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Principal Investigator: BRUNO DE BEZERRIL ANDRADE
Organization: VANDERBILT UNIVERSITY MEDICAL CENTER
Fiscal Year: 2019
Award: $726,648
Funding agency: National Institute of Allergy and Infectious Diseases
PROJECT SUMMARY
Recent studies from our group have reported a peripheral blood correlate of risk (COR) transcriptional
signature that identified individuals with incipient (asymptomatic) TB who progressed to active (symptomatic)
TB disease within 12 months. We have also identified human genetic polymorphisms in a DNA sensor gene
region (PYHIN1-IFI16-AIM2) associated with TB risk in Brazilian close TB contacts. Both the COR and
PYHIN1-IFI16-AIM2 include interferon stimulated genes (ISGs). We hypothesize that there are immunogenetic
pathophysiologic factors associated with incipient TB and progression to active TB. To address this question,
we will evaluate innate immune responses in macrophages and their correlates with human genetic
polymorphisms, acquired immunity to M. tuberculosis (Mtb), and epidemiologic factors associated with the risk
of incipient and active TB. These studies will be performed in the Regional Prospective Observational
Research in Tuberculosis (RePORT)-Brazil cohort, which includes culture-confirmed TB cases and their close
contacts in racially and ethnically diverse Brazil. Close contacts are followed for 2 years to identify
development of TB disease; most persons do not receive or complete preventive therapy, so 40 new culture-
confirmed TB cases are expected among 2,000 close contacts, ~45% of whom will be infected with Mtb.
Epidemiologic and clinical data, peripheral blood mononuclear cells (PBMC), RNA from whole blood
(PAXgene), and genomic DNA are available from all close contacts at baseline, 6 months, and at TB
diagnosis. Identification of these immunogenetic risk factors (including HIV) will illuminate host pathways
associated with both a) immunity to Mtb, which could be translated into host-directed and vaccine therapies,
and b) progression to TB—to identify persons who would benefit from TB preventive therapy.
Terms: <AIDS Virus><ATGN><Acquired Immune Deficiency Syndrome Virus><Acquired Immunodeficiency Syndrome Virus><Active Follow-up><Address><Africa><Anti-HIV Positivity><Antigens><BCG Vaccine><BCG immunization><BCG treatment><BCG vaccination><BCG-vaccinated><Bacille Calmette Guerin vaccine><Bacille Calmette-Guerin vaccinated><Bacille Calmette-Guerin vaccination><Bacillus Calmette Guerin Vaccine><Bacillus Calmette-Guerin vaccination><Bacillus Calmette-Guérin vaccination><Bacillus Calmette-Guérin vaccine><Brazil><CD4 Cells><CD4 Positive T Lymphocytes><CD4 T cells><CD4 helper T cell><CD4 lymphocyte><CD4+ T-Lymphocyte><CD4-Positive Lymphocytes><Cell Body><Cell Function><Cell Process><Cell physiology><Cells><Cellular Function><Cellular Physiology><Cellular Process><Clinical Data><DNA><Data><Deoxyribonucleic Acid><Development><Diagnosis><Disease><Disease Progression><Disorder><Enrollment><Epidemiologic Determinants><Epidemiologic Factors><Epidemiological Factors><Epidemiological data><Epidemiology><Epidemiology data><Expression Signature><Future><Gene Components><Gene Expression><Gene Expression Profile><Gene Transcription><Gene variant><Generalized Growth><Genes><Genetic><Genetic Polymorphism><Genetic Transcription><Genomic DNA><Goals><Growth><HIV><HIV Positive><HIV Positivity><HIV Seroconversion><HIV Seronegativities><HIV Seronegativity><HIV Seropositivity><HIV antibody positive><HIV negative><HTLV-III Seroconversion><HTLV-III Seronegativities><HTLV-III Seronegativity><HTLV-III Seropositivity><Human Genetics><Human Immunodeficiency Viruses><IFN><Immune><Immunes><Immunity><Immunochemical Immunologic><Immunogenetics><Immunologic><Immunologic Factors><Immunological><Immunological Factors><Immunologically><Immunologics><Individual><Infection><Innate Immune Response><Interferons><Knowledge><LAV-HTLV-III><Lymphadenopathy-Associated Virus><Lymphocyte Function><M tb><M tuberculosis><M tuberculosis infection><M. tb><M. tb infection><M. tuberculosis><M. tuberculosis infection><M.tb><M.tb infection><M.tuberculosis><M.tuberculosis infection><MHC Receptor><MTB infection><Major Histocompatibility Complex Receptor><Messenger RNA><Modeling><Mycobacterium tuberculosis><Mycobacterium tuberculosis (MTB) infection><Mycobacterium tuberculosis infection><Myeloid Cells><Non-Polyadenylated RNA><Observation in research><PBMC><Pathway interactions><Patients><Performance><Peripheral Blood Mononuclear Cell><Persons><Predisposing Factor><Predisposition><Preventative therapy><Preventive therapy><Prospective Studies><RNA><RNA Expression><RNA Gene Products><Receptors, Antigen, T-Cell><Reporting><Research Design><Ribonucleic Acid><Risk><Risk Factors><Study Type><Subcellular Process><Susceptibility><T cell response><T-Cell Receptor><T-Cells><T-Lymphocyte><T-cell receptor repertoire><T4 Cells><T4 Lymphocytes><TB infection><TCR repertoire><Tissue Growth><Transcription><Translating><Tuberculosis><VAC-TX><Vaccine Therapy><Vaccines><Variant><Variation><Virus-HIV><Whole Blood><acquired immunity><active followup><allele variant><allelic variant><analysis pipeline><anti-microbial><antigen-specific T cells><antimicrobial><cell type><cohort><computer based prediction><developmental><discover genes><disseminated TB><disseminated tuberculosis><enroll><epidemiologic><epidemiologic data><epidemiological><ethnic diversity><ethnically diverse><follow up><follow-up><followed up><followup><gDNA><gene discovery><gene expression pattern><gene expression signature><gene function><genetic variant><genomic variant><immunogen><immunologic substance><immunological substance><improved><infection due to Mycobacterium tuberculosis><intravesical BCG><mRNA><macrophage><mtb><ontogeny><pathogen><pathway><peripheral blood><polymorphism><prediction model><predictive modeling><prevent><preventing><prognostic model><prospective><protective factors><racial and ethnic><racial diversity><racially diverse><response><sensor><single cell analysis><study design><therapeutic vaccination><thymus derived lymphocyte><transcriptional signature><transcriptomics><tuberculosis infection><tuberculous spondyloarthropathy>