Cellular immune response to Mycobacterium tuberculosis-speciWc antigen culture Wltrate protein-10 in south India

The Mycobacterium tuberculosis (M. tuberculosis)- speciWc culture Wltrate protein-10 (CFP-10) is highly recognized by M. tuberculosis infected subjects. In the present study, the proliferative response and IFN-� secretion was found for C-terminal peptides of the protein (Cfp651–70, Cfp761–80, Cfp871–90, and Cfp981–100). The alleles HLA DRB1 *04 and HLA DRB1 *10 recognized the C-terminal peptides Cfp7, Cfp8, and Cfp9 in HHC. Cfp6 was predominantly recognized by the alleles HLA DRB1 *03 and HLA DRB1 *15 by PTB. The minimal nonameric epitopes from the C-terminal region were CFP-1056–64 and CFP-1076–84. These two peptides deserve attention for inclusion in a vaccine against tuberculosis in this region

Immune response to Mycobacterium tuberculosis specific antigen ESAT-6 among south Indians

The 6-kDa early secreted antigenic target (ESAT-6) is a T-cell antigen recognized by individuals infected with Mycobacterium tuberculosis. The aim of the study was to identify ‘‘protective epitopes’’ of ESAT-6 protein in the south Indian population. Proliferative and Interferon gamma (IFN-g) responses to ESAT-6 peptides were studied by flow cytometry and Enzyme linked immunosorbent assay (ELISA). Healthy household contacts (HHC) recognized Esp1 (10/17) and Esp6 (9/17) peptides. Among pulmonary tuberculosis patients (PTB), Esp1 (3/11) and Esp6 (5/11) were recognized. Maximal response (7/10) was found for Esp1 and Esp8 in treated patients (TR). Median values for the responding subjects gave the following results: Esp1 (76 pg/ml), Esp6 (64 pg/ml), induced IFN-g production in HHC; PTB gave low IFN-g responses for the peptides. TR responded to the peptides Esp1 (141 pg/ml), Esp8 (102 pg/ml). The proliferation of CD4 cells was similar in both PTB and TR for all peptides; but HHC showed an increase for Esp1 (p < 0.05) and Esp6 (p < 0.01). Esp1 (amino acids aa 1–20) and Esp6 (aa 51–70) were the immunogenic peptides recognized by the alleles HLA DRB1*04 and HLA DRB1*10 among HHC. But the association of the alleles with ESAT-6 peptide presentation needs to be confirmed in a large cohort of subjects. We speculate that ESAT-6 can be used along with other immune-eliciting proteins for vaccine design strategies in south Indian population

Prenatal phenotyping: A community effort to enhance the Human Phenotype Ontology

Technological advances in both genome sequencing and prenatal imaging are increasing our ability to accurately recognize and diagnose Mendelian conditions prenatally. Phenotype-driven early genetic diagnosis of fetal genetic disease can help to strategize treatment options and clinical preventive measures during the perinatal period, to plan in utero therapies, and to inform parental decision-making. Fetal phenotypes of genetic diseases are often unique and at present are not well understood; more comprehensive knowledge about prenatal phenotypes and computational resources have an enormous potential to improve diagnostics and translational research. The Human Phenotype Ontology (HPO) has been widely used to support diagnostics and translational research in human genetics. To better support prenatal usage, the HPO consortium conducted a series of workshops with a group of domain experts in a variety of medical specialties, diagnostic techniques, as well as diseases and phenotypes related to prenatal medicine, including perinatal pathology, musculoskeletal anomalies, neurology, medical genetics, hydrops fetalis, craniofacial malformations, cardiology, neonatal-perinatal medicine, fetal medicine, placental pathology, prenatal imaging, and bioinformatics. We expanded the representation of prenatal phenotypes in HPO by adding 95 new phenotype terms under the Abnormality of prenatal development or birth (HP:0001197) grouping term, and revised definitions, synonyms, and disease annotations for most of the 152 terms that existed before the beginning of this effort. The expansion of prenatal phenotypes in HPO will support phenotype-driven prenatal exome and genome sequencing for precision genetic diagnostics of rare diseases to support prenatal care

Prenatal phenotyping: A community effort to enhance the Human Phenotype Ontology.

Technological advances in both genome sequencing and prenatal imaging are increasing our ability to accurately recognize and diagnose Mendelian conditions prenatally. Phenotype-driven early genetic diagnosis of fetal genetic disease can help to strategize treatment options and clinical preventive measures during the perinatal period, to plan in utero therapies, and to inform parental decision-making. Fetal phenotypes of genetic diseases are often unique and at present are not well understood; more comprehensive knowledge about prenatal phenotypes and computational resources have an enormous potential to improve diagnostics and translational research. The Human Phenotype Ontology (HPO) has been widely used to support diagnostics and translational research in human genetics. To better support prenatal usage, the HPO consortium conducted a series of workshops with a group of domain experts in a variety of medical specialties, diagnostic techniques, as well as diseases and phenotypes related to prenatal medicine, including perinatal pathology, musculoskeletal anomalies, neurology, medical genetics, hydrops fetalis, craniofacial malformations, cardiology, neonatal-perinatal medicine, fetal medicine, placental pathology, prenatal imaging, and bioinformatics. We expanded the representation of prenatal phenotypes in HPO by adding 95 new phenotype terms under the Abnormality of prenatal development or birth (HP:0001197) grouping term, and revised definitions, synonyms, and disease annotations for most of the 152 terms that existed before the beginning of this effort. The expansion of prenatal phenotypes in HPO will support phenotype-driven prenatal exome and genome sequencing for precision genetic diagnostics of rare diseases to support prenatal care

The Human Phenotype Ontology in 2024: phenotypes around the world

\ua9 The Author(s) 2023. Published by Oxford University Press on behalf of Nucleic Acids Research. The Human Phenotype Ontology (HPO) is a widely used resource that comprehensively organizes and defines the phenotypic features of human disease, enabling computational inference and supporting genomic and phenotypic analyses through semantic similarity and machine learning algorithms. The HPO has widespread applications in clinical diagnostics and translational research, including genomic diagnostics, gene-disease discovery, and cohort analytics. In recent years, groups around the world have developed translations of the HPO from English to other languages, and the HPO browser has been internationalized, allowing users to view HPO term labels and in many cases synonyms and definitions in ten languages in addition to English. Since our last report, a total of 2239 new HPO terms and 49235 new HPO annotations were developed, many in collaboration with external groups in the fields of psychiatry, arthrogryposis, immunology and cardiology. The Medical Action Ontology (MAxO) is a new effort to model treatments and other measures taken for clinical management. Finally, the HPO consortium is contributing to efforts to integrate the HPO and the GA4GH Phenopacket Schema into electronic health records (EHRs) with the goal of more standardized and computable integration of rare disease data in EHRs

The Human Phenotype Ontology in 2024: phenotypes around the world.

The Human Phenotype Ontology (HPO) is a widely used resource that comprehensively organizes and defines the phenotypic features of human disease, enabling computational inference and supporting genomic and phenotypic analyses through semantic similarity and machine learning algorithms. The HPO has widespread applications in clinical diagnostics and translational research, including genomic diagnostics, gene-disease discovery, and cohort analytics. In recent years, groups around the world have developed translations of the HPO from English to other languages, and the HPO browser has been internationalized, allowing users to view HPO term labels and in many cases synonyms and definitions in ten languages in addition to English. Since our last report, a total of 2239 new HPO terms and 49235 new HPO annotations were developed, many in collaboration with external groups in the fields of psychiatry, arthrogryposis, immunology and cardiology. The Medical Action Ontology (MAxO) is a new effort to model treatments and other measures taken for clinical management. Finally, the HPO consortium is contributing to efforts to integrate the HPO and the GA4GH Phenopacket Schema into electronic health records (EHRs) with the goal of more standardized and computable integration of rare disease data in EHRs

Immunological and proteomic analysis of preparative isoelectric focusing separated culture filtrate antigens of Mycobacterium tuberculosis

Isolation of the secreted proteins and studying the immune response they induce is an essential prerequisite for understanding the pathogenesis of M. tuberculosis. In this study, preparative liquid-phase isoelectric focusing was used for the separation of culture filtrate protein (CFP) of M. tuberculosis. This procedure resolved culture filtrate proteins into 20 fractions with a pI range of 2.59 to 12.9. These 20 fractions were subjected to immunological analysis in healthy laboratory volunteers from our endemic area. Eleven fractions (Fractions 5, 6, 7, 8, 9, 10, 11, 13, 15, 16, and 19) showed increased interferon gamma (IFN-γ) secretion and 5 fractions induced increased proliferative response, when compared to unfractionated CFP. In the 11 fractions which showed increased IFN-γ secretion, mass spectrometric analysis identified 19 different proteins. Apart from the already reported immunodominant antigens like FbpB, CFP-10 and ESAT-6, two new T cell antigens (AcpM and PpiA) were also identified in the immunologically active fractions. Immunoinformatic analysis showed that PpiA was predicted to bind more number of class I and class II HLA alleles compared with the immunodominant ESAT-6 and CFP-10. Population coverage calculations also showed that PpiA protein (85%) had a higher population coverage compared with ESAT-6 (79%) and CFP-10 (77%). This result shows that the PpiA protein has a potential to be a novel T cell antigen

Molecular docking of azole drugs and their analogs on CYP121 of Mycobacterium tuberculosis

The Mycobacterium tuberculosis genome codes for 20 different cytochromes. These cytochromes are involved in the breakdown of recalcitrant pollutants and the synthesis of polyketide antibiotics and other complex macromolecules. It has been demonstrated that CYP121 is essential for viability of the bacterium by gene knock-out and complementation studies. CYP121 could therefore be a probable target for the development of new drugs for TB. It has been widely reported that orthologs of CYP121 in fungi are inhibited by azole drugs. We evaluated whether these azole drugs or their structural analogs could bind to and inhibit CYP121 of M. tuberculosis using molecular docking. Six molecules with known anti-CYP121 activity were selected from literature and PubChem database was searched to identify structural analogs for these inhibitors. Three hundred and fifty seven molecules were identified as structural analogs and used in docking studies. Fifty three molecules were found to be scored better than the azole drugs and five of them were ranked among the top 12 molecules by two different scoring functions. These molecules may be further tested by in vitro experimentation for their activity against CYP121 of M. tuberculosis

Informatics resources for tuberculosis e Towards drug discovery

Integration of biological data on gene sequence, genome annotation, gene expression, metabolic pathways, protein structure, drug target prioritization and selection, has resulted in several online bioinformatics databases and tools for Mycobacterium tuberculosis. Alongside there has been a growth in the list of cheminformatics databases for small molecules and tools to facilitate drug discovery. In spite of these efforts there is a noticeable lag in the drug discovery process which is an urgent need in the case of emerging and re-emerging infectious diseases. For example, more than 25 online databases are available freely for tuberculosis and yet these resources have not been exploited optimally. Informatics-centered drug discovery based on the integration and analysis of both bioinformatics and cheminformatics data could fill in the gap and help to accelerate the process of drug discovery. This article aims to review the current standing of developments in tuberculosis-bioinformatics and highlight areas where integration of existing resources could lead to acceleration of drug discovery against tuberculosis. Such an approach could be adapted for other diseases as well

The 1D4 antibody labels outer segments of long double cone but not rod photoreceptors in zebrafish

10.1167/iovs.12-9511Investigative Ophthalmology and Visual Science5384943-4951IOVS