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PubMed1994

RNA virus quasispecies: significance for viral disease and epidemiology.

The experimental evidence available for animal and plant RNA viruses, as well as other RNA genetic elements (viroids, satellites, retroelements, etc.), reinforces the view that many different types of genetic alterations may occur during RNA genome replication. This is fundamentally because of infidelity of genome replication and large population sizes. Homologous and heterologous recombination, as well as gene reassortments occur frequently during replication of retroviruses and most riboviruses, especially those that use enzymes with limited processivity. Following the generation of variant genomes, selection, which is dependent on environmental parameters in ways that are poorly understood, sorts out those genome fits enough to generate viable quasispecies. Chance events can also be destabilizing, as illustrated by recent results on fitness loss and other phenotypic changes accompanying bottleneck transmission. Variation, selection, and random sampling of genomes occur continuously and unavoidably during virus evolution. Evolution of RNA viruses is largely unpredictable because of the stochastic nature of mutation and recombination events, as well as the subtle effects of chance transmission events and host/environmental factors. Among environmental factors, alterations resulting from human intervention (deforestation, agricultural activities, global climatic changes, etc.) may alter dispersal patterns and provide new adaptive possibilities to viral quasispecies. Current understanding of RNA virus evolution suggests several strategies to control and diagnose viral diseases. The new generation of chemically defined vaccines and diagnostic reagents (monoclonal antibodies, peptide antigens, oligonucleotides for polymerase chain reaction amplification, etc.) may be adequate to prevent disease and detect some or even most of the circulating quasispecies of any given RNA pathogen. However, the dynamics of viral quasispecies mandate careful consideration of those reagents to be incorporated into diagnostic kits. Broadening diagnosis without jeopardizing specificity of detection will be challenging. There is a finite probability (impossible to quantify at present) that a defined vaccine may promote selection of escape mutants or a particular diagnostic kit may fail to detect a viral pathogen. Of particular concern are the potential long-term effects of weak selective pressures that may initially go unnoticed. Variant viruses resulting from evolutionary pressure imposed by vaccines or drugs may insidiously and gradually replace previous quasispecies. The great potential for variation and phenotypic diversity of some important RNA virus pathogens (human immunodeficiency virus, the hepatitis viruses, the newly recognized human hantaviruses, etc.) has become clear. Prevention and therapy should rely on multicomponent vaccines and antiviral agents to address the complexity of RNA quasispecies mutant spectra.(ABSTRACT TRUNCATED AT 400 WORDS)

Biological Evolution↗
PubMedDate not supplied

The protein expression of Streptococcus pyogenes is significantly influenced by human plasma.

During the course of infection, the common human pathogen Streptococcus pyogenes encounters plasma. We show that plasma causes S. pyogenes to rapidly remodel its cellular metabolism and virulence pathways. We also identified a variant of the major virulence factor, M1 protein, lacking 13 amino acids at the NH(2)-terminus in bacteria grown with plasma. The pronounced effect of plasma on protein expression, suggests this is an important adaptive mechanism with implications for S. pyogenes pathogenicity.

Amino Acids↗
PubMed1988

Purification, characterization, and pathogenicity of Moraxella bovis pili.

Pilins composed of the alpha or beta pilins of Moraxella bovis strain Epp63 were purified, subjected to chemical or enzymatic cleavage, and the resulting fragments sequenced by automated Edman degradation. alpha Pilin was found to be a 155-amino-acid polypeptide with a single intramolecular disulfide bridge. The beta pilin amino acid sequence substantiated the previously reported structure derived from the beta pilin gene DNA sequence, and indicated that the alpha and beta pilins of this strain are approximately 70% homologous. DNA hybridization studies of genomic DNA from the alpha- and beta-piliated variants of strain Epp63 indicated that the expression of the two pilin types was governed by an oscillating mechanism of chromosomal rearrangement. The alpha and beta pili were evaluated serologically and found to exhibit approximately 50% shared antigenicity, indicating that regions of conserved and heterologous sequence specify both type-specific and crossreacting epitopes. The pathogenicity of the alpha- and beta-piliated variants was studied by ocular inoculation of calves eyes; beta-piliated organisms were significantly more infectious than alpha-piliated organisms, indicating that beta pili confer, or are associated with, a relative advantage during the first stages of ocular infection. Preliminary analysis of other M. bovis strains suggests that each strain produces two types of pilin, and that this property may be characteristic of the species.

Amino Acid Sequence↗
PubMed2000

At the maize/Agrobacterium interface: natural factors limiting host transformation.

BACKGROUND: Agrobacterium tumefaciens has been successfully harnessed as the only natural vector for the incorporation of foreign genes into higher plants, but its use in the grain crops is often limited. Low transformation efficiency has been partly attributed to a failure in the initial events in the transformation process, specifically in the capacity of the VirA/VirG two-component system to induce expression of the virulence genes. RESULTS: Here we show that the root exudate of Zea mays seedlings specifically inhibits virulence gene expression, determine that 2-hydroxy-4,7-dimethoxybenzoxazin-3-one (MDIBOA), which constitutes > 98% of the organic exudate of the roots of these seedlings, is the most potent and specific inhibitor of signal perception in A. tumefaciens-mediated gene transfer yet discovered, and develop a model that is able to predict the MDIBOA concentration at any distance from the root surface. Finally, variants of A. tumefaciens resistant to MDIBOA-mediated inhibition of vir gene expression have been selected and partially characterized. CONCLUSIONS: These results suggest a strategy in which a plant may resist pathogen invasion by specifically blocking virulence gene activation and yet ensure that the 'resistance factor' does not accumulate to levels sufficient to impose toxicity and selection pressure on the pathogen. The data further establish that naturally occurring inhibitors directed against signal perception by the VirA/VirG two-component regulatory system can play an important role in host defense. Finally, selected variants resistant to specific MDIBOA inhibition may now be used to extend the transformation efficiency of maize and possibly other cereals.

Agrobacterium tumefaciens↗
PubMed1998

Bartter syndrome: unraveling the pathophysiologic enigma.

Familial hypokalemic, hypochloremic metabolic alkalosis, or Bartter syndrome, is not a single disorder but rather a set of closely related disorders. These Bartter-like syndromes share many of the same physiologic derangements, but differ with regard to the age of onset, the presenting symptoms, the magnitude of urinary potassium (K) and prostaglandin excretion, and the extent of urinary calcium excretion. At least three clinical phenotypes have been distinguished: (1) classic Bartter syndrome; (2) the hypocalciuric-hypomagnesemic Gitelman variant; and (3) the antenatal hypercalciuric variant (also termed hyperprostaglandin E syndrome). The fundamental pathogenesis of this complex set of disorders has long fascinated and stymied investigators. Physiologic investigations have suggested numerous pathogenic models. The cloning of genes encoding renal transport proteins has provided molecular tools to begin testing these hypotheses. To date, molecular genetic analyses have determined that mutations in the gene encoding the thiazide-sensitive sodium-chloride (Na-Cl) cotransporter underlie the pathogenesis of the Gitelman variant. In comparison, the antenatal variant is genetically heterogeneous with mutations in the genes encoding either the bumetanide-sensitive sodium-potassium-chloride (Na-K-2Cl) cotransporter or the luminal, ATP-regulated, K channel. With these data, investigators have begun to unravel the pathophysiologic enigma of the Bartter-like syndromes. Further studies will help refine pathogenic models for this set of disorders as well as provide new insights into the normal mechanisms of renal electrolyte transport.

Bartter Syndrome↗
PubMed1998

Population diversity in grapevine yellow speckle viroid-1 and the relationship to disease expression.

Vitis vinifera cultivars Zinfandel-1A and Mission were found to harbor different grapevine yellow speckle viroid-1 (GYSVd-1) variants and characterized to define the relationship to yellow speckle (YS) and vein-banding (VB) diseases. Products from the left terminal (T1), pathogenic (P), and a portion of the central (C) domains of Zinfandel-1A and Mission displayed distinct single-stranded conformation polymorphism (SSCP) patterns, presumably reflecting nucleotide changes in the P domain. The two selections were shown to contain homogeneous populations of type 1 and type 2 GYSVd-1 variants described in Australia. Symptoms of YS were induced only in vines containing the type 2 variant by treatment at a constant temperature of 32 degreesC in continuous light. SSCP of Pagadebit selections from Italy revealed the nonsymptomatic variant was essentially identical to Zinfandel-1A, whereas symptomatic selections were unlike any other previously described. Nucleotide sequence confirmed that nonsymptomatic selections from Italy contained the GYSVd-1 type 1 variant. A total of 43 changes were spread throughout the T1, C, V, and T2 domains from symptomatic selections. This study establishes the Australian type 1 variant as the non-symptom-inducing form of GYSVd-1 and type 2 as the symptom-inducing variant. The distinct symptom-inducing variant from Italy is proposed as a new type 3 variant of GYSVd-1.

Base Sequence↗
PubMed2003

Differentiating pathogenic mutations from polymorphic alterations in the splice sites of BRCA1 and BRCA2.

About 4% of all BRCA1 and BRCA2 alterations reported to the Breast Information Core database are splice site variants. Only a limited number of them have been studied at the RNA level. By BRCA1 and BRCA2 mutation analysis of breast/ovarian cancer families, we identified two novel and eight previously reported potential splice site mutations, never characterized at the cDNA level before. RT-PCR was performed to determine whether these variants disrupted correct splicing. To ensure efficient detection of transcripts containing premature termination codons, a nonsense-mediated mRNA decay inhibitor was added to the lymphoblastoid cell lines of the patients before RNA extraction. We found that BRCA1 IVS3+3A>C, 4304G>A (in the last codon of exon 12), and IVS19+2delT and BRCA2 IVS6+1G>A, IVS23-2A>G, and IVS24+1G>A lead to aberrant transcripts in lymphocytes. Therefore, they were considered to be true pathogenic mutations, predisposing carriers to cancers of the hereditary breast/ovarian cancer syndrome. BRCA2 IVS24-16T>C is a frequent polymorphism in linkage disequilibrium, with a polymorphic stop codon in exon 27, K3326X. BRCA1 IVS2-14C>T and BRCA2 IVS9-5insT and IVS25+9A>C represent rare variants, not disrupting normal splicing in blood lymphocytes. However, some of the alterations may act differently, qualitatively and/or quantitatively, in breast or ovarian tissues. The data provided in this paper allowed more accurate risk estimation of patients and relatives carrying the mutations described herein and have facilitated genetic counseling. Furthermore, our study is important for a better understanding of splicing mechanisms and revealed new patterns of alternative splicing in BRCA1 and BRCA2.

Adult↗
PubMed2026

Homozygous initiation codon-altering complex variant causes rapid-onset chorioretinopathy phenotype in ABCA4 disease.

PURPOSE: To characterize the clinical phenotype associated with a homozygous start codon-altering complex variant in the ABCA4 gene and evaluate its severity and prognosis in the context of Stargardt disease. METHODS: Patient records were retrospectively reviewed for homozygous ABCA4 start codon variants. Patients underwent ophthalmic exam, multimodal imaging, full-field electroretinography (ffERG), and inherited retinal disease panel testing. Structural and functional retinal assessments were reviewed to determine phenotype severity. RESULTS: Three brothers of Ashkenazi Jewish descent presented with profound early-onset vision loss beginning at age 7, with best-corrected visual acuity reduced to counting fingers or hand motion by early adulthood. Imaging revealed widespread macular atrophy, extensive intraretinal pigment migration, and near-complete foveal outer nuclear layer loss. ffERG demonstrated extinguished scotopic and photopic responses. The patients were found to be homozygous for a complex ABCA4 allele containing the start codon variant c.[1A > G;6089G > A]. These features were consistent with the rapid-onset chorioretinopathy phenotype, previously associated with null ABCA4 alleles. CONCLUSIONS: This report characterizes the clinical findings in patients homozygous for the c.[1A > G;6089G > A] variant in ABCA4, confirming its association with a severe, rapid-onset chorioretinopathy phenotype. The data support the pathogenic nature of this complex allele and expands the genotype-phenotype correlational spectrum of ABCA4-related disease, with implications for prognosis and genetic counseling.

Humans↗
PubMed2002

The pathogenic mechanisms of prion diseases.

Transmissible spongiform encephalopathies (TSEs) or prion diseases are a group of fatal neurodegenerative diseases of humans and animals, including bovine spongiform encephalopathy (BSE) of cattle, scrapie of sheep, and Creutzfeldt-Jakob disease (CJD) of humans. Prion diseases have become an important issue in public health and in the scientific world not only due to the possible relationship between BSE and new variant CJD (nvCJD) but also due to the unique biological features of the infectious agent. Although the nature of the infectious agent and the pathogenic mechanisms of prion diseases are not fully understood, considerable evidence suggests that an abnormal form (PrP(Sc)) of a host prion protein (PrP(C)) may compose substantial parts of the infectious agent and that various factors such as oxidative stress and calcium cytotoxicity are associated with the pathogenesis of prion diseases. Here, we briefly review and discuss the pathogenic mechanisms of prion diseases. These advances in understandings of fundamental biology of prion diseases may open the possibilities for the prevention and treatment of these unusual diseases and also suggest applications in more common neurodegenerative disorders such as Alzheimer's disease (AD) and Parkinson's disease (PD).

Animals↗
PubMed2004

Searching for genomic variants in IGF2 and CDKN1C in Silver-Russell syndrome patients.

Silver-Russell syndrome (SRS) is a heterogeneous syndrome with evidence for a substantial role of genetic factors in its etiology. Apart from other specific clinical features, severe intrauterine and postnatal growth retardation are the dominant characteristics of SRS. Therefore, studies on the genetic basis of the disease focus on genes involved in growth and its regulation. Another key for the identification of (a) SRS gene(s) is the finding of chromosomal disturbances in SRS patients: recently, four growth retarded patients carrying duplications in 11p15 of maternal origin have been described, two of these cases presented SRS-like features. The same region includes IGF2 and CDKN1C and is well known to harbour alterations in patients suffering from Beckwith-Wiedemann syndrome. We therefore decided to perform an extensive search for variants in the IGF2 and CDKN1C genes; mutations in these genes cause growth disturbances. More than 40 SRS patients were screened for mutations by different detection strategies, allele frequencies were compared between patients and controls. In both genes, we did not detect any obvious pathogenic mutation. In case of IGF2, slight differences in the allelic distribution of specific polymorphisms between SRS patients and controls were observed. In CDKN1C, several variants could be identified in both cohorts with similar frequencies, but only one patient showed a so far unknown variant not detectable in controls.

Base Sequence↗
PubMed2003

Novel MLH1 and MSH2 germline mutations in the first HNPCC families identified in Slovakia.

Hereditary nonpolyposis colorectal cancer (HNPCC) is a dominantly-inherited cancer predisposition syndrome, in which the susceptibility to cancer of the colon, endometrium and ovary is linked to germline mutations in DNA mismatch repair (MMR) genes. We have recently initiated a cancer prevention program in suspected HNPCC families in the Slovak Republic. The first ten families fulfilling Amsterdam criteria or Bethesda guidelines were screened for germline mutations in MLH1 and MSH2, two MMR genes most frequently mutated in HNPCC families. Six mutations were identified, five of which have not been reported previously. Two of the three new mutations in MLH1 (c.380+2T>A; c.307-2A>C) were absent from 100 chromosomes of healthy controls and probably cause a splicing defect, while the third was a 1 bp deletion (c.1261delA). In the MSH2 gene, one new nonsense (c.1030C>T [p.Q344X]) and one missense (c.524T>C [p.L175P]) mutation were identified. This latter variant was not found in 104 alleles of healthy control individuals. Moreover, a previously-reported pathogenic mutation (c.677G>T [p.R226L]) was found in one kindred. The clinical data and the genotypic and phenotypic evaluation of the tumors indicate that all the new alterations are pathogenic HNPCC mutations.

Adaptor Proteins, Signal Transducing↗
PubMed1994

Stable biological and antigenic characteristics of HIV-2SBL6669 in nonpathogenic infection of macaques.

The purpose of the present study was to investigate if the biological and antigenic properties of human immunodeficiency virus type 2 change over time in cynomolgus macaques (Macaca fascicularis) experimentally infected with HIV-2SBL6669. Sequential virus isolates and serum samples were obtained during a 2-year period and studied in autologous neutralization assays. All six macaques studied seroconverted shortly after infection and remained healthy during the observation period. Virus could be isolated from all six animals during the first 100 days postinfection. Thereafter four monkeys became virus isolation negative, either permanently or transiently (two macaques each), whereas two macaques remained virus isolation positive during the entire observation period. Sequential reisolates from the macaques invariably replicated in HUT-78, U937-2, and Jurkat-tat cell lines, similarly to the HIV-2SBL6669 inoculum virus. The ability to produce neutralizing antibodies correlated with positive virus isolations, hence four macaques produced neutralizing antibodies against inoculum virus and sequential reisolates. Once the neutralizing antibody appeared, sequential reisolates obtained at both early and late time after infection were neutralized, indicating that the neutralizing epitopes of the virus are conserved in the infected animals over time. This is different from the pathogenic SIVsm infection in macaques or HIV-1 infection in humans, where emergence of neutralization resistant variants seems to be the rule. In contrast, in HIV-2-infected macaques the biological properties of the virus are stable and the neutralizing antibody response shows extensive cross-reactivity.

Animals↗
PubMed2005

Comparative immunomodulatory properties of a chitosan-MDP adjuvant combination following intranasal or intramuscular immunisation.

As the precise functions of adjuvants become clearer, opportunities are presented in their complementary use for the induction of tailored immune responses to subunit vaccines. Here we comparatively investigate the immunological outcome following intranasal or intramuscular immunisation with Helicobacter pylori urease admixed to a chitosan and muramyl di-peptide (MDP) combination. MDP appeared to limit the antigenicity of rUre by either administration route. Nasal administration of the combined adjuvant formulation resulted in an up-regulation of type I recall responses in splenocytes as opposed to adjuvantisation with chitosan alone. In contrast, intramuscular immunisation appeared to limit the responsiveness to the antigen when adjuvanted with chitosan and even more so when chitosan was combined with MDP, suggesting that the mechanism of adjuvantisation and adjuvant synergy differed depending on the immunisation route. Recognising the benefit of improved delivery of MDP intranasally due to the specific physiological effects of chitosan, we discuss the impact of the newly identified pathogen associated molecular pattern (PAMP) role of MDP with respect to the adjuvanticity of proposed chemical variants of this peptide adjuvant.

Acetylmuramyl-Alanyl-Isoglutamine↗
PubMed2001

The rise and fall of antimicrobial resistance.

Antimicrobial resistance is a growing problem in nearly every infectious disease, but the extent and rate of increase of the problem varies widely with different pathogen-drug combinations. The rate of increase of resistance depends primarily on the availability of resistant variants and the intensity of selection imposed by antimicrobial treatment (appropriately measured). Declines in resistance following antimicrobial control measures are typically faster in hospital-acquired infections than in community-acquired ones, probably owing to the dependence in the latter case on the fitness cost of resistance. Open questions and approaches for testing the hypotheses proposed here are outlined.

Bacteria↗
PubMed1991

Early-onset Alzheimer's disease caused by mutations at codon 717 of the beta-amyloid precursor protein gene.

A mutation at codon 717 of the beta-amyloid precursor protein gene has been found to cosegregate with familial Alzheimer's disease in a single family. This mutation has been reported in a further five out of approximately 100 families multiply affected by Alzheimer's disease. We have identified another family, F19, in which we have detected linkage between the beta-amyloid precursor protein gene and Alzheimer's disease. Direct sequencing of exon 17 in affected individuals from this family has revealed a base change producing a Val----Gly substitution, also at codon 717. The occurrence of a second allelic variant at codon 717 linked to the Alzheimer's phenotype supports the hypothesis that they are pathogenic mutations.

Alzheimer Disease↗
PubMed2006

Dimerization and interactions of Brucella suis VirB8 with VirB4 and VirB10 are required for its biological activity.

VirB8-like proteins are essential components of type IV secretion systems, bacterial virulence factors that mediate the translocation of effector molecules from many bacterial pathogens into eukaryotic cells. Based on cell biological, genetic, and x-ray crystallographic data, VirB8 was proposed to undergo multiple protein-protein interactions to mediate assembly of the translocation machinery. Here we report the results of a structure-function analysis of the periplasmic domain of VirB8 from the mammalian pathogen Brucella suis, which identifies amino acid residues required for three protein-protein interactions. VirB8 variants changed at residues proposed to be involved in dimerization, and protein-protein interactions were purified and characterized in vitro and in vivo. Changes at M102, Y105, and E214 affected the self-association as measured by analytical ultracentrifugation and gel filtration. The interaction with B. suis VirB10 was reduced by changes at T201, and change at R230 inhibited the interaction with VirB4 in vitro. The in vivo functionality of VirB8 variants was determined by complementation of growth in macrophages by a B. suis virB8 mutant and by using a heterologous assay of type IV secretion system assembly in Agrobacterium tumefaciens. Changes at Y105, T201, R230, and at several other residues impaired the in vivo function of VirB8, suggesting that we have identified interaction sites of relevance in the natural biological context.

Bacterial Proteins↗
PubMed2026

GUANinE v1.1 reveals complementarity of supervised and genomic language models.

There has been much debate about the benefits of supervised versus unsupervised learning on genomes. Determining which is better in what contexts requires developing comprehensive benchmarks spanning functional and evolutionary tasks. Importantly, such benchmarks need large sample sizes to enable well-powered ranking of models. Having developed and applied such a benchmark here (GUANinE v1.1), we conclusively demonstrate each paradigm offers key advantages and outperforms on certain tasks. In accordance with training, supervised sequence-to-function models exhibit strong performance when annotating functional states characterized by chromatin accessibility or histone marks, while self-supervised language models outperform on evolutionary conservation. Our hundreds of new evaluations in this v1.1 expansion provide evidence for a tradeoff between input context size and model parameter count for a fixed compute budget, which we depict with new metrics such as kiloparameters/base pair. We also construct two new large-scale variant interpretation tasks in v1.1: cadd-snv measuring deleteriousness, and clinvar-snv measuring clinical pathogenicity. We find that conservation scores, and by extension, genomic language models, predict deleteriousness well, but successfully translating deleteriousness predictions to pathogenicity remains challenging. GUANinE v1.1 newly evaluates dozens of pretrained genomic models, and we conclude that moderate-context hybrid or post-trained language models may define the next era of machine learning in genomics.

Genomics↗
PubMed1986

Variation in the expression of pili and outer membrane protein by Neisseria meningitidis during the course of meningococcal infection.

The occurrence of antigenic shift during meningococcal infection has been investigated by comparison of paired isolates obtained from the blood, cerebrospinal fluid or nasopharynx of patients. Isolates from any individual produced identical DNA 'fingerprints' and showed stability in expression of both class 2 outer membrane protein and an antigen common to pathogenic Neisseria, confirming their origin as a single strain. One of the four strains examined produced variants which differed in the molecular mass of their class 5 outer membrane proteins. Three of the strains produced pili containing the epitope recognized by monoclonal antibody SM1 and two of these gave rise to variants which expressed pili of differing subunit molecular masses. The two variants of the remaining strain produced pilins lacking the common epitope detected by antibody SM1 but radioimmune precipitation with polyclonal anti-pilus antiserum revealed that variation in the molecular mass of the pilin expressed also occurred with this second class of pili. Antigenic variation in expression of both class 5 outer membrane proteins and pili therefore appears to be a common occurrence during meningococcal infection.

Antigens, Bacterial↗