Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Pathogenic variant”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 1,351 records · Page 75Linked to original sources
PubMed1997

Mechanisms of antifungal resistance.

The many drugs that are available at present to treat fungal infections can be divided into four broad groups on the basis of their mechanism of action. These antifungal agents either inhibit macromolecule synthesis (flucytosine), impair membrane barrier function (polyenes), inhibit ergosterol synthesis (allylamines, thiocarbamates, azole derivatives, morpholines), or interact with microtubules (griseofulvin). Drug resistance has been identified as the major cause of treatment failure among patients treated with flucytosine. A lesion in the UMP-pyrophosphorylase is the most frequent clinical determinant of resistance to 5FC in Candida albicans. Despite extensive use of polyene antibiotics for more than 30 years, emergence of acquired resistance seems not be a significant clinical problem. Polyene-resistant Candida isolates have a marked decrease in their ergosterol content. Acquired resistance to allylamines has not been reported from human pathogens, but, resistant phenotypes have been reported for variants of Saccharomyces cerevisiae and of Ustilago maydis. Tolerance to morpholines is seldom found. Intrinsic resistance to griseofulvin is due to the absence of a prolonged energy-dependent transport system for this antibiotic. Resistance to azole antifungal agents is known to be exceptional, although it does now appear to be increasing in importance in some groups of patients infected with e.g. Candida spp., Histoplasma capsulatum or Cryptococcus neoformans. For example, resistance to fluconazole is emerging in C. albicans, the major agent of oro-pharyngeal candidosis in AIDS patients, after long-term suppressive therapy. In the majority of cases, primary and secondary resistance to fluconazole and cross-resistance to other azole antifungal agents seems to originate from decreased intracellular accumulation of the azoles, which may result from reduced uptake or increased efflux of the molecules. In most C. albicans isolates the decreased intracellular levels can be correlated with enhanced azole efflux, a phenomenon linked to an increase in the amounts of mRNA of a C. albicans ABC transporter gene CDR1 and of a gene (BEN(r) or CaMDR) coding for a transporter belonging to the class of major facilitator multidrug efflux transporters. Not only fluconazole, ketoconazole and itraconazole are substrates for CDR1, terbinafine and amorolfine have also been established as substrates, BEN(r) overexpression only accounts for fluconazole resistance. Other sources of resistance: changes in membrane sterols and phospholipids, altered or overproduced target enzyme(s) and compensatory mutations in the Delta5,6-desaturase.

Journal Article↗
PubMed1988

Antigenic relationship between Mycobacterium paratuberculosis and Mycobacterium avium.

Four prototype strains of Mycobacterium paratuberculosis contained the type-specific glycopeptidolipid antigen of serovar 8 of the M avium complex. This glycolipid was distinguished by a 4,6-(1'-carboxyethylidene)-3-O-methyl-beta-D-glucopyranosyl terminal unit. Of 59 low-passage, field isolates of M paratuberculosis, 2 contained this antigen, and these 2 isolates were indistinguishable from M avium serovar 8. However, most M paratuberculosis isolates had no characteristic surface glycopeptidolipid. Seemingly, M paratuberculosis, long regarded as a single species and the causative agent of bovine paratuberculosis, is not a homogeneous taxon. Most isolates obtained from infected ruminants may be antigenically defective, variants of M avium and, thereby, more successful pathogens.

Antigens, Bacterial↗
PubMed1989

[Characteristics of the course of salmonellosis].

A study is presented of the etiological structure and proportion of salmonellosis among a wide group of intestinal diseases in an industrial city. The highest incidence was in June-August. The leading factors of infection transmission was food. Salmonella typhimurium was the main etiological pathogen. Different clinical forms were noted, the gastroenterological variant being observed in 50% of patients. Severe course was reported of the diseases when complicated by acute appendicitis, drug-induced allergy.

Acute Disease↗
PubMed1995

[Selective inhibition of DNA amplification in nonadhesive cultures of Mycoplasma pneumoniae].

Inhibition of amplification of various genome regions of Mycoplasma pneumoniae was observed in the polymerase chain reaction, and was dependent on cultivation conditions. A protein stably associated with DNA is responsible for the inhibitory effect. It is assumed that when the protein selectively associates with separate DNA regions, it can inhibit genes encoding pathogenicity factors, thus promoting mycoplasma transformation into persistent variants.

Bacterial Adhesion↗
PubMed1996

The emerging genetic diversity of HIV. The importance of global surveillance for diagnostics, research, and prevention.

The discovery of highly divergent strains of human immunodeficiency virus (HIV) not reliably detected by a number of commonly used diagnostic tests has underscored the need for effective surveillance to track HIV variants and to direct research and prevention activities. Pathogens such as HIV that mutate extensively present significant challenges to effective monitoring of pathogens and to disease control. To date, relatively few systematic large-scale attempts have been made to characterize and sequence HIV isolates. For most of the world, including the United States, information on the distribution of HIV strains among different population groups is limited. We describe herein the implications resulting from the rapid evolution of HIV and the need for systematic surveillance integrated with laboratory science and applied research. General surveillance guidelines are provided to assist in identifying population groups for screening, in applying descriptive epidemiology and systematic sampling, and in developing and evaluating efficient laboratory testing algorithms. Timely reporting and dissemination of data is also an important element of surveillance efforts. Ultimately, the success of global surveillance network depends on collaboration and on coordination of clinical, laboratory, and epidemiologic efforts.

AIDS Vaccines↗
PubMedDate not supplied

Infectious bursal disease viral RNA amplification using RT/PCR from bursa tissue following phenol: chloroform inactivation of the virus.

The preservation of viable infectious agents for future studies could create complicated logistic problems, and at times it is not feasible. Methods for preserving the genetic integrity of inactivated agents would not only facilitate these studies but would also make it possible to transport inactivated preparations around the world. In this report, the effect of inactivation on the genetic material of infectious bursal disease virus (IBDV) was studied. Tissues from the bursa of Fabricius of birds experimentally infected 3 days earlier with the classic STC strain of IBDV were collected and immediately placed in a solution of phenol:chloroform:isoamyl alcohol (25:24:1) for 24, 48, 72, or 96 hr. Infected bursal tissue not treated with the phenol:chloroform solution and uninfected phenol: chloroform bursal tissue were used as controls. In a separate experiment, bursal tissues collected 5 days following infection of specific-pathogen-free birds with the classic STC or variant 1084-E strain were placed in the phenol:chloroform solution for 2 wk. All bursal samples were tested for viable IBDV following phenol:chloroform treatment. The tissues were washed in phosphate-buffered saline to remove phenol and then homogenized. Viability of the viruses in homogenized bursal tissue was examined by inoculation of embryonated chicken eggs. Viable IBDV was not observed in any phenol:chloroform-treated bursal tissue but was observed in the infected but non-phenol:chloroform-treated control bursa. The reverse transcriptase/polymerase chain reaction (RT/PCR) was used to test the integrity of the viral RNA. Viral RNA from the nontreated control and all infected bursal samples treated with phenol:chloroform solution at all the time points examined were transcribed into DNA, and a 394-bp fragment of the VP2 gene was amplified using specific primers in the PCR. The RT/PCR assay was negative using the phenol:chloroform-treated uninfected bursal tissue. This study clearly demonstrated that phenol:chloroform treatment of infected bursal tissue inactivated the classic and variant IBDV strains tested and preserved the viral RNA for use in the RT/PCR assay.

Animals↗
PubMed2025

Genome-to-genome analysis reveals associations between human and mycobacterial genetic variation in tuberculosis patients from Tanzania.

The risk and prognosis of tuberculosis (TB) are influenced by a complex interplay between human and bacterial genetic factors. While previous genomic studies have largely examined human and bacterial genomes separately, we adopted an integrated approach to uncover host-pathogen interactions. We leveraged paired human and Mycobacterium tuberculosis (M.tb) genomic data from 1000 adult TB patients from Tanzania and used a "genome-to-genome" approach to search for associations between human and M.tb genetic variants and to identify interacting genetic loci. Our analyses revealed two significant host-pathogen genetic associations. The first significant association (p = 4.7e-11) links a human intronic variant in PRDM15 (rs12151990), a gene involved in apoptosis regulation, with an M.tb variant in Rv2348c (I101M), which encodes a T cell-stimulating antigen. The second significant association (p = 6.3e-11) connects a human intergenic variant near TIMM21 and FBXO15 (rs75769176) - also associated with TB severity (p = 0.04) - with an M.tb variant in FixA (T67M). While FBXO15 is involved in the regulation of antigen processing and TIMM21 affects mitochondrial function, FixA's role remains undefined due to limited functional characterization. Additionally, we observed that a group of M.tb T cell epitope variants were significantly associated with HLA-DRB1 variation, suggesting that, despite their rarity, certain epitopes may still be subjected to immune selective pressure. Together, these findings identify previously unknown sites of genomic conflicts between humans and M.tb, advancing our understanding of how this pathogen evades selection pressure and persist in human populations.

Humans↗
PubMed2003

Highly adherent small-colony variants of Pseudomonas aeruginosa in cystic fibrosis lung infection.

Pseudomonas aeruginosa, an opportunistic human pathogen and ubiquitous environmental bacterium, is capable of forming specialized bacterial communities, referred to as biofilm. The results of this study demonstrate that the unique environment of the cystic fibrosis (CF) lung seems to select for a subgroup of autoaggregative and hyperpiliated P. aeruginosa small-colony variants (SCVs). These morphotypes showed increased fitness under stationary growth conditions in comparison with clonal wild-types and fast-growing revertants isolated from the SCV population in vitro. In accordance with the SCVs being hyperpiliated, they exhibited increased twitching motility and capacity for biofilm formation. In addition, the SCVs attached strongly to the pneumocytic cell line A549. The emergence of these highly adherent SCVs within the CF lung might play a key role in the pathogenesis of P. aeruginosa lung infection, where a biofilm mode of growth is thought to be responsible for persistent infection.

Bacterial Adhesion↗
PubMed1998

A novel toxinotyping scheme and correlation of toxinotypes with serogroups of Clostridium difficile isolates.

Two hundred nineteen Clostridium difficile isolates from 22 serogroups were screened for changes in the genes coding for toxin B (tcdB) and toxin A (tcdA). Parts of the toxin genes were amplified, and the PCR fragments were checked for length polymorphisms and cut with several restriction enzymes to monitor restriction fragment length polymorphisms (RFLPs). For 47 strains (21%), differences in the toxin genes were found compared to the toxin genes of reference strain VPI 10,463. Polymorphisms were usually observed in both toxin genes. RFLPs were more commonly found in the tcdB gene, in which a single restriction enzyme could give up to five different patterns. Restriction sites seemed to be less heterogeneous in the tcdA gene, in which for most enzymes only two different RFLPs were recognized. However, deletions were observed in tcdA, and four new types of shortened tcdA genes are described. According to the changes in their toxin genes, variant strains could be divided into 10 groups (toxinotypes I to X). A toxinotype was characterized by similar patterns of changes in the toxin genes and in other regions of the pathogenicity locus and also similar pulsed-field gel electrophoresis patterns. Variant toxinotypes were found in 9 of the 22 serogroups studied, and some toxinotypes were clearly associated with specific serogroups. Toxinotype VIII is characteristic for all strains of serogroup F. Other serogroups in which variant toxinotypes were commonly found are A1, A15, E, and X. Testing of variability in C. difficile toxin genes not only might be useful as a molecular typing system but also could have implications in diagnostics and pathogenesis.

Bacterial Proteins↗
PubMed2005

[Primary characterization of the properties and diagnostic value of the antigenic complex "fraction V" in a plague microbe].

The experimentally obtained antigenic complex isolated by extraction in the gradient surfactants from live and acetone-dried bacteria of the capsule-free vaccine strain EV76 of a plague microbe that had lost its ability to synthesize the diagnostic species-specific capsular antigen F1 was investigated. The antigenic complex fraction V (FV) was obtained after the fifth stage of extraction at a concentration of 1.28% of surfactants and after additional purification. The thermostable FV was found to consist mainly of protein. The protein having a molecular mass of about 43 kD predominates in the fraction. The latter is nontoxic for albino mice and antigenic. It forms a precipitate with commercial antiplague serum antibodies. FV antigenic sensitization of tanned sheep red blood cells gave rise to a diagnostic agent that specifically reacted with an antiplague serum rather than with heterologous sera against enterobacteria. The sera immunized with FV specifically reacted in the JDJFR with all the strains of the pathogen of plague irrespective of the temperature of their cultivation, including "fraction-free", which did not interact with a diagnosticum on F1. The animal sera immunized with capsule-free plague microbial strain reacted only with a FV-erythrocytic diagnosticum and they did not interact with F1 antigen-sensitized red blood cells. The erythrocytic FV diagnosticum was tested in ABNR with 130 typical and atypical plague microbial strains and with 133 strains of heterologous bacteria of different species of the family Enterobacteriaceae. The FV diagnosticum identified all the variants of a plague microbe, while the F1 diagnosticum revealed only its capsular variants. Among the heterologous bacteria, some strains of the closely related pathogen of pseudotuberculosis in those who were in the R form, rather than S form, positively reacted. The use of FV identified 2 groups of hybridomas obtained after immunization of albino mice with the capsule-free variant of a plague microbe. Some hybridomas reacted only with plague bacteria while others did with two above pathogens. The authors substantiate the expediency of using FV, its components, and obtained monoclonal plague pathogen antibodies to improve antiplague diagnosticums with an activity spectrum that exceeds that of the existing commercial F1 antigen-based diagnosticums. They also discuss the lines of further studies.

Animals↗
PubMed1986

Restoration of wild-type pathogenicity to an attenuated DNA polymerase mutant of herpes simplex virus type 1.

The drug-resistant variant, RSC-26, which was derived from the herpes simplex virus type 1 wild-type strain SC16, expresses an altered DNA polymerase and has reduced pathogenicity in animal models. To determine whether the attenuation in pathogenicity was due solely to mutation in the polymerase gene, a fragment of the wild-type gene was cloned, transferred into the genome of RSC-26 and recombinants were isolated. Three recombinants examined had similar properties to wild-type virus with respect to their sensitivity to antiviral drugs, DNA polymerase activities and their pathogenicity for mice. These results strongly suggest that expression of the altered polymerase of RSC-26 results in attenuated pathogenicity.

Animals↗
PubMed2003

BRCA1 germline mutations in Indian familial breast cancer.

Germline mutation analysis of BRCA1 gene has demonstrated significant allelic heterogeneity. These differences represent historical influences of migration, population structure and geographic or cultural isolation. To date, there have been no reports of Indian families with mutations in BRCA1. We have screened for mutations in selected coding exons of BRCA1 and their flanking intron regions in three breast or breast and ovarian cancer families with family history of three or more cases of breast cancer under age 45 and/or ovarian cancer at any age. We have also analyzed 10 female patients with sporadic breast cancer regardless of age and family history, as well as 50 unrelated normal individuals as controls. Thus a total of 90 samples were analyzed for BRCA1 mutations using polymerase chain reaction-mediated site directed mutagenesis (PSM) and single stranded conformation polymorphism (SSCP) analysis for various selected exons followed by sequencing of variant bands. Eight point mutations were identified. Two deleterious pathogenic, protein truncating non-sense mutations were detected in exon 11 (E1250X) and exon 20 (E1754X) and six novel and unique amino acid substitutions (F1734S, D1739Y, V1741G, Q1747H, P1749A, R1753K). One complex missense mutation of exon 20 [V1741G; P1749A] was seen in two out of three families and another complex combination of missense and non-sense mutations of the same exon [V1741G; E1754X] was observed in only one family. These complex mutations exist only in breast cancer families but not in control populations of women. Three splice site variants (IVS20+3A>C, IVS20+4A>T, IVS20+5A>T) and two intronic variants (IVS20+21_22insG, IVS20+21T>G) were also detected. In the group of 10 sporadic female patients no mutations were found.

Adult↗
PubMed2002

Partitioning of human and sheep forms of the pathogenic prion protein during the purification of therapeutic proteins from human plasma.

BACKGROUND: Therapeutic proteins derived from human plasma and other biologic sources have demonstrated an excellent safety record relative to the potential threat of transmissible spongiform encephalopathy (TSE) transmission. Previously, hamster-adapted scrapie was used as a model agent to assess TSE clearance in purification steps leading to the isolation of biopharmaceutical proteins. The current study investigated the validity of hamster scrapie as a model for human TSE clearance studies. The partitioning of the pathogenic forms of the prion protein associated with human variant CJD (PrP(vCJD)), human sporadic CJD (PrP(sCJD)) and Gerstmann-Sträussler-Scheinker (PrP(GSS)) syndrome was compared to the partitioning of hamster scrapie (PrP(Sc)) in three plasma protein purification steps. Sheep scrapie (PrP(Sc)) was similarly evaluated. STUDY DESIGN AND METHODS: The starting materials for three plasma protein purification steps, cryoseparation, 3 percent PEG separation, and 11.5 percent PEG separation, were spiked with brain homogenates containing human PrP(vCJD), human PrP(sCJD), human PrP(GSS), sheep PrP(Sc), and hamster 263K PrP(Sc). The partitioning of the pathogenic form of the PrP was analyzed. RESULTS: Clearance of the pathogenic form of the PrP was measured relative to the effluent fraction. Regardless of the source of the pathogenic prion, clearance was similar to hamster PrP(Sc). A nominal amount of clearance (approx., 1 log), an intermediate amount of clearance (approx., 2 log), and a substantial amount of clearance (> or = 3 log) were observed for the cryoseparation, 3 percent PEG separation, and 11.5 percent PEG separation steps, respectively. In the latter step, no PrP was detected in the effluents. CONCLUSIONS: These data demonstrate that human prions, including vCJD prions, can be removed during the purification of human therapeutic proteins and indicate that partitioning of human prions is similar to that observed in the hamster scrapie model.

Animals↗
PubMed2005

SuperSAGE.

The application of transcriptomics to study host-pathogen interactions has already brought important insights into the mechanisms of pathogenesis, and is expanding further keeping pace with the accumulation of genomic sequences of host organisms (human and economically important organisms such as food crops) and their pathogens (viruses, bacteria, fungi and protozoa). In this review, we introduce SuperSAGE, a substantially improved variant of serial analysis of gene expression (SAGE), as a potent tool for the transcriptomics of host-pathogen interactions. Notably, the generation of 26 bp tags in the SuperSAGE procedure allows to decipher the 'interaction transcriptome', i.e. the simultaneous monitoring of quantitative gene expression, of both a host and one of its eukaryotic pathogens. The potential of SuperSAGE tags for a rapid functional analysis of target genes is also discussed.

Animals↗
PubMed1994

Specific genetic variants of Actinobacillus actinomycetemcomitans correlate with disease and health in a regional population of families with localized juvenile periodontitis.

A geographically homogeneous population of 83 subjects, from 21 families with localized juvenile periodontitis (LJP), and 35 healthy control subjects was monitored, over a 5-year period, for the presence of the periodontal pathogen Actinobacillus actinomycetemcomitans. Restriction fragment length polymorphism (RFLP) analysis was used to monitor the distribution of genetic variants of this bacterium in LJP-susceptible subjects that converted from a healthy to a diseased periodontal status. A. actinomycetemcomitans was cultured from 57% of the LJP family members accessioned into the study. Nine of 36 LJP-susceptible subjects, in seven families, developed signs of periodontal destruction. All but one of these conversion subjects harbored A. actinomycetemcomitans. Bacterial variants representative of a single RFLP group (II) showed the strongest correlation with conversion (P < 0.002). Six of nine conversion subjects were infected with A. actinomycetemcomitans from this group. RFLP group II variants also prevailed in 8 of 22 probands but were absent in the 35 healthy control subjects. In contrast to the selective distribution of group II variants is diseased individuals, variants belonging to RFLP groups XIII and XIV were found exclusively in the control subjects. Thus, the use of RFLP to type clinical isolates of A. actinomycetemcomitans has resulted in the identification of genetic variants that predominate in LJP and health. These results indicate that studies concerned with the pathogenicity of this bacterium in LJP should be focused on the group II variants.

Adult↗
PubMed2026

Structural modeling and functional characterization of a novel gain-of-function TLR8 variant causing severe inflammatory syndrome.

With the increasing use of genetic sequencing to investigate inborn errors of immunity, rare variants are frequently identified, yet their clinical relevance often remains uncertain. Establishing pathogenicity requires a multidisciplinary approach that integrates genetic, structural, functional, and clinical data. Here, we used such a strategy to investigate a previously unreported hemizygous missense variant - alanine (A) to threonine (T) at residue 518 - in Toll-like receptor 8 (TLR8), identified in 2 male siblings with recurrent infections and systemic inflammation, characterized by a proinflammatory immune signature and B cell dysregulation. Functional studies showed that the TLR8 A518T variant enhanced NF-&#x3ba;B activation and increased secretion of proinflammatory cytokines compared with WT TLR8 upon stimulation, consistent with a gain-of-function effect. Protein degradation and turnover assays revealed reduced abundance of the mutant TLR8 protein due to faster turnover and increased proteasomal degradation. Computational modeling predicted enhanced structural stabilization of the active TLR8 homodimer interface via additional water-mediated hydrogen bonds introduced by the A518T substitution. Together, these findings integrating structural modeling with functional assays identify a novel TLR8 ligand-specific gain-of-function mutation resulting in complex immunopathology in 2 siblings.

Humans↗
PubMed2006

Pathogenicity of MSH2 missense mutations is typically associated with impaired repair capability of the mutated protein.

BACKGROUND & AIMS: Inherited deleterious mutations in mismatch repair genes MLH1, MSH2, and MSH6 predispose to hereditary nonpolyposis colorectal cancer. A major diagnostic challenge is the difficulty in evaluating the pathogenicity of missense mutations. Previously we showed that most missense variants in MSH6 do not impair MMR capability and are associated with no or low cancer susceptibility, whereas in MLH1, functional studies distinguished nontruncating mutations with severe defects from those not or slightly impaired in protein expression or function. The present study was undertaken to evaluate the pathogenicity of inherited missense mutations in MSH2. METHODS: Fifteen mutated MSH2 proteins including 14 amino acid substitutions and one in-frame deletion were tested for expression/stability, MSH2/MSH6 interaction, and repair efficiency. The genetic and biochemical data were correlated with the clinical data. Comparative sequence analysis was performed to assess the value of sequence homology as a tool for predicting functional results. RESULTS: None of the studied MSH2 mutations destroyed the protein or abolished MSH2/MSH6 interaction, whereas 12 mutations impaired the repair capability of the protein. Comparative sequence analysis correctly predicted functional studies for 13 of 14 amino acid substitutions. CONCLUSIONS: Interpretation was pathogenic for 12, nonpathogenic for 2, and contradictory for 1 mutation. The pathogenicity could not be distinguished unambiguously by phenotypic characteristics, although correlation between the absence of staining for MSH2 and pathogenicity of the missense mutation was notable. Unlike in MSH6 and MLH1, the pathogenicity of missense mutations in MSH2 was always associated with impaired repair capability of the mutated protein.

Adaptor Proteins, Signal Transducing↗