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Results for “Pathogen diversity”

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PubMed2005

Protective efficacy of a recombinant plague vaccine when co-administered with another sub-unit or live attenuated vaccine.

Vaccines against bioterrorism agents offer the prospect of providing high levels of protection against airborne pathogens. However, the diversity of the bioterrorism threat means that it may be necessary to use several vaccines simultaneously. In this study we have investigated whether there are changes to the protective immune response to a recombinant sub-unit plague vaccine when it is co-administered with other sub-unit or live attenuated vaccines. Our results indicate that the co-administration of these vaccines did not influence the protection afforded by the plague vaccine. However, the co-administration of the plague sub-unit vaccine with a live vaccine resulted in markedly increased levels of IgG2a subclass antibodies, and markedly reduced levels of IgG1 subclass antibodies, to the plague sub-unit vaccine. This finding might have implications when considering the co-administration of other vaccine combinations.

Animals↗

PubMed2005

Molecular characterization of Mycobacterium tuberculosis isolates in a region of Brazil with a high incidence of tuberculosis.

One hundred and seventy Mycobacterium tuberculosis clinical isolates were characterized by spoligotyping to evaluate the biodiversity of tubercle bacilli in a region of Brazil with a high incidence of tuberculosis (Pelotas and Rio Grande cities - Rio Grande do Sul State). The spoligotyping results were compared to the World Spoligotyping Database (Institut Pasteur de Guadeloupe), which contains data from >14,000 worldwide isolates of M. tuberculosis. The isolates clustered by spoligotyping were further characterized by IS6110-RFLP to confirm the clonal relationship. Sixty-six different spoligotypes were identified, grouping 125 of the isolates (74%). Approximately half of the isolates belonged to seven of the most frequently occurring spoligotypes in the database. Three shared types (with two or more isolates) not previously identified were given the type numbers 826, 827 and 863. An additional 45 spoligotypes were identified that did not match any existing database pattern. RFLP characterization reduced the number of isolates in most of the clusters, thereby showing a higher differentiation capacity than spoligotyping. These results highlight the importance of molecular epidemiology studies of tuberculosis in insufficiently studied regions with a high TB burden, in order to uncover the true extent of genetic diversity of the pathogen.

Bacterial Typing Techniques↗

PubMed2006

A common structural motif in the binding of virulence factors to bacterial secretion chaperones.

Salmonella invasion protein A (SipA) is translocated into host cells by a type III secretion system (T3SS) and comprises two regions: one domain binds its cognate type III secretion chaperone, InvB, in the bacterium to facilitate translocation, while a second domain functions in the host cell, contributing to bacterial uptake by polymerizing actin. We present here the crystal structures of the SipA chaperone binding domain (CBD) alone and in complex with InvB. The SipA CBD is found to consist of a nonglobular polypeptide as well as a large globular domain, both of which are necessary for binding to InvB. We also identify a structural motif that may direct virulence factors to their cognate chaperones in a diverse range of pathogenic bacteria. Disruption of this structural motif leads to a destabilization of several chaperone-substrate complexes from different species, as well as an impairment of secretion in Salmonella.

Amino Acid Motifs↗

PubMed2006

Systemic immunity.

Systemic acquired resistance (SAR) provides enhanced, long-lasting systemic immunity to secondary infection by a range of biotrophic, hemibiotrophic and necrotrophic pathogens that have diverse modes of infection. Considerable effort has focussed on the conserved central positive regulator of SAR, NON-EXPRESSOR OF PATHOGENESIS-RELATED1 (NPR1), and its control by changes in cellular redox potential. Recently, genetic and genomic approaches have highlighted a critical role for nucleocytoplasmic communication and protein secretion in establishing effective systemic immunity. Identification of the mobile signals and the mechanisms by which they are perceived in distal tissues remains challenging, but emerging evidence suggests that signal translocation uses lipid-derived (possibly jasmonate-based) signals and lipid-binding chaperones. Furthermore, the demonstration that autophagy interdicts and inactivates a systemic cell death signal adds further complexity to elucidating how mobile signals are decoded and transduced for effective immunity.

Gene Expression Regulation, Plant↗

PubMed2006

The Role of histidine residues in low-pH-mediated viral membrane fusion.

A central event in the invasion of a host cell by an enveloped virus is the fusion of viral and cell membranes. For many viruses, membrane fusion is driven by specific viral surface proteins that undergo large-scale conformational rearrangements, triggered by exposure to low pH in the endosome upon internalization. Here, we present evidence suggesting that in both class I (helical hairpin proteins) and class II (beta-structure-rich proteins) pH-dependent fusion proteins the protonation of specific histidine residues triggers fusion via an analogous molecular mechanism. These histidines are located in the vicinity of positively charged residues in the prefusion conformation, and they subsequently form salt bridges with negatively charged residues in the postfusion conformation. The molecular surfaces involved in the corresponding structural rearrangements leading to fusion are highly conserved and thus might provide a suitable common target for the design of antivirals, which could be active against a diverse range of pathogenic viruses.

Amino Acid Sequence↗

PubMed2004

Cloning and purification of the Streptococcus suis serotype 2 glyceraldehyde-3-phosphate dehydrogenase and its involvement as an adhesin.

Streptococcus suis serotype 2 is a swine pathogen responsible for diverse diseases and may be present in the tonsils of pigs which show no sign of illness. Because adhesion to host cells may be important in the carrier state, this study was undertaken to characterize a 39 kDa surface protein identified as a glyceraldehyde-3-phosphate dehydrogenase (GAPDH), possibly implicated in the adhesion of the bacteria. The gene encoding for the GAPDH of S. suis was cloned and sequenced. The DNA sequence contained an open reading frame encoding for a 336 amino acid polypeptide exhibiting 95% sequence identity with the GAPDH from Streptococcus pyogenes and from other streptococci. Using the Qiaexpress expression plasmids, the gapdh gene was inducibly overexpressed in E. coli to produce GAPDH with a hexahistidyl N-terminus to permit its purification. The (His)6GAPDH protein was found to possess functional GAPDH enzymatic activity after the purification. An adherence assay with S. suis and porcine tracheal rings pre-incubated with (His)6GAPDH and non-incubated rings was showed a significant reduction in the adhesion of S. suis in the (His)6GAPDH pre-incubated rings compared to the non-incubated rings. The GAPDH protein of S. suis seems to be involved in the first steps of the bacterial adhesion to host cells.

Amino Acid Sequence↗

PubMed2004

The dsRNA viruses.

The dsRNA viruses represent a large, diverse group of pathogens (affecting a very wide range of host species), several of which are of medical, veterinary or agricultural importance. Many of the icosahedral dsRNA viruses show striking structural and functional similarities that reflect the similar problems that they face replicating their dsRNA genomes while avoiding the dsRNA activated defence mechanisms of their host species. These similarities appear to indicate a common if distant ancestry that is not always evident simply by comparison of nucleotide or amino acid sequences. To facilitate the identification and comparisons of cognate proteins from different species, genera and families of dsRNA viruses, a series of tables were originally constructed for the 7th International Symposium of dsRNA viruses held in Aruba in 2000. These have now been updated and extended (for the 8th Symposium, held in Tuscany 2003) and are available from the dsRNA virus website at.

Animals↗

PubMed2003

Chimeric flaviviruses: novel vaccines against dengue fever, tick-borne encephalitis, and Japanese encephalitis.

Many arthropod-borne flaviviruses are important human pathogens responsible for diverse illnesses, including YF, JE, TBE, and dengue. Live, attenuated vaccines have afforded the most effective and economical means of prevention and control, as illustrated by YF 17D and JE SA14-14-2 vaccines. Recent advances in recombinant DNA technology have made it possible to explore a novel approach for developing live attenuated flavivirus vaccines against other flaviviruses. Full-length cDNA clones allow construction of infectious virus bearing attenuating mutations or deletions incorporated in the viral genome. It is also possible to create chimeric flaviviruses in which the structural protein genes for the target antigens of a flavivirus are replaced by the corresponding genes of another flavivirus. By combining these molecular techniques, the DNA sequences of DEN4 strain 814669, DEN2 PDK-53 candidate vaccine and YF 17D vaccine have been used as the genetic backbone to construct chimeric flaviviruses with the required attenuation phenotype and expression of the target antigens. Encouraging results from preclinical and clinical studies have shown that several chimeric flavivirus vaccines have the safety profile and satisfactory immunogenicity and protective efficacy to warrant further evaluation in humans. The chimeric flavivirus strategy has led to the rapid development of novel live-attenuated vaccines against dengue, TBE, JE, and West Nile viruses.

Amino Acid Sequence↗

PubMed1999

A review of worldwide experience with sparfloxacin in the treatment of community-acquired pneumonia and acute bacterial exacerbations of chronic bronchitis.

The worldwide occurrence of community-acquired pneumonia (CAP) shows an undiminished prevalence of this serious illness and hospitalisation is common in those patients with severe illness. The diversity of bacterial pathogens that can act as aetiologic agents presents a challenge to initial empiric antimicrobial management. In recent years, treatment has been further complicated by an increased incidence of antibiotic resistance in pathogens such as Streptococcus pneumoniae, Haemophilus influenzae and Moraxella catarrhalis. The newly available fluoroquinolones including sparfloxacin offer an alternative approach to empiric management. Sparfloxacin is active against many typical and atypical pathogens, as well as strains resistant to conventional agents. In comparative studies, the in vitro potency of sparfloxacin and its pharmacokinetic profile have been confirmed. The clinical trial efficacy and safety data suggest it might be a useful empiric therapy for both CAP and acute bacterial exacerbation of chronic bronchitis.

Acute Disease↗

PubMed2003

Shaping the immune response to parasites: role of dendritic cells.

Parasites represent a diverse group of pathogens that often trigger highly polarized immune responses that become tightly regulated during chronic infection. Recent studies have implicated the parasite-dendritic-cell interaction as a key determinant of the host response to these eukaryotic invaders. Dendritic cells appear to be pivotal in the initiation of cellular immunity against parasites as well as in directing Th1/Th2 effector choice. Moreover, there is increasing evidence that parasites regulate dendritic-cell function for the purposes of evading host immunity. This regulation also benefits parasites by protecting their host niche from the potentially lethal consequences of an uncontrolled inflammatory response.

Animals↗

PubMed2004

Plasticity of T cell memory responses to viruses.

Virus-specific memory T cell populations demonstrate plasticity in antigenic and functional phenotype, in recognition of antigen, and in their ability to accommodate new memory T cell populations. The adaptability of complex antigen-specific T cell repertoires allows the host to respond to a diverse array of pathogens and accommodate memory pools to many pathogens in a finite immune system. This is in part accounted for by crossreactive memory T cells, which can be employed in immune responses and mediate protective immunity or life-threatening immunopathology.

Animals↗

PubMed2003

Lysosomes and brain aging in mammals.

Hypotheses about the factors controlling the rate of brain aging are usually derived from 1) correlates of maximum life span across mammals or 2) investigations into the causes of age-related neuropathologies in humans. With regard to the former, the strong correlation between metabolic rate and longevity prompted a variety of free radical hypotheses of aging. There is also evidence that brain size affects life span independently of body metabolism rates. The second approach has led to a diverse array of pathogenic mechanisms and, importantly for the development of general hypotheses, the discovery of animal analogues. The present paper discusses the possibility that age-associated lysosomal dysfunction constitutes a generalized mammalian phenomenon that accounts for specific features of the aged human brain. Immunocytochemical studies using rats and dogs have identified lysosomal changes that begin early in adulthood and are most pronounced in brain areas known to be particularly vulnerable to age-related pathogenesis in humans. Experimentally induced lysosomal dysfunction in cultured brain slices from rats and mutant mice triggers a wide array of changes associated with the aged human brain, including meganeurites and intraneuronal tangles. Finally, there is evidence that at least some forms of proteolysis decrease with increasing brain size across the mammals. The above observations lead to the suggestion that the expansion of neuronal arborizations that occurred in conjunction with increases in brain size secondarily slowed both neuronal metabolism and protein turnover. These events could have served to reduce the rate at which lysosomes (and other organelles) fail.

Aging↗

PubMed2001

An essential role for phoP in Mycobacterium tuberculosis virulence.

Two-component regulatory proteins function in bacteria as sensory and adaptive factors in response to a wide range of environmental stimuli. Some two-component systems, such as PhoP/PhoQ, control transcription of key virulence genes essential for survival in host cells in diverse intracellular bacterial pathogens, including Salmonella sp., Shigella sp. and Yersinia sp. In this study, we have disrupted the phoP gene from Mycobacterium tuberculosis, which codes for a putative transcription regulator factor of the two-component system PhoP/PhoR. The phoP mutant strain exhibited impaired multiplication when cultured in mouse bone marrow-derived macrophages. However, the mutation did not appear to affect survival of the organisms adversely inside macrophages. The mutant strain was also attenuated in vivo in a mouse infection model, with impaired growth observed in the lungs, livers and spleens. The results suggest that the phoP gene is required for intracellular growth of M. tuberculosis but is not essential for persistence of the bacilli.

Animals↗

PubMed2003

Distribution and function of new bacterial intein-like protein domains.

Hint protein domains appear in inteins and in the C-terminal region of Hedgehog and Hedgehog-like animal developmental proteins. Intein Hint domains are responsible and sufficient for protein-splicing of their host-protein flanks. In Hedgehog proteins the Hint domain autocatalyses its cleavage from the N-terminal domain of the Hedgehog protein by attaching a cholesterol molecule to it. We identified two new types of Hint domains. Both types have active site sequence features of Hint domains but also possess distinguishing sequence features. The new domains appear in more than 50 different proteins from diverse bacteria, including pathogenic species of humans and plants, such as Neisseria meningitidis and Pseudomonas syringae. These new domains are termed bacterial intein-like (BIL) domains. Bacterial intein-like domains are present in variable protein regions and are typically flanked by domains that also appear in secreted proteins such as filamentous haemagglutinin and calcium binding RTX repeats. Phylogenetic and genomic analysis of BIL sequences suggests that they were positively selected for in different lineages. We cloned two BIL domains of different types and showed them to be active. One of the domains efficiently cleaved itself from its C-terminal flank and could also protein-splice its two flanks, in E. coli and in a cell free system. We discuss several possible biological roles for BIL domains including microevolution and post translational modification for generating protein variability.

Amino Acid Sequence↗

PubMed2003

Genome-based analysis of virulence genes in a non-biofilm-forming Staphylococcus epidermidis strain (ATCC 12228).

Staphylococcus epidermidis strains are diverse in their pathogenicity; some are invasive and cause serious nosocomial infections, whereas others are non-pathogenic commensal organisms. To analyse the implications of different virulence factors in Staphylococcus epidermidis infections, the complete genome of Staphylococcus epidermidis strain ATCC 12228, a non-biofilm forming, non-infection associated strain used for detection of residual antibiotics in food products, was sequenced. This strain showed low virulence by mouse and rat experimental infections. The genome consists of a single 2499 279 bp chromosome and six plasmids. The chromosomal G + C content is 32.1% and 2419 protein coding sequences (CDS) are predicted, among which 230 are putative novel genes. Compared to the virulence factors in Staphylococcus aureus, aside from delta-haemolysin and beta-haemolysin, other toxin genes were not found. In contrast, the majority of adhesin genes are intact in ATCC 12228. Most strikingly, the ica operon coding for the enzymes synthesizing interbacterial cellular polysaccharide is missing in ATCC 12228 and rearrangements of adjacent genes are shown. No mec genes, IS256, IS257, were found in ATCC 12228. It is suggested that the absence of the ica operon is a genetic marker in commensal Staphylococcus epidermidis strains which are less likely to become invasive.

Adhesins, Bacterial↗

PubMed2002

Mutator clones of Neisseria meningitidis in epidemic serogroup A disease.

Serogroup A Neisseria meningitidis has repeatedly caused widespread epidemics of meningitis and septicemia throughout the 20th century. Recently, in a limited collection of strains, epidemic serogroup A isolates were found to have elevated mutation rates that was caused by defects in mismatch repair pathways. To ascertain the role of these mutators in the epidemic spread of this serogroup, the prevalence of hypermutability in a collection of 95 serogroup A N. meningitidis invasive isolates was determined. Overall mutability in Neisseriae can be described by measuring both missense mutation rates as well as phase variation frequencies of "contingency loci." Fifty-seven percent of serogroup A isolates possessed elevated mutability, which could be divided into two classes: intermediate and high level. Eleven of 20 high-level mutators, with phase variation rates >100-fold higher than wild-type isolates, were defective in mismatch repair. Ten of the 34 intermediate mutators possessing >10-fold increases in phase variation rates could be partially complemented by a wild-type mutL allele. A high prevalence of mutators in epidemic isolates indicates that hypermutability may play a major role in the transmission of this pathogen. The added diversity derived from increased phase variation rates may allow fixation of mutator alleles more frequently during epidemic spread.

Alleles↗

PubMed2000

Gene genealogies reveal global phylogeographic structure and reproductive isolation among lineages of Fusarium graminearum, the fungus causing wheat scab.

During the past decade, the plant disease called scab or Fusarium head blight of wheat and barley has reached epidemic proportions in North America and elsewhere in the world. Scab is an economically devastating plant disease, not only because it causes significant reduction in seed yields and quality, but also because infested seeds are often contaminated with trichothecene and estrogenic mycotoxins that pose a serious threat to animal health and food safety. To test whether the primary etiological agent of scab, the fungus Fusarium graminearum, is panmictic throughout its range, allelic genealogies were constructed from six single-copy nuclear genes from strains selected to represent the global genetic diversity of this pathogen. Excluding one hybrid strain, all six genealogies recovered the same seven biogeographically structured lineages, suggesting that they represent phylogenetically distinct species among which gene flow has been very limited during their evolutionary history. Parsimony analysis of the combined data set comprising 7,120 aligned nucleotide characters resolved most relationships among the seven lineages of the F. graminearum clade and related fusaria included in the study. Phylogenetic evidence is also presented for introgressive hybridization and intragenic recombination among lineages of the F. graminearum clade in nature.

Biological Evolution↗

PubMed1994

Posttranslational modifications in microcin B17 define an additional class of DNA gyrase inhibitor.

Drugs that inhibit the activity of DNA gyrase fall almost exclusively into two structural classes, the quinolones and the coumarins. A third class of DNA gyrase inhibitor is defined by the ribosomally synthesized peptide antibiotic microcin B17 (MccB17). MccB17 contains 43 amino acid residues, but 14 of these are posttranslationally modified. Here we describe the characterization of the structure of these modifications. We propose that four cysteine and four serine side chains undergo condensation with the carbonyl group of the preceding residue, followed by alpha/beta dehydrogenation to yield four thiazole and four oxazole rings, respectively. The three proteins implicated in catalyzing these modifications (McbBCD) would constitute the only thiazole/oxazole biosynthetic enzymes identified. These results open up possibilities for the design of DNA gyrase inhibitors and add to the repertoire of posttranslational modifications with potential for protein engineering. Escherichia coli sbmA mutants, which lack the inner membrane protein (SbmA) involved in MccB17 uptake, were found to be resistant to bleomycin. Bleomycin is structurally unrelated to MccB17 except for the fact that it contains two thiazole rings. This suggests that thiazole rings are part of the MccB17 structure recognized by SbmA. This observation and the finding that SbmA homologs are widely conserved and can play developmental roles [Glazebrook, J., Ichige, A. & Walker, G. C. (1993) Genes Dev. 7, 1485-1497] suggest that thiazole- and oxazole-containing compounds may serve as signaling molecules for a wide variety of bacteria in diverse environments, including pathogen interactions with plant and animal hosts.

Amino Acid Sequence↗