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Redox defenses and evasion of reactive oxygen species mediated host immunity in Mycobacterium tuberculosis

结核分枝杆菌的氧化还原防御和活性氧逃避介导的宿主免疫

基本信息

批准号：
10685474
负责人：
Steven Joseph Grigsby
金额：
$ 4.77万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-01 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10685474
关键词：
Alveolar Macrophages Attenuated Autophagocytosis Bacillus Bacteria Bone Marrow C57BL/6 Mouse Cause of Death Cell Separation Cells Cessation of life Chemicals Chronic Complement Defect Disinhibition Doctor of Philosophy Drug Metabolic Detoxication Drug Targeting Drug resistance Genetic Immune Immune Evasion Immune response Immunity Immunology In Vitro Infection Infection Control Inflammatory Inflammatory Response Innate Immune Response Isoniazid resistance Knockout Mice Lung Macrophage Mediating Mediator Medical Microbe Microbiology Molecular Mus Mutation Mycobacterium tuberculosis Myeloid Cells NADPH Oxidase Natural Immunity Neutrophil Infiltration Oxidation-Reduction Oxidative Stress Pathogenesis Peroxidases Persons Phagocytosis Phagosomes Pharmaceutical Preparations Phase Phenotype Physicians Plasmids Play Production Protein Secretion Pulmonary Tuberculosis Reactive Oxygen Species Reporter Research Resistance Resources Respiratory Burst Role SCID Mice Scientist Signal Transduction Signaling Molecule Sorting Stress T-Lymphocyte Testing Tetanus Helper Peptide Therapeutic Time Training Training Programs Tuberculosis Universities Vaccine Design Vaccines Virulence Virulence Factors Washington Wild Type Mouse Work acute infection adaptive immune response adaptive immunity antigen-specific T cells antimicrobial career development catalase cell type chronic infection conditional knockout design experimental study immunoregulation in vivo inflammatory milieu isoniazid medical schools microbial microbicide monocyte mutant neutrophil novel therapeutics novel vaccines pandemic disease pathogen promoter recruit transmission process tuberculosis drugs tuberculosis treatment

项目摘要

Project Summary Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB), caused 1.4 million deaths in 2017, more than any other pathogen. TB treatment remains difficult, and an effective vaccine has eluded research efforts for the past century. A major barrier to ending the TB pandemic is a limited understanding of effective host immune responses and Mtb’s immune evasion strategies. Much in vitro work has been done to characterize Mtb infection of macrophages, its predominant cellular niche. Whereas reactive oxygen species (ROS) are an important antimicrobial defense against diverse pathogens, Mtb is resistant to ROS. We recently identified CpsA as a secreted virulence factor that inhibits NADPH oxidase recruitment to the Mtb-containing phagosome, thereby protecting Mtb from an oxidative burst. ROS is also an essential signal for LC3-associated phagocytosis (LAP), a noncanonical form of autophagy. Indeed, the ΔcpsA mutant is rescued in mice defective in the NADPH oxidase and LAP. Interestingly, in mice the ΔcpsA mutant is severely attenuated during the first two weeks of infection and recovers substantially by 6 weeks, suggesting that CpsA is most important during the innate phase of infection before the activation of adaptive immunity. This phenotype coincides with a shift in cell types that are infected and the inflammatory response. Therefore, we hypothesize that CpsA specifically protects Mtb against ROS in the cell types infected and inflammatory environment of the innate immune phase. We will test our hypothesis by characterizing the ΔcpsA mutant within different myeloid cells in vivo using flow-assisted cell sorting (FACS) and in mice that are deficient in alveolar macrophages, neutrophils, or monocyte-derived macrophages, as well as in mice that fail to mount an adaptive immune response against Mtb or that have cell type specific defects in LAP. KatG is a catalase-peroxidase that is also important in ROS defense in Mtb. We will test whether CpsA and KatG cooperate in virulence by charactering a ΔcpsA ΔkatG double mutant. We hypothesize that the ΔcpsA ΔkatG mutant will be more attenuated than either single mutant due to disinhibited ROS production by the host and reduced ROS detoxifying activity by Mtb. KatG activates the first-line drug isoniazid (INH), and mutations in katG confer INH resistance. CpsA, therefore, may permit transmission of INH- resistant katG mutants by protecting them against ROS. Investigating the roles of ROS and the diverse myeloid cells involved in Mtb infection will impact strategies for host-directed therapies, targeting drug-resistant bacilli, and novel vaccine design. This proposal is the topic of Steven Grigsby’s PhD thesis in Molecular Microbiology & Microbial Pathogenesis in the Medical Scientist Training Program at Washington University School of Medicine (WUSM). The strength at WUSM in microbial pathogenesis and immunology makes it a perfect fit for the studies proposed by Steven Grigsby. He has all of the necessary resources, input from a group of outstanding scientists, and a robust training plan, which will support his career development as an independent physician-scientist.

项目总结