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PubMed2000

Drug target validation: lethal infection blocked by inducible peptide.

Genome projects are generating large numbers of potential new targets for drug discovery. One challenge is target validation, proving the usefulness of a specific target in an animal model. In this paper, we demonstrate a new approach to validation and assay development. We selected in vitro specific peptide binders to a potential pathogen target. By inducing the expression of a selected peptide in pathogen cells causing a lethal infection in mice, the animals were rescued. Thus, by combining in vitro selection methods for peptide binders with inducible expression in animals, the target's validity was rigorously tested and demonstrated. This approach to validation can be generalized and has the potential to become a valuable tool in the drug discovery process.

Amino Acid Sequence↗

PubMed1997

Two PR-1 genes from tomato are differentially regulated and reveal a novel mode of expression for a pathogenesis-related gene during the hypersensitive response and development.

Pathogenesis-related (PR) proteins form a heterogeneous family of plant proteins that are likely to be involved in defense and are inducible by pathogen attacks. One group of PRs, represented by the subfamily PR-1, are low-molecular-weight proteins of unknown biochemical function. Here we describe the cloning and characterization of two closely related genes encoding a basic and an acidic PR-1 protein (PR1b1 and PR1a2) from tomato (Lycopersicon esculentum). We present a comparative study of the mode of transcriptional regulation of these two genes in transgenic tobacco plants using a series of promoter-GUS fusions. Unexpectedly, the chimeric PR1a2/GUS gene is not induced by pathogenic signals but instead shows constitutive expression with a reproducible developmental expression pattern. It is expressed in shoot meristems, trichomes, and cortical cells as well as in vascular and nearby tissues of the mature stem. This constitutive expression pattern may represent preemption of plant defenses against potential pathogens. Conversely, the chimeric PR1b1/GUS gene does not show any constitutive expression in the plant, but it is transcriptionally activated following pathogen attack. Upon infection by tobacco mosaic virus, the PR1b1 gene is strongly activated locally in tissues undergoing the hypersensitive response but not systemically in uninoculated tissues. Furthermore, its expression is induced by both salicylic acid and ethylene precursors, two signals that coexist and apparently mediate the activation of local defenses during the hypersensitive response. We speculate that the different mode of expression of the two genes presented here, together with that reported previously for the induction of other PR-1 genes in systemic, uninoculated tissues, may all be complementary and necessary for the plant to acquire an efficient refractory state to resist pathogen attacks.

Amino Acid Sequence↗

PubMed1988

Scedosporium inflatum, an emerging pathogen.

The salient morphologic and physiologic characteristics of 18 isolates of Scedosporium inflatum, a newly reported human pathogen, were compared with those of the morphologically similar fungi Scedosporium apiospermum, Scopulariopsis brevicaulis, and Scopulariopsis brumptii. The formation by S. inflatum of annelloconidia in wet clumps at the apices of annellides with swollen bases was found to be the most useful characteristic in differentiating this potential pathogen.

Animals↗

PubMed1980

Legionnaires' disease: unusual clinical and laboratory features.

During a nosocomial epidemic of Legionnaires' disease, clinical and laboratory observations led to the recognition of remarkable aspects in six patients. Features included two episodes of disease, dual or sequential infections with Legionella pneumophila and other pathogens; transient deafness with erythromycin therapy, and Legionnaires' disease with a pleural effusion but no pulmonary infiltrate. Expectorated sputum culture yielded two serogroups of L. pneumophila in one patient. Cultures of transtracheal and endotracheal aspirates and of blood led to the diagnosis, permitted evaluation of confounding potential pathogens, and confirmed Legionnaires' disease in the absence of seroconversion. Although many manifestations of Legionnaires' disease were quite typical in this outbreak, these additional unusual features expand the spectrum and illustrate the value of rapid diagnostic methods.

Aged↗

PubMed2002

Clinical, electrophysiological, and serological overlap between Miller Fisher syndrome and acute sensory ataxic neuropathy.

We report a patient with severe sensory ataxia, areflexia, and ophthalmoplegia with preservation of limb muscle strength. Electrophysiological examinations revealed peripheral sensory nerve involvement. A serological examination showed the elevation of IgG antibodies to various b-series gangliosides as well as GT1a. These indicated that this case is an overlap between acute sensory ataxic neuropathy and Miller Fisher syndrome. Autoantibody is implicated as potential pathogenic agents in some cases of acute sensory ataxic neuropathy.

Acute Disease↗

PubMed2001

Adherence of Shigella dysenteriae 1 to human colonic mucin.

The pathogenic potential of Shigella is correlated with the ability of the organism to invade and multiply within the cells of colonic epithelium. Although invasion is the ultimate event, a preceding step is adherence. Shigella dysenteriae 1 preferentially adhered to colonic mucin and not to small intestinal mucin. The pathogen showed a very strong adherence pattern to human colonic mucin when compared with guinea pig and rat mucin. The adherence pattern of S. dysenteriae 1 was not altered on preincubation with monosaccharides present in mucins, suggesting that the receptor for the pathogen is not a simple sugar. Binding of S. dysenteriae 1 to human colonic mucin was not by weak hydrophobic forces. The bacterium also adhered to glycolipids, emphasizing the role of glycoconjugates as receptors for S. dysenteriae 1.

Adhesins, Bacterial↗

PubMed2006

Etiology and epidemiology of diarrhea in children in Hanoi, Vietnam.

OBJECTIVES: This paper provides a preliminary picture of diarrhea with regards to etiology, clinical symptoms, and some related epidemiologic factors in children less than five years of age living in Hanoi, Vietnam. METHODS: The study population included 587 children with diarrhea and 249 age-matched healthy controls. The identification of pathogens was carried out by the conventional methods in combination with ELISA, immunoseparation, and PCR. The antibiotic susceptibility was determined by MIC following the NCCLS recommendations. RESULTS: Of those with diarrhea, 40.9% were less than one year old and 71.0% were less than two years old. A potential pathogen was identified in 67.3% of children with diarrhea. They were group A rotavirus, diarrheagenic Escherichia coli, Shigella spp, and enterotoxigenic Bacteroides fragilis, with prevalences of 46.7%, 22.5%, 4.7%, and 7.3%, respectively. No Salmonella spp or Vibrio cholerae were isolated. Rotavirus and diarrheagenic E. coli were predominant in children less than two years of age, while Shigella spp, and enterotoxigenic B. fragilis were mostly seen in the older children. Diarrheagenic E. coli and Shigella spp showed high prevalence of resistance to ampicillin, chloramphenicol, and to trimethoprim/sulfamethoxazole. Children attending the hospitals had fever (43.6%), vomiting (53.8%), and dehydration (82.6%). Watery stool was predominant with a prevalence of 66.4%, followed by mucous stool (21.0%). The mean episodes of stools per day was seven, ranging from two to 23 episodes. Before attending hospitals, 162/587 (27.6%) children had been given antibiotics. Overall, more children got diarrhea in (i) poor families; (ii) families where piped water and a latrine were lacking; (iii) families where mothers washed their hands less often before feeding the children; (iv) families where mothers had a low level of education; (v) families where information on health and sanitation less often reached their households. CONCLUSIONS: Group A rotavirus, diarrheagenic Escherichia coli, Shigella spp, and enterotoxigenic Bacteroides fragilis play an important role in causing diarrhea in children in Hanoi, Vietnam. Epidemiological factors such as lack of fresh water supply, unhygienic septic tank, low family income, lack of health information, and low educational level of parents could contribute to the morbidity of diarrhea in children.

Bacteroides Infections↗

PubMed1993

The equine herpesviruses.

Two viruses, EHV-1 and EHV-4, are now known to be responsible for disease conditions formerly considered caused by "equine rhinopneumonitis virus." Although these viruses share several laboratory and clinical features, they differ in epidemiology and pathogenic potential. EHV-4 is primarily associated with clinical respiratory disease, whereas EHV-1 is more frequently isolated from aborted fetuses, sickly foals, and neurologic cases. Both viruses frequently establish latent infections, but the relevance of latency to clinical disease is unclear. Diagnosis based on identification of the pathogen is generally superior to serologic methods. Vaccines containing each virus are available, and vaccination in concert with careful management limits the number of clinical cases. Immunity following vaccination or disease is not absolute, however, and improved disease prophylaxis awaits a better understanding of protective immune responses.

Abortion, Veterinary↗

PubMed2002

Coiled-coil proteins associated with type III secretion systems: a versatile domain revisited.

The pathogenic potential of many Gram-negative bacteria is indicated by the possession of a specialized type III secretion system that is used to deliver virulence effector proteins directly into the cellular environment of the eukaryotic host. Extracellular assemblies of secreted proteins contrive a physical link between the pathogen and host cytosol and enable the translocated effectors to bypass the bacterial and host membranes in a single step. Subsequent interactions of some effector proteins with host cytoskeletal and signalling proteins result in modulation of the cytoskeletal architecture of the aggressed cell and facilitate entry, survival and dissemination of the pathogen. Although the secreted components of type III secretion systems are diverse, many are predicted to share a common coiled-coil structural feature. Coiled-coils are ubiquitous and highly versatile assembly motifs found in a wide range of structural and regulatory proteins. The prevalence of these domains in secreted virulence effector proteins suggests a fundamental contribution to multiple aspects of their function, and evidence accumulating from functional studies suggests an intrinsic involvement of coiled-coils in subunit assembly, translocation and flexible interactions with multiple bacterial and host proteins. The known functional flexibility that coiled-coil domains confer upon proteins provides insights into some of the pathogenic mechanisms used during interaction with the host.

Bacteria↗

PubMedDate not supplied

Impact of pathogenicity islands in bacterial diagnostics.

Pathogenicity islands (PAIs) are a distinct class of genomic islands (GEIs), which are acquired by horizontal gene transfer. PAIs harbour virulence genes and some, in addition, antibiotic resistance genes. More often genes conferring antibiotic resistance are encoded by GEIs not containing virulence genes. Both types of genetic elements are found in genomes of various human, animal and plant pathogens. There are PAIs and GEIs which are specific for a certain serotype(s), strain, or pathotype of a species. Furthermore, there are also PAIs which are more widespread and found in bacterial pathogens causing a certain pathogenic effect in the host. Even the lack of a certain PAI might be characteristic for a defined subspecies. Obviously, PAIs can be used as markers for diagnostic purposes to help identify a certain bacterial pathogen, subtype it, estimate the pathogenic potential, and in some cases predict its antibiotic resistance. This all might be achieved for known PAIs/GEIs without cultivating the microorganism of interest by employing PCR and/or DNA-chip technology. Even yet unknown PAIs can be identified in silico if the genome sequence of the bacterial pathogen under investigation is known. The more PAIs and antibiotic harbouring GEIs are identified and characterized the greater will be the benefits also for diagnostics.

Bacteria↗

PubMed1991

Enteral feeding and infection in the immunocompromised patient.

Evidence is accumulating that immunocompromised individuals are at an increased risk of infection from foodborne pathogens including Campylobacter jejuni, Listeria monocytogenes, Salmonella spp. Normal bacterial flora and contaminants of foods and enteral feeds can also result in nosocomial infection in susceptible individuals. Safe food handling, low-microbial diets, and measures to reduce bacterial contamination of enteral foods can reduce exposure to potential pathogens in the food supply.

Cross Infection↗

PubMed1997

A study on the aerobic intestinal microflora in patients with salmonellosis and shigellosis.

Human intestinal microflora provides substantial protection of the body against intestinal pathogens and affects the course and outcome of intestinal infections with diarrheal syndrome. We studied the aerobic intestinal microflora in 120 patients with salmonellosis and 60 patients with shigellosis. Intestinal microflora was determined qualitatively assessing the relative share of E. coli and other aerobic representatives of the potentially pathogenic microorganisms. Disturbances of the aerobic intestinal microflora were found in 76% of the patients with salmonellosis and 80% of the patients with shigellosis in the acute stage of the disease. They occurred more commonly and were graver in the severe clinical forms of intestinal infections. Their frequency in convalescent bacterial carriers was greater.

Adolescent↗

PubMed2007

Hereditary gingival fibromatosis: characteristics and novel putative pathogenic mechanisms.

Hereditary gingival fibromatosis (HGF) is a rare condition that can occur as an isolated disease or as part of a syndrome or chromosomal abnormality. In severe cases, the gingival enlargement may cover the crowns of teeth and cause severe functional and esthetic concerns. Histological and cell culture studies have uncovered some of the molecular and cellular changes associated with HGF. However, the pathogenesis of the disease is still largely unknown. Recent studies about the genetic characteristics of HGF have provided novel clues about the potential pathogenic mechanisms. In particular, mutation in the son-of-sevenless (SOS-1) gene has been associated with one form of the disease. However, HGF displays genetic heterogeneity, and mutations in other genes are also likely involved. This review outlines the current knowledge about the histological, cellular, and genetic characteristics of HGF. In addition, the potential role of the SOS-1 molecule and related novel intracellular signaling pathways in the pathogenesis of HGF will be discussed.

Cell Proliferation↗

PubMed2003

Potential biological indicators for glutaraldehyde and formaldehyde sterilization processes.

The present study aimed to isolate, select, and evaluate bacterial isolates with potential for use as biological indicators for sterilization with glutaraldehyde and/or formaldehyde. A total of 340 local Bacillus isolates were screened for glutaraldehyde and/or formaldehyde resistance by determination of minimum inhibitory concentrations (MICs), minimum bactericidal concentrations (MBCs), and extinction time and were compared with B. subtilis (var. niger) ATCC 9372, the biological indicator for ethylene oxide sterilization, as reference. Of these, 85 isolates had glutaraldehyde MICs of 0.5% or higher, while 29 had formaldehyde MICs of 0.04% or higher. Of the 29 resistant isolates, 15 had MBCs of 0.05% or more. Extinction times were used to evaluate the bactericidal/sporicidal activity of glutaraldehyde. Eight had inactivation times of more than 5 h in 2% glutaraldehyde (pH 8), whereas 12 had inactivation times of more than 3 h in l% formaldehyde, with one isolate in common. These 19 isolates were selected and evaluated as potential biological indicators for aldehydes by determination of the decimal reduction times ( D values), compared with the reference strain. Eight glutaraldehyde-resistant isolates exhibited D values 2.0- to 3.5-fold higher than the reference strain (30 min.). Only five of 12 formaldehyde resistant isolates had D values higher than that of the reference strain. Using six resistant isolates, temperature coefficient values between 2.11 and 3.02 were obtained for 2% formaldehyde. Finally, 14 isolates were tested for potential pathogenicity and were identified to species level. All of the eight glutaraldehyde-resistant isolates, including the isolate with dual resistance, and three formaldehyde-resistant isolates were B. licheniformis, while two other formaldehyde-resistant isolates were B. cereus. Six of the selected B. licheniformis isolates are potential biological indicators for sterilization processes using aldehydes. Three can be suggested for glutaraldehyde only and three for both aldehydes.

Bacillus subtilis↗

PubMed2003

Pacemaker endocarditis due to Propionibacterium acnes.

Propionibacterium acnes belongs to the cutaneous flora of humans; it is often considered to be contaminant but has also been found to be a pathogen in human diseases. It is an uncommon causal agent in infective endocarditis and appears to have a predilection for prosthetic valves and foreign bodies. We describe a case of pacemaker endocarditis which shows that so-called harmless bacteria like P. acnes must be considered to be potential pathogens.

Adult↗

PubMed1995

Severe Burkholderia (Pseudomonas) gladioli infection in chronic granulomatous disease: report of two successfully treated cases.

Chronic granulomatous disease (CGD) is characterized by a defect in phagocytic cells that leads to recurrent superficial and deep pyogenic infections. Burkholderia (Pseudomonas) gladioli is a gram-negative bacillus in the pseudomallei group of pseudomonads that is known primarily as a plant pathogen. We report two cases of pneumonia, one accompanied by septicemia, caused by B. gladioli in patients with CGD and their successful treatment with antibiotics. We believe these represent the first reports of human disease caused by this organism. We conclude that B. gladioli should be considered a potential pathogen in patients with CGD.

Adult↗

PubMed2026

Donor Microbiota Features Associated With Liver Transplant Recipient Infectious Complications: A Pilot Study Using Deep Intestinal Sampling During Liver Procurement.

BACKGROUND: The gut microbiota of living organ donors has been linked to transplant outcomes. However, little is known about the characteristics of the deceased donor gut microbiota or its potential impact on recipient outcomes. METHODS: We analyzed the deep intestinal microbiota from 24 deceased donors. Samples included luminal stool from the right and left colon as well as bile. Microbial composition was characterized using 16S V4 rRNA sequencing. α- and β-diversity analyses were performed to compare microbial communities between donor enteric sites and against stool samples from 28 healthy community controls, 14 critically ill intensive care comparators, and 12 matched liver transplant recipients. Machine learning models and logistic regression analysis were applied to explore whether features of the donor microbiota could predict recipient post-transplant complications. FINDINGS: The deceased donor microbiota showed an absence of the expected compositional variability between sampling sites, with no significant differences in either α- or β-diversity observed between bile, right and left colonic samples (all p > 0.05). Donor samples exhibited distinct microbial profiles compared with stool from both healthy and ICU comparators, including increased abundance of potential pathogens within the Enterobacteriaceae family (all p < 0.001). Features of the donor microbiota, particularly enrichment of Enterobacteriaceae, were associated with an increased risk of early post-transplant infection in recipients (≤ 30 days; p = 0.011). INTERPRETATION: The deceased donor gut microbiota may represent a distinct microbial community with potential clinical relevance. Microbial profiling of donor enteric microbiota may help identify recipients at heightened risk of early post-transplant infectious complications.

Enterobacteriaceae↗

PubMed1994

Central nervous system damage produced by expression of the HIV-1 coat protein gp120 in transgenic mice.

Many people infected with human immunodeficiency virus type 1 (HIV-1) develop neurological complications that can culminate in dementia and paralysis. The discrepancy between the severity of impairment and the paucity of detectable HIV-1 within neurons has led to an intense search for diffusible virus- and host-derived factors that might be neurotoxic (see ref. 2 for review). The HIV-1 envelope glycoprotein gp120 is an extracellular protein that is shed from infected cells and so has the potential to diffuse and interact with distant uninfected brain cells. Studies on cultured immature cells suggest that gp120 induces neurotoxicity (reviewed in refs 2, 4), and systemic injection of gp120 in neonatal rats and intracerebroventricular injection in adult rats results in deleterious effects on the brain. To assess the pathogenic potential of gp120 in the intact brain, we have now produced gp120 in the brains of transgenic mice and found a spectrum of neuronal and glial changes resembling abnormalities in brains of HIV-1-infected humans. The severity of damage correlated positively with the brain level of gp120 expression. These results provide in vivo evidence that gp120 plays a key part in HIV-1-associated nervous system impairment. This model should facilitate the evaluation and development of therapeutic strategies aimed at HIV-brain interactions.

AIDS Dementia Complex↗