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Principal Investigator: Thomas R Hawn
Organization: UNIVERSITY OF WASHINGTON
Fiscal Year: 2022
Award: $176,343
Funding agency: National Institute of Allergy and Infectious Diseases
Despite the discovery of Mycobacterium tuberculosis (Mtb) over 100 years ago and the availability of
effective drugs for over 60 years, there remain formidable hurdles for controlling tuberculosis (TB) disease
including the lack of a highly efficacious vaccine, long drug treatment regimens, prevention of infection, and
killing dormant bacilli within macrophages. After close contact with a person with pulmonary TB, most people
develop latent Mtb infection (LTBI). However, some individuals are naturally resistant to infection (RSTRs).
The mechanisms of resistance are unknown and may provide insight into novel therapeutic strategies. In a
large TB household contact study in urban Uganda over the past 20 years, we found that ~9% of close adult
household contacts remained persistently TST and Interferon-gamma Release Assay (IGRA) negative during
extended follow-up. To our knowledge, this large Ugandan cohort is unique with rigorous longitudinal clinical
and epidemiologic data. Using genome-wide profiling of mRNA isolated from Mtb-infected peripheral blood-
derived monocytes, we compared transcriptional signatures in the RSTR and LTBI groups. We found that the
histone deacetylase (HDAC) gene family distinguishes RSTRs from LTBIs and may regulate resistance to Mtb
infection. HDACs regulate transcription and some family members mediate the innate immune response to
microbes. We also found polymorphisms in HDAC1 that are associated with resistance to infection. In
peripheral blood monocyte-derived and alveolar macrophages, HDAC inhibitor treatment decreased Mtb
replication in comparison to untreated cells. These findings support the concept that RSTRs have protective
innate immune responses that are monocyte-dependent. However, several critical questions need to be
addressed including elucidation of the molecular and genetic mechanisms of HDAC-mediated control of Mtb
replication in macrophages and clinical resistance to Mtb infection. In addition, the role of alveolar
macrophages in regulating HDAC-mediated immune responses is poorly understood. We hypothesize that
HDACs mediate resistance to infection by inhibiting Mtb replication through transcriptional regulation of anti-
microbial pathways. Characterization of HDAC-dependent immune responses will enable identification of
natural resistance mechanisms to Mtb infection. The latter will provide new insight into our understanding of
TB pathogenesis, point to novel approaches to TB vaccine and drug development, and identify biomarkers of
resistance to and/or clearance of Mtb infection. The research aims will be integrated with a mentoring strategy
for mentees that fosters development of patient-oriented research with a pathway to independence.
Terms: <21+ years old><Active Follow-up><Address><Adult><Adult Human><Alveolar Macrophages><Assay><Autoregulation><Bacillus><Bioassay><Biologic Assays><Biological Assay><Biological Markers><Biology><Blood monocyte><Cell Body><Cells><Clinical><Clinical Data><Data><Development><Disease><Disorder><Drug Therapy><Drugs><Environment><Enzyme Gene><Enzymes><Epidemiological data><Epidemiology data><Expression Signature><Faculty><Family><Family member><Fostering><Gamma interferon><Gene Expression><Gene Expression Profile><Gene Family><Gene Transcription><Gene variant><Genetic Polymorphism><Genetic Transcription><Goals><HD1><HDAC><HDAC Agent><HDAC Proteins><HDAC inhibitor><HDAC1><HDAC1 gene><Histone Deacetylase><Histone Deacetylase 1><Histone Deacetylase Inhibitor><Histone deacetylase inhibition><Homeostasis><Host resistance><Household><Human><Human Genetics><IFN-Gamma><IFN-g><IFN-γ><IFNG><IFNγ><Immune Interferon><Immune Modulation Therapy><Immune response><Immunity><Immunological response><Individual><Infection><Infection prevention><Innate Immune Response><Innate Immunity><Interferon Gamma><Interferon Type II><Interferon-gamma><Laboratories><Lead><Lung><Lung Respiratory System><Lung TB><Lung Tuberculosis><M tb><M tuberculosis><M tuberculosis infection><M. tb><M. tb infection><M. tuberculosis><M. tuberculosis infection><M.tb infection><M.tuberculosis infection><MTB infection><MTB vaccine><Marrow monocyte><Mediating><Medication><Mentors><Messenger RNA><Microbe><Modern Man><Molecular Genetics><Mycobacterium tuberculosis><Mycobacterium tuberculosis (MTB) infection><Mycobacterium tuberculosis infection><Mφ><Native Immunity><Natural Immunity><Natural Resistance><Non-Specific Immunity><Nonspecific Immunity><Pathogenesis><Pathway interactions><Pb element><Persons><Pharmaceutic Preparations><Pharmaceutical Preparations><Pharmacotherapy><Phenotype><Physicians><Physiological Homeostasis><Postdoc><Postdoctoral Fellow><Predisposition><Prevent infection><Property><Pulmonary Macrophages><Pulmonary TB><Pulmonary Tuberculosis><RNA Expression><RPD3-Like 1><RPD3L1><Reduced Potassium Dependency 3, Yeast, Homolog-Like 1><Research><Research Associate><Research Design><Research Resources><Resistance><Resistance to infection><Resources><Role><Scientist><Study Type><Susceptibility><TB infection><TB vaccine><Transcription><Transcription Regulation><Transcriptional Control><Transcriptional Regulation><Treatment Protocols><Treatment Regimen><Treatment Schedule><Tuberculosis><Tuberculosis Vaccines><Uganda><Vaccine for TB><Vaccine for Tuberculosis><Vaccines><Variant><Variation><active followup><adulthood><allele variant><allelic variant><anti-TB vaccine><anti-microbial><anti-microbial peptide><antimicrobial><antimicrobial peptide><bio-markers><biologic marker><biomarker><career><cathelicidin><cohort><develop a vaccine><develop vaccines><development of a vaccine><developmental><disseminated TB><disseminated tuberculosis><drug development><drug treatment><drug/agent><epidemiologic data><follow up><follow-up><followed up><followup><gene expression pattern><gene expression signature><genetic variant><genome scale><genome-wide><genomewide><genomic variant><heavy metal Pb><heavy metal lead><host response><immune modulating therapies><immune modulatory therapies><immune system response><immune-modulation treatment><immunomodulation therapy><immunomodulation treatment><immunomodulatory therapies><immunomodulatory therapy><immunomodulatory treatment><immunoresponse><infection due to Mycobacterium tuberculosis><infection resistance><insight><knock-down><knockdown><lFN-Gamma><latent infection><mRNA><macrophage><monocyte><mtb><naturally resistant><new approaches><new therapeutic approach><new therapeutic intervention><new therapeutic strategies><new therapy approaches><new vaccines><next generation vaccines><novel approaches><novel strategies><novel strategy><novel therapeutic approach><novel therapeutic intervention><novel therapeutic strategies><novel therapy approach><novel vaccines><pathway><patient oriented research><patient oriented study><peripheral blood><polymorphism><post-doc><post-doctoral><pulmonary><resistance mechanism><resistant><resistant mechanism><response><shRNA><short hairpin RNA><small hairpin RNA><small molecule><social role><study design><transcriptional profile><transcriptional signature><treatment strategy><tuberculosis infection><tuberculous spondyloarthropathy><vaccine development>