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Principal Investigator: Javeed Ali Shah
Organization: UNIVERSITY OF WASHINGTON
Fiscal Year: 2024
Award: $200,075
Funding agency: National Institute of Allergy and Infectious Diseases
Project Summary/Abstract. Over one million people died from tuberculosis in 2021. Current treatments are
long, costly, and often induce severe adverse effects, but the current vaccine has not been improved in over 100
years. Improved understanding of the host factors that influence Mtb pathogenesis in the lung may dramatically
improve control and transmission of Mtb between individuals. Before entering the alveolar macrophage, Mtb
encounters respiratory mucins. Mucins are glycosylated macromolecules that encompass the first line of defense
against pathogens. Respiratory mucins MUC5B and MUC5AC protect the lung from pathogens via mucociliary
clearance, directly inhibiting antimicrobial growth, and altering macrophage signaling. However, little is known
about how these macromolecules influence Mtb susceptibility and severity. In this pilot grant, we will evaluate
how respiratory mucins impact Mtb pathogenesis using human genetic studies, combined with interrogation of
their mechanism of action via small animal models recapitulating Muc5b or Muc5ac insufficiency, deficiency, or
overexpression. Our long-term goal is to identify strategies for effective Mtb killing within the lung and improve
mucosal delivery of relevant candidate Mtb vaccines. The objective of this grant is to characterize the
mechanisms by which MUC5B and MUC5AC, the two commonest respiratory mucins, influence Mtb
susceptibility and severity in human populations. The rationale for this study is that respiratory mucins are
essential for mucociliary clearance, support a host of extracellular antimicrobial peptides and proteins in the lung,
and coats pathogens to alter their pathogenicity in the lung. Our preliminary data demonstrates that common
genetic variants in the MUC5B promoter region are associated with pulmonary TB and MUC5B mRNA
expression in the lung, while variation in the MUC5AC gene region is associated with TB meningitis mortality
and MUC5AC mRNA expression. The central hypothesis is that MUC5B and MUC5AC are physical barriers to
infection and also modulate macrophage function and systemic immune homeostasis to worsen TB disease
severity. In this grant, we will test this hypothesis by achieving the following specific aims: 1) We will define the
functional SNPs that regulate MUC5B and MUC5AC gene expression in the lung, systemic immune responses
to TB meningitis, and susceptibility to and severity of TB in a Vietnamese cohort. 2) We will determine the
mechanism by which Muc5b and Muc5ac deficiency, knockout, and overexpression influence clinical and
immune responses to Mtb using genetically modified mice infected with Mtb. This contribution is significant
because mucins represent the first line of defense against Mtb infection, but their role in Mtb pathogenesis is
unknown. The proposed work is innovative because we will investigate the mechanisms and effects of a known
TB susceptibility gene using innovative mouse models of disease, combined with the genetic cohorts of TB
susceptibility. These studies will provide evidence that Mtb host defense begins prior to macrophage infection
and provide clues toward the role of the immune microenvironment on Mtb outcomes.
Terms: <(TNF)-α><Adverse effects><Alveolar><Alveolar Macrophages><Animal Model><Animal Models and Related Studies><Autoregulation><Bacterial Infections><Bacterial Pneumonia><Biology><Body Tissues><CTLA-8><CTLA-8 Gene><CTLA8><CTLA8 Gene><Cachectin><Cause of Death><Cell Communication and Signaling><Cell Signaling><Characteristics><Clinical><Complement><Complement Proteins><Complex><Cytotoxic T-Lymphocyte-Associated Antigen 8><Cytotoxic T-Lymphocyte-Associated Antigen 8 Gene><Cytotoxic T-Lymphocyte-Associated Serine Esterase 8><Cytotoxic T-Lymphocyte-Associated Serine Esterase 8 Gene><Data><Development><Diathesis><Disease><Disease susceptibility><Disorder><Dissection><Dysfunction><Environment><Functional disorder><Future><Gene Expression><Gene Modified><Gene variant><Generalized Growth><Genetic><Genetic Diversity><Genetic Polymorphism><Genetic Variation><Genetic study><Goals><Grant><Growth><Homeostasis><Host Defense><Host Factor><Host Factor Protein><Human><Human Genetics><IL-13><IL-17><IL-17 Gene><IL-17A><IL-17A Gene><IL-23><IL13><IL17><IL17 Protein><IL17 gene><IL17A><IL17A Gene><Immune><Immune Cell Activation><Immune response><Immunes><Immunological response><Impairment><Individual><Infection><Inflammation><Inflammatory Response><Innate Immune Response><Integration Host Factors><Interleukin 17 (Cytotoxic T-Lymphocyte-Associated Serine Esterase 8)><Interleukin 17 (Cytotoxic T-Lymphocyte-Associated Serine Esterase 8) Gene><Interleukin 17 Precursor><Interleukin 17 Precursor Gene><Interleukin-13><Interleukin-17><Intracellular Communication and Signaling><Investigation><Knock-out><Knockout><Knowledge><Lung><Lung Diseases><Lung Parenchyma><Lung Respiratory System><Lung TB><Lung Tissue><Lung Tissue Fibrosis><Lung Tuberculosis><M protein><M tb><M tuberculosis><M tuberculosis infection><M. tb><M. tb infection><M. tuberculosis><M. tuberculosis infection><M.tb infection><M.tuberculosis infection><MG1><MTB infection><MTB vaccine><MUC5AC><MUC5AC gene><MUC5B><MUC5B gene><Macrophage><Macrophage-Derived TNF><Maps><Measures><Meningeal TB><Meningeal Tuberculosis><Metabolic Glycosylation><Mice><Mice Mammals><Modern Man><Monocyte-Derived TNF><Mucins><Mucociliary Clearance><Mucociliary Transport><Mucosa><Mucosal Tissue><Mucous Membrane><Mucus Glycoprotein><Murine><Mus><Mycobacterium tuberculosis><Mycobacterium tuberculosis (MTB) infection><Mycobacterium tuberculosis infection><Mφ><Organism><Outcome><Pathogenesis><Pathogenicity><Pathologic><Pathology><Persons><Phenotype><Physiological Homeostasis><Physiopathology><Play><Population><Predisposition><Predisposition gene><Promoter Regions><Promotor Regions><Proteins><Pulmonary Diseases><Pulmonary Disorder><Pulmonary Fibrosis><Pulmonary Macrophages><Pulmonary Pathology><Pulmonary TB><Pulmonary Tuberculosis><Respiratory Mucin><Role><Sampling><Severities><Severity of illness><Shapes><Signal Transduction><Signal Transduction Systems><Signaling><Specificity><Structure of parenchyma of lung><Susceptibility><Susceptibility Gene><Symptoms><TB infection><TB meningitis><TB vaccine><TNF><TNF A><TNF Alpha><TNF gene><TNF-α><TNFA><TNFα><Testing><Therapeutic><Tissue Growth><Tissues><Transmission><Tuberculosis><Tuberculosis Meningitis><Tuberculosis Vaccines><Tuberculous Meningitis><Tumor Necrosis Factor><Tumor Necrosis Factor-alpha><Vaccine for TB><Vaccine for Tuberculosis><Vaccines><Variant><Variation><Viet Nam><Vietnam><Vietnamese><Viral><Work><adaptive immune response><allele variant><allelic variant><anti-TB vaccine><anti-microbial><anti-microbial peptide><antimicrobial><bacteria infection><bacteria pneumonia><bacterial disease><biobank><biological signal transduction><biorepository><cohort><complementation><cost><cytokine><developmental><disease model><disease of the lung><disease severity><disorder model><disorder of the lung><disseminated TB><disseminated tuberculosis><extracellular><fibrosis in the lung><gene modification><genetic promoter element><genetic promoter sequence><genetic variant><genetically modified><genomic variant><glycosylation><host response><immune activation><immune microenvironment><immune system response><immunoresponse><immunosuppressive microenvironment><immunosuppressive tumor microenvironment><improved><in vivo><infection due to Mycobacterium tuberculosis><innovate><innovation><innovative><interest><interleukin-23><liability to disease><living system><lung disorder><lung fibrosis><lung pathogen><lung pathology><mRNA Expression><macromolecule><migration><model of animal><mortality><mouse model><mtb><mucosal vaccination><multiple myeloma M Protein><murine model><mycobacterial><new vaccines><next generation vaccines><novel><novel vaccines><ontogeny><overexpress><overexpression><pathogen><pathophysiology><polymorphism><predisposing gene><prevent><preventing><promoter sequence><pulmonary><pulmonary pathogen><response><social role><susceptibility allele><susceptibility locus><susceptibility variant><translational impact><transmission process><treatment strategy><tuberculosis infection><tuberculous spondyloarthropathy><tumor><tumor immune microenvironment><tumor-immune system interactions><vaccine against M. tuberculosis><vaccine against Mtb><vaccine against Mycobacterium tuberculosis><vaccine against TB><vaccine against tuberculosis><vaccine candidates against tuberculosis><vaccine strategy>