recent epidemic diseases of animal origin are the 1918-1919 influenza pandemic, and the acquired immune deficiency syndrome pandemic caused by human immunodeficiency virus. Some retroviruses move into and out of the chromosomal DNA of the host germline, so that they may oscillate between being an avirulent inherited Mendelian trait in one species and an infectious pathogen in another. Cross-species viral and other infections are reviewed historically with respect to the evolution of virulence and the concern about iatrogenic enhancement of cross-species transfer by medical procedures akin to xenotransplantation.

Animals↗

PubMed1995

Bacteriophage resistance in Lactococcus.

Lactic acid bacteria are industrial microorganisms used in many food fermentations. Lactococcus species are susceptible to bacteriophage infections that may result in slowed or failed fermentations. A substantial amount of research has focused on characterizing natural mechanisms by which bacterial cells defend themselves against phage. Numerous natural phage defense mechanisms have been identified and studied, and recent efforts have improved phage resistance by using molecular techniques. The study of how phages overcome these resistance mechanisms is also an important objective. New strategies to minimize the presence, virulence, and evolution of phage are being developed and are likely to be applied industrially.

Attachment Sites, Microbiological↗

PubMed1994

Variability and its implications for host-parasite interactions.

Variability in host-parasite interactions has considerable impact on the ecology and evolution of parasites and on the epidemiology of disease. The nature of the impact depends largely on the level of ecological organization where variability occurs: variability of parasites within their individual hosts, variability of host individuals within populations, or variability of hosts and parasites among populations. In this review, Paul Schmid-Hempel and Jacob Koella give some examples of variability at each of these levels, with particular emphasis on microparasites (defined broadly as viruses, bacteria and protozoa), consider the maintenance of the variability, and describe the implications of variability for the epidemiology of disease and the ecology of host parasite associations. In particular, they describe how variability at each level of ecological organization can affect the perception of AIDS and the evolution of virulence.

Journal Article↗

PubMed2005

Multiple-locus variable-number tandem repeat analysis for strain typing of Clostridium perfringens.

Clostridium perfringens is ubiquitous in the environment and causes diseases in man and animals, with syndromes ranging from enteritis, enterotoxemia, and sudden death to food poisoning and gas gangrene. Understanding the epidemiology of these infections and of the evolution of virulence in C. perfringens necessitate an efficient, time and cost effective strain typing method. Multiple-locus variable-number tandem repeat analysis (MLVA) has been applied to typing of other pathogens and we describe here the development of a MLVA scheme for C. perfringens. We characterized five variable tandem repeat (VNTR) loci, four of which are contained within protein encoding genes and screened 112 C. perfringens isolates to evaluate typability, reproducibility, and discriminatory power of the scheme. All the isolates were assigned a MLVA genotype and the technique has excellent reproducibility, with a numerical index of discrimination for the five VNTR loci of 0.995. Thus MLVA is an efficient tool for C. perfringens strain typing, and being PCR based makes it rapid, easy, and cost effective. In addition, it can be employed in epidemiological, ecological, and evolutionary investigations of the organism.

Journal Article↗