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PubMed1993

Acute lung injury during bacterial or fungal sepsis.

We compared physiological and ultrastructural indices of acute lung injury (ALI) during septic shock caused by taxonomically diverse pathogens to distinguish ALI due to endogenous inflammatory mediators vs. microbial exotoxins or other factors. Conscious rats were infected i.v. with gram-negative Escherichia coli (EC, serotype 055:B5), exotoxin-C producing gram-positive Staphylococcus aureus (SA), or yeast-phase Candida albicans (CA, a clinical isolate). Viable inocula of 10(10) EC, 10(10) SA, or 10(9) CA caused lethal shock in < 24 h, but distinct types of ALI were noted after bacteria vs. fungi. Within 0.5 h of EC infection, leukocytes marginated in the lung vasculature; by death at 6-14 h, animals were hyperoxemic but not acidemic, and showed slight interstitial edema with increased wet/dry weight ratios (W/D = 5.22 +/- 0.10, mean +/- SE, vs. 4.86 +/- 0.07 in controls, P < 0.05). Similarly mild ALI occurred after 10(10) SA. In contrast, within 0.5 h of CA infection, yeast were visible within lung intravascular leukocytes. By death at 6-12 h, CA animals showed hyperoxic acidemia and moderate ALI with capillary obstruction, interstitial hemorrhage, and elevated lung W/D (5.52 +/- 0.13, P < 0.01 vs. controls) associated with yeast-mycelial transformation. Prior neutropenia accelerated mortality and worsened ALI after CA, with hypoxemic acidemia, increased lung W/D (7.23 +/- 0.34, P < 0.05 vs. other groups), capillary occlusion, perivascular and alveolar hemorrhage, and septal disruption by mycelia. Bacteremia induced large increases in serum tumor necrosis factor-alpha (TNF) and interleukin-1 alpha within 1.5 h, but these cytokines remained low in CA animals, even at death. Neither survival nor ALI after EC or CA was altered by pentoxifylline, which attentuated TNF production, or by cyclooxygenase inhibition with ibuprofen. Thus, overall ALI severity correlated with physiological indices of pulmonary function, but ultrastructural changes correlated better with pathogen type than circulating cytokine or eicosanoid mediators. Whereas lethal bacteremia induced early cytokinemia and mild ALI with or without bacterial exotoxins, moderate ALI apparently was mediated by fungal exotoxins during lethal candidemia, which worsened during neutropenia due to enhanced mycelial proliferation.

Animals↗

PubMed1983

Tn1525, a kanamycin R determinant flanked by two direct copies of IS15.

We have isolated plasmid pIP112 (IncI1) from Salmonella panama and characterized by restriction endonucleases analysis and by recombinant DNA techniques a transposable element designated Tn1525. This 4.44 kilobase (kb) transposon confers resistance to kanamycin by synthesis of an aminoglycoside phosphotransferase (3') (5") type I and contains two copies of IS15 (1.5 kb) in direct orientation. The modular organisation of Tn1525 offers the possibility for intramolecular homologous recombination between the two terminal direct repeats and thus accounts for the in vivo structural lability of plasmid pIP112: instability of kanamycin resistance and tandem amplification of the kanamycin determinant. Other transposons mediating resistance to kanamycin by the same enzymatic mechanism were analysed by agarose and polyacrylamide gel electrophoresis, following digestion with restriction endonucleases, and by Southern hybridizations. These comparisons indicate that, although the structural genes for the phosphotransferases are homologous, Tn1525 differs from Tn903 and Tn2350 and is closely related but distinct from Tn6. Using the same techniques Tn1525 was detected on plasmids belonging to different incompatibility groups and originating from various species of Gram-negative clinical isolates. These results indicate that Tn1525 is representative of a new family of class I composite transposons already spread in diverse pathogenic bacterial genera.

Chromosome Mapping↗

PubMed2005

SCAR markers linked to the common bean rust resistance gene Ur-13.

Rust in common bean (Phaseolus vulgaris L.) is caused by Uromyces appendiculatus Pers.:Pers. (Unger) which exhibits a high level of pathogenic diversity. Resistance to this disease is conditioned by a considerable number of genes. Pyramiding resistance genes is desirable and could be simplified by the use of molecular markers closely linked to the genes. The resistance gene Ur-13, present in the South African large seeded cultivar Kranskop, has been used extensively in the local breeding program. The purpose of this study was the development of a molecular marker linked to Ur-13. An F(2) population derived from a cross between Kranskop and a susceptible (South African) cultivar Bonus was used in combination with bulked segregant analysis utilizing the amplified fragment length polymorphism (AFLP) technique. Seven AFLP fragments linked significantly to the rust resistance and five were successfully converted to sequence characterized amplified region (SCAR) markers. The co-dominant SCAR markers derived from a 405 bp EAACMACC fragment, KB 126, was located 1.6 cM from the gene. Two additional SCAR markers and one cleaved amplified polymorphic sequence marker were located further from the gene. The gene was mapped to linkage group B8 on the BAT 93/Jalo EEP 558 core map (chromosome 3).

Base Sequence↗

PubMed2006

Potato chromosomes IX and XI carry genes for resistance to potato virus M.

Two new loci for resistance to potato virus M (PVM), Gm and Rm, have been mapped in potato. The gene Gm was derived from Solanum gourlayi, whereas, Solanum megistacrolobum is the source of the gene Rm. Gm confers resistance to PVM infection after mechanical inoculation. Rm induces a hypersensitive response in potato plants. Two diploid populations segregating for Gm and Rm, bulked segregant analysis (BSA) using random amplified polymorphic DNA (RAPD) and inter-simple sequence repeat (ISSR), and available potato molecular maps were instrumental for mapping the resistance loci. The novel locus Gm was mapped to a central region on potato chromosome IX. The locus Rm was placed on the short arm of chromosome XI, close to the marker loci GP250 and GP283, where a hotspot for monogenic and polygenic resistance to diverse pathogens is located in the potato and tomato genome.

Carlavirus↗

PubMed2000

Epidemiology of antibiotic resistance.

Three biological processes contribute to the accumulation of bacterial drug resistance: new selection, gene epidemics and strain epidemics. New resistance emerges by (i) the advantaging of entire species, (ii) by mutation, and (iii) by the escape of resistance genes to mobile DNA. Organisms to have 'benefited' from modern patterns of cephalosporins and quinolone use include enterococci, Clostridium difficile, coagulase-negative staphylococci and Enterobacter spp. Mutational resistance notoriously occurs with certain antibiotic/organism combinations and allows rapid multifocal accumulation of resistance. At worst, therapy can fail when resistant mutants are selected in individual patients. Escape of new genes to mobile DNA is rare but, having occurred, permits massive 'gene epidemics', as the same genes and plasmids spread into diverse pathogens. Strain epidemics notoriously occur in individual units, reflecting break-downs of hygiene. Some strains achieve a much wider distribution: thus, much of the MRSA problem in the UK depends on the dissemination of two epidemic strains, EMRSA15 and 16; penicillin resistant pneumococci of serotypes 6 and 23 have disseminated internationally from Spain and a serotype K25 strain of Klebsiella pneumoniae with SHV-4 beta-lactamase has spread widely in France. It remains unknown why some strains and genes achieve wide spread whereas others, equally resistant, fail to do so. There is no simple cure for resistance but the best opportunities for control lie in lesser and better use of antibiotics backed by swifter and more accurate microbiology; in developing new antibiotics; and in protecting old ones from resistance determinants. All this must be supported by good local knowledge of the epidemiology of infections and resistance and of the likelihood of particular antibiotics to select resistance.

Anti-Bacterial Agents↗

PubMed2002

Characterisation of an Indonesian very virulent strain of infectious bursal disease virus.

An Indonesian very virulent (vv) strain of infectious bursal disease virus (IBDV), designated Tasik94, was characterised both in vivo and at the molecular level. Inoculation of Tasik94 into 5-week-old specific-pathogen-free (SPF) chickens resulted in 100% morbidity and 45% mortality. The complete nucleotide and predicted amino acid sequences of genomic segments A and B were determined. Across each of the three deduced open reading frames (ORFs), Tasik94 shared the greatest nucleotide homology to Dutch vv strain D6948. Phylogenetic analyses were performed using 15 full-length polyprotein sequences and a total of 105 VP2 hypervariable region sequences from geographically and pathogenically diverse strains. In each case, Tasik94 grouped closely with vv strains, particularly those from Europe. The deduced VP1, VP2, VP3, VP4 and VP5 protein sequences of Tasik94 were aligned with those from published strains and putative virulence determinants were identified in VP2, VP3 and VP4. Alignment of additional protein sequences across the VP2 hypervariable region confirmed that residues Ile[242], Ile[256] and Ile[294] were highly-conserved amongst vv strains, and may account for their enhanced virulence.

Amino Acid Sequence↗

PubMed2003

Variability and transmission by Aphis glycines of North American and Asian Soybean mosaic virus isolates.

The variability of North American and Asian strains and isolates of Soybean mosaic virus was investigated. First, polymerase chain reaction (PCR) products representing the coat protein (CP)-coding regions of 38 SMVs were analyzed for restriction fragment length polymorphisms (RFLP). Second, the nucleotide and predicted amino acid sequence variability of the P1-coding region of 18 SMVs and the helper component/protease (HC/Pro) and CP-coding regions of 25 SMVs were assessed. The CP nucleotide and predicted amino acid sequences were the most similar and predicted phylogenetic relationships similar to those obtained from RFLP analysis. Neither RFLP nor sequence analyses of the CP-coding regions grouped the SMVs by geographical origin. The P1 and HC/Pro sequences were more variable and separated the North American and Asian SMV isolates into two groups similar to previously reported differences in pathogenic diversity of the two sets of SMV isolates. The P1 region was the most informative of the three regions analyzed. To assess the biological relevance of the sequence differences in the HC/Pro and CP coding regions, the transmissibility of 14 SMV isolates by Aphis glycines was tested. All field isolates of SMV were transmitted efficiently by A. glycines, but the laboratory isolates analyzed were transmitted poorly. The amino acid sequences from most, but not all, of the poorly transmitted isolates contained mutations in the aphid transmission-associated DAG and/or KLSC amino acid sequence motifs of CP and HC/Pro, respectively.

Animals↗

PubMedDate not supplied

Myelopathy in a previously asymptomatic HIV-1-infected patient.

A wide variety of disorders of diverse pathogenic mechanisms can trigger spinal cord dysfunction in HIV-1-infected patients. The most common such condition is HIV-1-associated myelopathy (HM) which characteristically complicates advanced HIV-1 disease in patients with low CD4 cell counts and previous AIDS-defining diagnoses. We describe an unusual presentation of HM in a previously asymptomatic patient with a relatively preserved CD4 cell count (458 cells/mm3) who was even unaware of his serological status. The patient presented with a clinically severe, slowly progressive myelopathy and could not walk unassisted. Significant neurological improvement could be obtained as rapidly as within 4 weeks after the institution of an antiretroviral combination of only two nucleoside analog HIV-1 reverse transcriptase inhibitors (zidovudine and didanosine). An HIV-1 protease inhibitor was also prescribed at that point but could only be added to intensify the regimen 3 months later, when significant neurological improvement had already been recorded. We also review the disorders reported to derange spinal cord function in previously asymptomatic HIV-1-infected patients.

CD4 Lymphocyte Count↗

PubMed1996

Amyotrophic lateral sclerosis: the involvement of intracellular Ca2+ and protein kinase C.

The neurodegenerative disease, amyotrophic lateral sclerosis (ALS), is characterized by the selective death of motoneurones and corticospinal tract neurones. Abnormalities in excitatory amino acids and their receptors, as well as disordered function of voltage-dependent Ca2+ channels and superoxide dismutase have been reported in ALS patients. Furthermore, the activity of protein kinase C (PKC), a Ca2+, phospholipid-dependent enzyme, is also substantially increased in tissue from ALS patients, suggesting that alterations in intracellular free Ca2+ may be central to many of the diverse pathogenic mechanisms potentially responsible for ALS as discussed here by Charles Krieger and colleagues. Increased PKC activity, in turn, may have direct or indirect effects on neuronal viability and influence the pathogenic process in ALS by modifying the phosphorylation of voltage-dependent Ca2+ channels, neurotransmitter receptors and structural proteins.

Amyotrophic Lateral Sclerosis↗

PubMed1989

The polymerase chain reaction.

The polymerase chain reaction (PCR) is a novel technique that amplifies specific sequences with remarkable efficiency. Repeated cycles of denaturation, primer annealling and extension carried out with the heat stable enzyme, Taq polymerase, leads to exponential increases in the target DNA sequences. The technique has been widely applied in immunology to define HLA polymorphism, T-cell receptor and immunoglobulin diversity, pathogen detection, quantification of lymphokines and lymphoma or leukaemia detection. In addition, it has been very widely applied in all areas of molecular biology and human genetics. Because of its simplicity and sensitivity, PCR represents a major technical development for molecular biologists and will continue to have a great impact on molecular immunology. This review by John Bell describes the basic PCR technique and some variations on it and briefly explores their uses in molecular immunology.

DNA↗

PubMed2003

Positive selection on a human-specific transcription factor binding site regulating IL4 expression.

A single nucleotide polymorphism in the promoter of the multifunctional cytokine Interleukin 4 (IL4) affects the binding of NFAT, a key transcriptional activator of IL4 in T cells. This regulatory polymorphism influences the balance of cytokine signaling in the immune system, with important consequences-positive and negative-for human health. We determined that the NFAT binding site is unique to humans; it arose by point mutation along the lineage separating humans from other great apes. We show that its frequency distribution among human subpopulations has been shaped by the balance of selective forces on IL4's diverse roles. New statistical approaches, based on parametric and nonparametric comparisons to neutral variants typed in the same individuals, indicate that differentiation among subpopulations at the IL4 promoter polymorphism is too great to be attributed to neutral drift. The allele frequencies of this binding site represent local adaptation to diverse pathogenic challenges; disease states associated with the common derived allele are side-effects of positive selection on other IL4 functions.

Animals↗

PubMed2026

From commensal to pathobiont: The emergence of virulence-enhanced Escherichia coli in China's food-animal systems - insights with future implications.

A fundamental shift in Escherichia coli epidemiology is being driven by convergence of virulence determinants and antimicrobial resistance within linked human-animal-environment systems. In China, the rapid growth of food-animal production, extensive antimicrobial use, and complex food networks are accelerating the emergence and dissemination of virulence-enhanced E. coli pathobionts. This review synthesizes recent epidemiological, genomics, and outbreak data to characterize China's evolving landscape of food-animal-associated E. coli. We highlight a significant shift from classical pathotypes to hybrid lineages that simultaneously carry virulence factors and last-resort antibiotic resistance determinants, including mcr-1, tet(X4), and blaNDM. These traits disseminate rapidly via plasmid-mediated horizontal gene transfer, facilitating rapid adaptation and enabling cross-sectoral One Health transmission. National surveillance, foodborne outbreak investigations, and whole-genome sequencing data show that food-animal reservoirs are active evolutionary niches that drive pathogen diversity and fitness, rather than serving merely as contamination sources. Whole-genome sequencing also pinpoints high-risk clones (e.g., ST394) and plasmid-mediated co-selection of virulence and AMR. The emergence of hybrid pathotypes (e.g., STEC/ETEC) and AMR-virulence co-selection challenges traditional classification and limits the effectiveness of conventional surveillance approaches. The 2017 colistin ban reduced mcr-1, yet ongoing resistance and emerging tet(X4) demand integrated surveillance. Collectively, these findings call for reconceptualizing E. coli as a dynamic genomic entity embedded within a unified ecological network. Addressing this threat requires an integrated One Health strategy including genomic surveillance, agricultural antimicrobial stewardship, and coordinated food-environment-clinical monitoring to prevent high-risk clone emergence and global spread.

Animals↗

PubMed2006

DNA adenine methylation and bacterial pathogenesis.

Methylation of DNA by the DNA adenine methyltransferase (Dam) provides an epigenetic signal that influences and regulates numerous physiological processes in the bacterial cell including chromosome replication, mismatch repair, transposition, and transcription. A growing number of reports describe a role for DNA adenine methylation in regulating the expression of various bacterial genes related to virulence in diverse pathogens, suggesting that DNA methylation may be a widespread and versatile regulator of virulence gene expression. Here, we summarize the current knowledge about the influence of DNA methylation on virulence functions and discuss perspectives for future research.

Adaptation, Physiological↗

PubMed2005

Complexity and complementarity of outer membrane protein A recognition by cellular and humoral innate immunity receptors.

Outer membrane protein A (OmpA) is a conserved major component of the outer membrane of Enterobacteriaceae. Here, we report that OmpA from Klebsiella pneumoniae (KpOmpA) activates macrophages and dendritic cells (DCs) in a TLR2-dependent way. However, TLR2 does not account for binding of KpOmpA to innate immune cells. KpOmpA binds the scavenger receptors (SRs) LOX-1 and SREC-I, but not other members of the same family. LOX-1 colocalizes and cooperates with TLR2 in triggering cellular responses. The TLR2-activated functional program includes production of the long pentraxin PTX3, a soluble pattern recognition receptor involved in resistance against diverse pathogens. PTX3, in turn, binds KpOmpA but does not affect recognition of this microbial moiety by cellular receptors. KpOmpA-elicited in vivo inflammation is abrogated in TLR2(-/-) mice and significantly reduced in PTX3(-/-) mice. Thus, SR-mediated KpOmpA recognition and TLR2-dependent cellular activation set in motion a nonredundant PTX3-mediated humoral amplification loop of innate immunity.

Animals↗

PubMed2004

Sensor domain of the Mycobacterium tuberculosis receptor Ser/Thr protein kinase, PknD, forms a highly symmetric beta propeller.

Diverse pathogenic bacteria produce transmembrane receptor Ser/Thr protein kinases (STPKs), but little is known about the signals mediated by these "eukaryotic-like" proteins. To explore the basis for signaling in the bacterial STPK receptor family, we determined the structure of the sensor domain of Mycobacterium tuberculosis PknD. In two crystal forms, the PknD sensor domain forms a rigid, six-bladed beta-propeller with a flexible tether to the transmembrane domain. The PknD sensor domain is the most symmetric beta-propeller structure described. All residues that vary most among the blade subdomains cluster in the large "cup" motif, analogous to the ligand-binding surface in many beta-propeller proteins. These results suggest that PknD binds a multivalent ligand that signals by changing the quaternary structure of the intracellular kinase domain.

Amino Acid Sequence↗

PubMed2004

Brain targeting through the autonomous nervous system: lessons from prion diseases.

The human central nervous system (CNS) is targeted by diverse pathogens that use distinct pathways to bypass the blood-brain barrier, such as trafficking into the brain via infected blood cells or using retrograde axonal transport through sensory or motor fibers. Prions are transmissible agents that induce a devastating subacute neurodegeneration when they successfully reach the CNS. Two recent studies focusing on pathways of prion neuroinvasion provide converging evidence that, in the case of peripheral transmission, such as human consumption of contaminated tissue, the infectious agent uses the sympathetic noradrenergic neurons to reach the CNS after early replication in lymphoid tissues.

Adrenergic Fibers↗

PubMed2006

Androstenetriol improves survival in a rodent model of traumatic shock.

UNLABELLED: Trauma results in activation of the hypothalamic-pituitary-adrenal axis to mediate a cascade of neurohormonal changes as a defensive mechanism. Its prolongation, however, leads to a hypermetabolic, hypoperfused, and immunosuppressed state, setting the stage for subsequent sepsis and organ failure. Androstenetriol (5-androstene-3beta, 7beta, 17betatriol - AET), a metabolite of dehydroepiandrosterone, up-regulates the host immune response markedly, prevents immune suppression and controls inflammation, leading to improved survival after lethal infections by several diverse pathogens and lethal radiation. Such actions may be useful in improving survival from traumatic shock. HYPOTHESIS: The neurosteroid AET will increase survival following traumatic shock. METHODS: A combat relevant model of traumatic shock was used. Male Sprague-Dawley rats were anesthetized, catheterized and subjected to soft tissue injury (laparotomy). Animals were allowed to regain consciousness over the next 0.5 h and then bled 40% of their blood volume over 15 min. Forty-five minutes after the onset of hemorrhage animals were randomized to receive either a single subcutaneous dose of AET (40 mg/kg, sc) or vehicle (methylcellulose). Volume resuscitation consisted of l-lactated Ringer's (three times the shed blood volume), followed by packed red blood cells (one-third shed red cell volume). Animals were observed for three days. RESULTS: A total of 24 animals were studied. Of the 12 animals randomized to receive AET, all (100%) survived compared to 9 of 12 animals (75%) randomized to receive the vehicle (p < 0.05). CONCLUSION: AET significantly improved survival when administered subcutaneously in a single dose in this rodent model of traumatic shock. Further survival and mechanism studies are warranted.

Androstenols↗

PubMed1997

Vaccine design, evaluation, and community-based use for antigenically variable infectious agents.

A major challenge for vaccine design and development, and for trials of new vaccines, is to tackle antigenically variable infectious agents. Here we outline a few general conceptual issues and then discuss new frameworks that are being developed to help understand how vaccination might change the distribution, abundance, and type of strains in a population. Herd Immunity is a key concept in population-based immunisation programmes and has to be considered in vaccine design and use even though it may cause a conflict between the needs of the individual versus those of the community. This issue is of increasing importance since once common infections are becoming rare due to effective vaccination. Concomitantly, adverse effects arising from immunisation are becoming more apparent as infection-induced morbidity declines to very low levels. Efficacy is widely regarded as a key criterion in vaccine design but duration of protection is of equal importance. Whether it is possible to produce effective vaccines to antigenically diverse pathogens remains uncertain but progress towards this goal will be enhanced by a better understanding of the population genetics of the target infectious agent facilitated by molecular epidemiological studies to assess the genetic constitution of pathogen populations and changes therein over time.

Antigenic Variation↗