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PubMed2025

A pan-beta-coronavirus vaccine bearing conserved and asymptomatic B- and T-cell epitopes protects against highly pathogenic Delta and highly transmissible Omicron SARS-CoV-2 variants.

Over the last five years of the COVID-19 pandemic, the repetitive mutations and deletions in the SARS-CoV-2 genome, primarily targeting the Spike gene, resulted in the emergence of multiple viral variants and sub-variants. The non-updated mismatched Spike-based sub-unit vaccines are less effective due to the ability of these SARS-CoV-2 variants and sub-variants to evade vaccine-induced humoral immunity. To reduce reliance on neutralizing antibodies and prevent potential mismatches between circulating variants, sub-variants, and the vaccines, we have identified highly conserved Spike and non-Spike viral epitopes associated with protective asymptomatic B- and T-cell immune responses, respectively. We demonstrated that unvaccinated asymptomatic patients with COVID-19 recognized these conserved B- and T-cell epitopes. Using the mRNA-LNP-based antigen delivery system, we developed a multi-epitope vaccine that incorporates the conserved B-cell epitopes, CD4+ T-cell epitopes, and CD8+ T-cell epitopes. To assess the efficacy of this "asymptomatic" multi-epitope vaccine, we used the HLA-A*02:01/HLA-DRB1* 01:01-hACE-2 triple transgenic mouse model. We demonstrated that this "asymptomatic" multi-epitope vaccine conferred robust protection against infection and disease caused by the SARS-CoV-2 Delta (B.1.617.2) and Omicron (XBB.1.5) variants as assessed by: (i) prevention of weight loss, (ii) reduction of virus replication, and (iii) lung pathology. This protection was associated with: (i) strong antibody responses; and (ii) high frequency of anti-viral IFN-γ-producing CD4+ and CD8+ T-cells. These findings illustrate the possibility of developing a pan-beta-coronavirus vaccine to induce broad-spectrum protective immunity against SARS-CoV-2 variants and sub-variants by targeting highly conserved "asymptomatic" B- and T-cell epitopes identified from both structural and non-structural viral proteins.

Epitopes, T-Lymphocyte↗
PubMed2003

Variation in a repeat sequence determines whether a common variant of the cystic fibrosis transmembrane conductance regulator gene is pathogenic or benign.

An abbreviated tract of five thymidines (5T) in intron 8 of the cystic fibrosis transmembrane conductance regulator (CFTR) gene is found in approximately 10% of individuals in the general population. When found in trans with a severe CFTR mutation, 5T can result in male infertility, nonclassic cystic fibrosis, or a normal phenotype. To test whether the number of TG repeats adjacent to 5T influences disease penetrance, we determined TG repeat number in 98 patients with male infertility due to congenital absence of the vas deferens, 9 patients with nonclassic CF, and 27 unaffected individuals (fertile men). Each of the individuals in this study had a severe CFTR mutation on one CFTR gene and 5T on the other. Of the unaffected individuals, 78% (21 of 27) had 5T adjacent to 11 TG repeats, compared with 9% (10 of 107) of affected individuals. Conversely, 91% (97 of 107) of affected individuals had 12 or 13 TG repeats, versus only 22% (6 of 27) of unaffected individuals (P<.00001). Those individuals with 5T adjacent to either 12 or 13 TG repeats were substantially more likely to exhibit an abnormal phenotype than those with 5T adjacent to 11 TG repeats (odds ratio 34.0, 95% CI 11.1-103.7, P<.00001). Thus, determination of TG repeat number will allow for more accurate prediction of benign versus pathogenic 5T alleles.

Base Sequence↗
PubMed2005

Immunoregulatory and susceptibility genes in thyroid and polyglandular autoimmunity.

The etiology of autoimmune thyroid diseases (AITD) is based on genetic and nongenetic factors. Genome-wide screening and linkage analyses have identified several chromosomal regions that are linked to AITD. These are HT-1 (on chromosome 13q33) and HT-2 (chromosome 12q22) for Hashimoto's thyroiditis (HT), and GD-1 (chromosome 14q31), GD-2 (chromosome 20q11.2), and GD-3 (chromosome Xq21) for Graves' disease (GD). Several genes have been proposed as susceptibility or immunoregulatory genes. Most promising genes are those of the major histocompatibility complex (MHC) complex (chromosome 6), the cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) gene (chromosome 2), the CD40 (chromosome 20), the thyroglobulin gene (chromosome 8), and the autoimmune regulator gene (chromosome 21). This review summarizes evidence for pathogenetic involvement of several of these genes in various forms of autoimmune thyropathies. Most genetic data refer to GD, whereas less data are available for HT and thyroid-associated ophthalmopathy. Scarce data refer to AITD within the autoimmune polyglandular syndromes I and II. The realization of family studies in large samples from different populations might provide further insight in the genetic contribution to AITD. Data are also needed on the interaction among susceptibility genes. Finally, additional functional studies are warranted to clarify the possible role of allelic variants in the underlying pathogenic mechanisms of AITD.

Autoimmune Diseases↗
PubMed2001

Allelic imbalance on chromosomes 13 and 17 and mutation analysis of BRCA1 and BRCA2 genes in monozygotic twins concordant for breast cancer.

To study genetic changes associated with the development of breast cancer and the extent of its hereditary predisposition, paraffin-embedded tissue samples were obtained from monozygotic twin pairs concordant for breast cancer through the linked Swedish Twin and Cancer Registries. DNA samples extracted from the matched tumour and normal tissues of nine twin pairs were analysed for allelic imbalance using a series of microsatellite markers on chromosomes 13 and 17, containing loci with known tumour suppressor genes. Multiple losses of constitutional heterozygosity (LOH), consistent with a loss of large genomic region, the whole chromosome or chromosome arm, was found in at least three pairs of twins. One double mitotic crossover was identified in one tumour sample in a pair concordant for LOH at multiple loci on both chromosomes. Recombination breakpoints were mapped to regions delineated by D13S218 and D13S263, and D13S155 and D13S279, respectively. In general, no genetic effect of losing the same allele within a twin pair was found. However, for one marker at chromosome 13 (D13S328, between the BRCA2 and the RB-1 loci) and two markers on chromosome 17 (D17S786, distal to the p53 locus, and D17S855, an intragenic BRCA1 marker) the proportion of twin pairs with the same LOH was significantly higher than expected. These regions may reflect hereditary genomic changes in our sample set. In addition, tumour DNA samples from a subset of 12 twin pairs were analysed for BRCA1 and BRCA2 mutations using exon-by-exon single-strand conformation polymorphism analysis. Two unclassified BRCA2 variants, with a putative pathogenic effect, were identified, but no pathogenic alterations were found in the BRCA1 gene.

Adult↗
PubMed2001

Stromal-cell-derived factor 1 prevents the emergence of the syncytium-inducing phenotype of HIV-1 in vivo.

In a correlative study, the mean plasma level of the chemokine stromal-cell-derived factor 1 (SDF-1) was lower in subjects with syncytium-inducing (SI) than in subjects with non-syncytium-inducing (NSI) HIV isolates, regardless of the CD4 cell count or when compared with HIV-negative individuals. Individuals with high SDF-1 had an 81% probability of having an NSI virus phenotype compared with individuals with lower SDF-1. Increased expression of SDF-1 may help explain why the more pathogenic SI HIV-1 variants do not appear in some individuals.

Chemokine CXCL12↗
PubMed2026

Expanded detection of canine enteric viruses in UK dogs with diarrhoea.

Canine enteric viruses are an important cause of gastrointestinal disease in pet dogs worldwide. Routine diagnosis often relies on pathogen-specific PCR assays, which may fail to detect some viruses, particularly neglected pathogens or genetically divergent variants of established threats. This limits both clinical characterization of affected patients and broader understanding of disease ecology. To address these limitations, we applied metagenomics and a viral discovery bioinformatics pipeline to faecal samples from diarrhoeic dogs in the UK that had been submitted routinely for PCR-based diagnostic testing. Across 80 dogs, we identified 12 viruses known to infect canids, 9 of which have not previously been reported in UK dogs. Among these, several taxa with prior associations to gastrointestinal disease were identified, including canine sapovirus and canine minute virus. By contrast, for other viruses newly detected in the UK, including bufavirus and rotavirus C, clinical relevance in dogs remains unclear. Notably, an identified protoparvovirus fell within the same species as human-canine-associated parvovirus 1, a recently described lineage detected in both canine and human oropharyngeal samples. We also identified a canine parvovirus 2 strain that clustered with a predominantly wildlife-associated lineage, consistent with occasional exposure at the domestic-wildlife interface rather than established circulation in dogs. These two detections illustrate how genome-level surveillance can help prioritize viruses for targeted investigation of host range and transmission context. Overall, these data broaden the catalogue of viruses associated with diarrhoeic dogs in the UK and support periodic review of diagnostic targets informed by viral metagenomic surveillance, while highlighting the need for controlled studies to assess causality and clinical relevance.

Animals↗
PubMed2007

Recombinant dimeric small immunoproteins neutralize transmissible gastroenteritis virus infectivity efficiently in vitro and confer passive immunity in vivo.

Small immunoproteins (SIPs) are single-chain molecules comprising the variable regions of an antibody assembled in a single polypeptide (scFv) and joined to the immunoglobulin heavy-chain dimerizing domain. To investigate the potential of these molecules to provide protection against enteric infections when supplied orally, SIPs were generated against Transmissible gastroenteritis virus (TGEV), a highly pathogenic porcine virus. Different variants of TGEV-specific SIPs were created, of epsilon and alpha isotypes, by exploiting the dimerizing domains epsilonCH4 and alphaCH3 of human and swine origin. Transfected cells secreted these recombinant mini-antibodies efficiently, mainly as dimers stabilized covalently by inter-chain disulphide bridges. The specificity and functionality of the recombinant TGEV-specific SIPs were determined by in vitro binding, neutralization and infection-interference assays. The neutralization indices of the TGEV-specific SIPs were all very similar to that of the original TGEV-specific mAb, thus confirming that the immunological properties have been preserved in the recombinant SIPs. In vivo protection experiments on newborn piglets have, in addition, demonstrated a strong reduction of virus titre in infected tissues of animals treated orally with TGEV-specific SIPs. It has therefore been demonstrated that it is possible to confer passive immunization to newborn pigs by feeding them with recombinant SIPs.

Animals↗
PubMed1997

Novel ITGB4 mutations in a patient with junctional epidermolysis bullosa-pyloric atresia syndrome and altered basement membrane zone immunofluorescence for the alpha6beta4 integrin.

Immunofluorescence studies of junctional epidermolysis bullosa with pyloric atresia (JEB-PA) have suggested abnormalities in the expression of the alpha6 beta4 integrin, an integral component of hemidesmosomes. In this study, we examined a family with two affected individuals with JEB-PA for mutations in the ITGA6 and ITGB4 genes which encode the alpha6 and beta4 integrin polypeptides, respectively. Mutation detection strategy based on PCR amplification of genomic DNA, followed by heteroduplex analysis and direct nucleotide sequencing, did not reveal sequence variants in ITGA6. Putative pathogenic mutations, however, were identified in both ITGB4 alleles. Specifically, the proband was a compound heterozygote for a 1-bp maternal deletion, 3434delT, and an 8-bp paternal deletion, 4050de18. Both mutations result in a frameshift and premature termination codon downstream from the deletion. At the protein level, immunofluorescence of the skin of the proband revealed negative staining for the integrin alpha6 and markedly reduced staining for the beta4 subunit. Thus, the results support the notion of close association of the alpha6 beta4 integrin subunits and further attest to the critical role of this integrin in providing physiologic stability to the dermal-epidermal junction.

Alleles↗
PubMedDate not supplied

Long-range restriction mapping of megabase-sized chromosomes that may be homologs in Trypanosoma brucei.

Trypanosoma brucei is a blood-borne pathogen that changes its variant surface glycoprotein coat, thus evading immune destruction. Restriction digestion, combined with probe hybridization studies, was used to construct long-range restriction maps of the 1.4 (M4) and 1.5 megabase (M3) chromosomes from the IsTaR1 serodeme of T. b. brucei. Comparison of the two chromosomes suggests that they are a homologous pair. Hybridization with a repetitive sequence probe also identifies several copies on the M4 chromosome and a relative paucity of cross-hybridizing repetitive sequence on the larger M3 chromosome.

Animals↗
PubMed1996

Pattern dystrophies of the retinal pigment epithelium.

Pattern dystrophies of the retinal pigment epithelium are infrequent fundus abnormalities arranged in various patterns of dots, lines and branches. The basic lesion appears to be yellow deposits of abnormal lipofuscin accumulated within degenerated retinal pigment epithelium cells. Examinations were carried out on two families who had developed different patterned alterations in the retinal pigment epithelium. The proband of family 1 had diffuse changes associated with equatorial folds. One sister had a macular alteration. A daughter was normal; a son had bilateral atrophy of the temporal retinal pigment epithelium. The proband of family 2 had bilateral, symmetrical retinal pigment epithelium lesions that simulated fundus flavimaculatus. His first daughter had a central lesion in her right eye. The second daughter, a peripapillary crescent of hyperpigmentation in her right eye, and circumpapillary chorioretinal atrophy associated with foveolar abnormalities in the left. This report provides further evidence that variable types of pattern dystrophy can occur within a single family pedigree and support the current opinion that all forms of pattern dystrophies are variants of a single pathogenic mechanism.

Adult↗
PubMed1998

Naturally occurring deletion mutants are parasitic genotypes in a wild-type nucleopolyhedrovirus population of spodoptera exigua

A wild-type nucleopolyhedrovirus (NPV) isolate from Spodoptera exigua from Florida (Se-US2) is a variant of the SeMNPV type strain since it has a unique DNA profile but is closely related to other known geographical isolates of SeMNPV. It consists of several genotypic variants, of which seven were identified in a Se-US2 virus stock by a modification of the in vivo cloning method developed by Smith and Crook (Virology 166:240-244, 1988). The US2A variant was the most prevalent genotype, and it was designated the prototype Se-US2 variant, while four of the variants (US2B, US2D, US2F, and US2H) were found at low frequency. US2C and US2E were also very abundant, and their diagnostic bands were easily observed in wild-type isolate restriction endonuclease patterns. The analysis of each variant, compared to the prototype US2A, showed that US2B and US2H presented minor differences, while US2D and US2F contained slightly larger insertions or deletions. Variants US2C and US2E contained major deletions of 21.1 and 14 kb, respectively, mapping at the same genomic region (between 14.5 and 30.2 map units [m.u.] and between 12.8 and 23 m.u., respectively). This is the first report of such deletion mutants in a natural baculovirus population. Variants US2A, US2B, US2D, US2F, and US2H were isolated as pure genotypes, but we failed to clone US2C and US2E in vivo. When these two variants appeared without apparent contamination with any other variant, they lost their pathogenicity for Spodoptera exigua larvae. A further biological characterization showed evidence that these two naturally occurring deletion mutants act as parasitic genotypes in the virus population. Bioassay data also demonstrated that pure US2A is significantly more pathogenic against second-instar S. exigua larvae than the wild-type isolate. The need for precise genotypic characterization of a baculovirus prior to its development as a bioinsecticide is discussed.

Journal Article↗
PubMed2005

Binding of Pseudomonas aeruginosa AlgZ to sites upstream of the algZ promoter leads to repression of transcription.

Mucoid variants of the opportunistic pathogen Pseudomonas aeruginosa produce the exopolysaccharide alginate and colonize the respiratory tracts of cystic fibrosis patients. The genes encoding the alginate biosynthetic enzymes are clustered in a single operon, which is under tight transcriptional control. One essential activator of the alginate operon is AlgZ, a proposed ribbon-helix-helix DNA binding protein that shares 30% amino acid identity with the Mnt repressor of Salmonella enterica serovar Typhimurium bacteriophage P22. In the current study, we examined the role of AlgZ as an autoregulator. Using single-copy algZ-lacZ transcription fusions, an increase in algZ transcription was observed in an algZ mutant compared to the isogenic wild-type strain, suggesting that AlgZ may have an additional role as a repressor. To identify the AlgZ binding site, overlapping regions upstream of algZ were incubated with AlgZ and analyzed by electrophoretic mobility shift assays. Specific binding activity was localized to a region spanning from 66 to 185 base pairs upstream of the algZ transcriptional start site. Two AlgZ binding sites were defined using copper-phenanthroline footprinting and deletion analyses, with one site centered at 93 base pairs and the other centered at 161 base pairs upstream of the algZ promoter. Deletion of both binding sites resulted in the loss of AlgZ binding. These results indicate that AlgZ represses algZ transcription, and this activity is mediated by multiple AlgZ-DNA interactions.

Bacterial Proteins↗
PubMed1998

PCR for detection and identification of Abiotrophia spp.

Members of the genus Abiotrophia, formerly known as nutritionally variant streptococci, are important pathogens causing septicemia and endocarditis. Cultivation and biochemical differentiation of Abiotrophia spp. are often difficult. Based on 16S rRNA sequences, two PCR assays for detection and identification of Abiotrophia spp. were developed. The first PCR assay was positive for all Abiotrophia spp. Subsequently performed restriction fragment length polymorphism analysis allowed the verification of the PCR amplicons and the differentiation of the three species. The second PCR assay was positive only for A. elegans, the most fastidious species of Abiotrophia. Both PCR assays were shown to be specific and sensitive and should facilitate the identification of Abiotrophia spp.

Bacteremia↗
PubMed1999

Coreceptor specificity of temporal variants of simian immunodeficiency virus Mne.

The simian immunodeficiency virus (SIV) Mne envelope undergoes genetic changes that alter tropism, syncytium-inducing capacity, and antigenic properties of the emerging variant virus population during the course of an infection. Here we investigated whether the mutations in envelope of SIVMne also influence coreceptor usage. The data demonstrate that the infecting macrophage-tropic SIVMne clone as well as the envelope variants that are selected during the course of disease progression all recognize both CCR5 and Bob (GPR15) but not Bonzo (STRL33), CXCR4, or CCR3. Although it remains to be determined if there are other coreceptors specific for dualtropic or T-cell-tropic variants of SIVMne that emerge during late stages of infection, these data suggest that such SIV variants that evolve in pathogenic infections do not lose the ability to recognize CCR5 or Bob/GPR15.

Amino Acid Sequence↗
PubMed2006

Systemic immunization with an ALVAC-HIV-1/protein boost vaccine strategy protects rhesus macaques from CD4+ T-cell loss and reduces both systemic and mucosal simian-human immunodeficiency virus SHIVKU2 RNA levels.

Transmission of human immunodeficiency virus type 1 (HIV-1) occurs primarily via the mucosal route, suggesting that HIV-1 vaccines may need to elicit mucosal immune responses. Here, we investigated the immunogenicity and relative efficacy of systemic immunization with two human ALVAC-HIV-1 recombinant vaccines expressing Gag, Pol, and gp120 (vCP250) or Gag, Pol, and gp160 (vCP1420) in a prime-boost protocol with their homologous vaccine native Env proteins. The relative efficacy was measured against a high-dose mucosal exposure to the pathogenic neutralization-resistant variant SHIV(KU2) (simian-human immunodeficiency virus). Systemic immunization with both vaccine regimens decreased viral load levels not only in blood but unexpectedly also in mucosal sites and protected macaques from peripheral CD4+ T-cell loss. This protective effect was stronger when the gp120 antigen was included in the vaccine. Inclusion of recombinant Tat protein in the boosting phase along with the Env protein did not contribute further to the preservation of CD4+ T cells. Thus, systemic immunization with ALVAC-HIV-1 vaccine candidates elicits anti-HIV-1 immune responses able to contain virus replication also at mucosal sites in macaques.

AIDS Vaccines↗
PubMed1990

Effects of translocations on transcription from PVT.

We have previously described a transcription unit on human chromosome 8, designated as PVT, that is consistently disrupted by the minority forms of translocations [t(2;8) and t(8;22)] in Burkitt's lymphoma. PVT begins 57 kilobase pairs downstream of the proto-oncogene MYC and is more than 200 kilobase pairs in length. In order to explore the pathogenic impact of translocations affecting PVT, we have characterized further the structure and transcription of the locus. In normal cells, PVT is transcribed into a variety of RNAs, the diversity of which remains unexplained. Alleles of PVT affected by translocations give rise to additional RNAs. These RNAs arise from a fusion of the first exon of PVT on chromosome 8 to the constant region of an immunoglobulin light chain on either chromosome 2 or chromosome 22. We have found no evidence that any of the normal or abnormal transcripts of PVT give rise to a protein. Our results suggest that the pathogenic effects of the variant translocations in Burkitt's lymphoma are not executed by a gene situated in a vicinity of the chromosomal breakpoints. Instead, our data leave open the possibility that the effects of the translocations may be mediated by activation of the relatively distant MYC gene.

Base Sequence↗
PubMed2005

ETHE1 mutations are specific to ethylmalonic encephalopathy.

Mutations in ETHE1, a gene located at chromosome 19q13, have recently been identified in patients affected by ethylmalonic encephalopathy (EE). EE is a devastating infantile metabolic disorder, characterised by widespread lesions in the brain, hyperlactic acidaemia, petechiae, orthostatic acrocyanosis, and high levels of ethylmalonic acid in body fluids. To investigate to what extent ETHE1 is responsible for EE, we analysed this gene in 29 patients with typical EE and in 11 patients presenting with early onset progressive encephalopathy with ethylmalonic aciduria (non-EE EMA). Frameshift, stop, splice site, and missense mutations of ETHE1 were detected in all the typical EE patients analysed. Western blot analysis of the ETHE1 protein indicated that some of the missense mutations are associated with the presence of the protein, suggesting that the corresponding wild type amino acid residues have a catalytic function. No ETHE1 mutations were identified in non-EE EMA patients. Experiments based on two dimensional blue native electrophoresis indicated that ETHE1 protein works as a supramolecular, presumably homodimeric, complex, and a three dimensional model of the protein suggests that it is likely to be a mitochondrial matrix thioesterase acting on a still unknown substrate. Finally, the 625G-->A single nucleotide polymorphism in the gene encoding the short chain acyl-coenzyme A dehydrogenase (SCAD) was previously proposed as a co-factor in the aetiology of EE and other EMA syndromes. SNP analysis in our patients ruled out a pathogenic role of SCAD variants in EE, but did show a highly significant prevalence of the 625A alleles in non-EE EMA patients.

Alleles↗
PubMed2000

Detection of human herpesvirus 6 variant A in peripheral blood mononuclear cells from multiple sclerosis patients.

Several authors report that human herpesvirus 6 (HHV-6) variants have different epidemiologies, in vivo tropism and pathogenic potentials. However, it is not well known what pathogenic roles its neurotropism might have in the variant type. As some active plaques of multiple sclerosis (MS) brain tissue harbor HHV-6 DNA divergent from the prototype virus, the possibility that the variant strain may play a role in the pathogenesis of MS has been suggested. Therefore, we tried to investigate the role of HHV-6 variants in the pathogenesis of MS. As HHV-6 is predominantly a T-cell-tropic virus, we examined HHV-6 DNA sequences in peripheral blood mononuclear cells (PBMC) from 34 MS patients, 6 with idiopathic transverse myelitis, 2 with optic neuritis and 20 healthy controls. Nested polymerase chain reaction was used to detect the HHV-6 genome. To discern HHV-6 variants A and B, amplification products were digested by restriction enzyme. We found that 7 of 34 MS patients and 2 of 6 patients with idiopathic transverse myelitis had the HHV-6 genome. On the contrary, there was no HHV-6 genome in the control group. All genomic sequences were of HHV-6 variant A (HHV-6A). Our results suggest that the detection of HHV-6A in the PBMC of patients with MS may raise the possibility of a relationship between latent HHV-6A infection and the pathogenesis of MS.

Adolescent↗