Investigating the Role of the GTPase Arl8b in Plasma Membrane Repair of Mtb-Infected Macrophages

研究 GTPase Arl8b 在 Mtb 感染的巨噬细胞质膜修复中的作用

• 批准号: 9060247
• 负责人: HEINZ Gernot REMOLD
• 金额: $ 22.19万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-15 至 2017-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9060247
• 关键词: Apoptosis; Bacillus (bacterium); Bacteria; Biological Assay; Boxing; Cathepsins; Cell Death; Cell Line; Cell membrane; Cells; Cessation of life; Consequences of HIV; Containment; Development; Dominant-Negative Mutation; Drug resistance; Enzymes; Event; Exocytosis; Gene Silencing; Genus Mycobacterium; Goals; Guanosine Triphosphate Phosphohydrolases; HIV; HIV Infections; Health; Hela Cells; Immune; Immune response; Immune system; Infection; Intracellular Transport; Ionophores; LAMP-1; Lead; Lesion; Lung; Lysosomes; Mass Spectrum Analysis; Mediating; Membrane; Membrane Proteins; Modeling; Monomeric GTP-Binding Proteins; Muramidase; Mycobacterium tuberculosis; Necrosis; Outcome; Pathway interactions; Phagosomes; Prevention; Recombinants; Recurrence; Reporting; Role; Small Interfering RNA; Streptolysins; Technology; Testing; Therapeutic; Therapeutic Intervention; Treatment Protocols; Tuberculosis; Vaccination; Vesicle Transport Pathway; Virulence; Virulent; base; cell motility; insight; killings; macrophage; microbial; mycobacterial; novel therapeutic intervention; pathogen; protein transport; repaired; research study; residence; resistant strain; screening; trafficking; tuberculosis treatment

 DESCRIPTION (provided by applicant): Mycobacterium tuberculosis (Mtb) is an extraordinarily successful pathogen that infects 8.6 million people yearly and causes 1.3 million deaths. The principal host cell of Mtb is the lung macrophage (M). It is not well understood how in some cases the internalized Mtb remain sequestered and are ultimately killed and in other cases persist and escape recognition by the immune system. We have shown that membrane repair mechanisms are extremely important in determining the outcome of infection. Membrane repair maintains the integrity of the Mφ plasma membrane after infection of M with avirulent Mtb, a requisite step for apoptosis of infected Mφ, which kills the pathogen. Virulent Mtb, in contrast, block membrane repair and instead actively induce necrosis, supporting spread of infection and escape from immune control. Mechanistically both avirulent and virulent Mtb induce microdisruptions of the host M plasma membrane. These plasma membrane lesions are repaired in M infected with avirulent Mtb, but in the case of virulent Mtb, necrosis ensues because the bacillus inhibits plasma membrane repair. The goal of this project is the delineation of membrane repair in Mtb-infected M, which will lead to increased understanding of the protective host response mechanism and of the critical steps, by which virulent Mtb escape host containment. A major component of the membrane repair mechanism is Arl8b, a small GTPase involved in lysozyme motility and trafficking. In Aim 1 we will use a cell line model (HeLa cells) to (a) determine the role of Arl8b and (b) identify additional interacting effector molecules in plasma membrane repair. In Aim 2 we will test whether Arl8b and the validated effectors are required for plasma membrane repair of Mtb-infected M and whether virulent Mtb subverts their function. The described studies are directed towards therapeutic interventions to enhance the host anti-mycobacterial response (host-directed tuberculosis therapy).



项目成果

A Rab3a-dependent complex essential for lysosome positioning and plasma membrane repair.

• DOI: 10.1083/jcb.201511093
• 发表时间: 2016-06-20
• 期刊: The Journal of cell biology
• 作者: Encarnação M;Espada L;Escrevente C;Mateus D;Ramalho J;Michelet X;Santarino I;Hsu VW;Brenner MB;Barral DC;Vieira OV
• 通讯作者: Vieira OV