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Elucidating the mechanisms and consequences of MDSC-regulated immunity in TB

阐明结核病中 MDSC 调节的免疫机制和后果

基本信息

批准号：
10670440
负责人：
Bryan David Bryson
金额：
$ 60.38万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-07-22 至 2027-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10670440
关键词：
Acute Address Affect Animals Antimycobacterial Agents Antitubercular Agents Bacille Calmette-Guerin vaccination Bacteria Biological Assay Cavia Cell Communication Cell Count Cell physiology Cells Cellular biology Competence Data Development Disease Disease Progression Effectiveness Effector Cell FDA approved Flow Cytometry Functional disorder Future Gene Expression Profile Genetic Transcription Granuloma HIV/TB Human Image Cytometry Immune Immune System Diseases Immune response Immunity Immunosuppression Impairment In Situ Infection Infiltration Inflammation Intervention Knowledge Lesion Link Literature Lung Macaca Macrophage Mediating Microbiology Modeling Molecular Mouse Strains Mus Mycobacterium tuberculosis Myeloid Cells Myeloid-derived suppressor cells Nitric Oxide Organ Outcome PET/CT scan Pathogenesis Pathogenicity Pathologic Patients Persons Phagosomes Pharmaceutical Preparations Pharmacotherapy Physiological Play Positron-Emission Tomography Predisposition Property Public Health Publishing Pulmonary Inflammation Regimen Reporter Resistance Role Severities Severity of illness Site Supporting Cell System T cell response T-Cell Activation T-Lymphocyte Testing Tissues Treatment Efficacy Tuberculosis Umbilical Cord Blood Work X-Ray Computed Tomography cell free DNA cell type design experience fluorescence imaging high dimensionality human model immune function improved improved outcome inhibitor innovation interest molecular imaging mycobacterial nonhuman primate novel peripheral blood permissiveness recruit response restraint safety assessment small molecule small molecule inhibitor success synergism targeted agent targeted treatment transcriptomics translational study tuberculosis drugs tuberculosis immunity tuberculosis treatment vaccination against tuberculosis

项目摘要

PROJECT SUMMARY: Myeloid derived suppressor cells (MDSCs) are immature myeloid cells with potent inhibitory properties for macrophages and T cells. The link between MDSCs and tuberculosis (TB), a disease caused by Mycobacterium tuberculosis (Mtb), is supported by work in mice where MDSC recruitment to the lungs correlates with disease severity, and in humans, where peripheral blood MDSC abundance positively correlates with TB progression. Work in mice also demonstrates that MDSCs are recruited to sites of BCG vaccination where they phagocytose bacteria and suppress local T cell activation, suggesting that MDSCs may reduce the effectiveness of anti-TB vaccination and contribute to TB’s status as a global public health concern. The relationship between MDSCs and TB has generated interest in targeting them with host-directed therapies to improve TB treatment. Recent work using tasquinimod (TSQ), an FDA-approved small molecule MDSC inhibitor, in guinea pigs and mice finds that targeting MDSCs lowers reduces granuloma formation, lowers bacteria loads, and improves the treatment efficacy of anti-TB drugs. These results are encouraging but critical questions need to be answered before MDSCs can be safely targeted in human TB. Knowledge gaps include an incomplete understanding of how MDSCs interact with macrophages in diseased tissue, if MDSCs restrain or promote pathologic inflammation in TB, how MDSC activity relates to bacterial burden in granulomas, and if MDSCs permit or restrict Mtb replication. These gaps are particularly acute in human TB where progress is inhibited by the inability to access granulomas to study MDSCs in situ and fundamental differences between mouse and human TB pathophysiology. Our proposal addresses these gaps with innovative studies using MDSCs from human cord blood and a nonhuman primates (NHPs) model that accurately reflects human TB pathophysiology. We hypothesize that MDSCs suppress macrophage-mediated anti-Mtb activity and are permissive hosts for Mtb and inhibiting their functions will improve immunity, restrict bacterial persistence, and improve outcomes in TB. In Aim 1, we propose mechanistic studies investigating relationships between MDSCs, macrophages, and Mtb that influence immunity. We will determine if cell-free DNA release is a novel MDSC effector that suppresses macrophage function. We also determine if MDSCs support Mtb as a permissive host cell and define molecular features at the phagosomal level that contribute to competency for hosting Mtb. In Aim 2, we infect NHPs with mCherry-expressing Mtb and use TSQ-mediated MDSC inhibition as an intervention to assess how MDSCs regulate lung inflammation, immunity, and if they host Mtb. Here, we use PET/CT and fluorescence imaging, quantitative microbiology, and flow cytometry to identify MDSC-regulated correlates of immunity in granulomas. We also define MDSC transcriptional profiles in scRNAseq and use CosMx spatial molecular imaging to identify how MDSCs regulate granuloma-level immunity in physiologic and spatial context. These studies address significant questions on MDSCs-regulated immunity in TB and provide valuable data for future trials targeting MDSCs in TB.

项目总结: