Vitamin D Inhibition of HIV and M. Tuberculosis Coinfection in Macrophages

维生素 D 对巨噬细胞中 HIV 和结核分枝杆菌混合感染的抑制作用

• 批准号: 7755309
• 负责人: STEPHEN A SPECTOR
• 金额: $ 23.18万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-21 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7755309
• 关键词: Autophagocytosis; Biogenesis; Biological Assay; CD4 Lymphocyte Count; Calcitriol; Calcium; Cause of Death; Cell Line; Cells; Cholecalciferol; Clinical Research; Clinical Trials; Complex; Data; Developed Countries; Developing Countries; Drug Interactions; Drug usage; Grant; HIV-1; Human; Immune; Immunosuppression; Infection; Laboratories; Macrophage-1 Antigen; Mediating; Mono-S; Multi-Drug Resistance; Mycobacterium tuberculosis; Natural Immunity; Outcome; Persons; Phagolysosome; Phagosomes; Pharmaceutical Preparations; Relative (related person); Research; Sirolimus; Staging; Starvation; Tuberculosis; Viral Load result; Vitamin D; antimicrobial; base; cathelicidin; cathelicidin antimicrobial peptide; design; improved; killings; macrophage; microbial; monocyte; mortality; mycobacterial; novel strategies; pathogen; public health relevance; reconstitution; research study; small hairpin RNA; standard care

DESCRIPTION (provided by applicant): Human Immunodeficiency Virus type-1 (HIV) and Mycobacterium tuberculosis (Mtb) are among the leading causes of death worldwide with coinfection associated with increased mortality and greater likelihood of selection for Mtb multi-drug resistance. Treatment of Mtb in the presence of HIV/AIDS is complicated by the immunosuppression associated with HIV infection and the pharmacologic interactions between drugs used for treatment of both pathogens. New approaches for treatment are needed that can inhibit Mtb, permit treatment of HIV without complex drug-drug interactions and are affordable in developing countries. Mtb is an intracellular pathogen that persists within macrophage phagosomes through interference with phagolysosome biogenesis. Increasing evidence suggests that the induction of autophagy promotes the maturation of phagosomes containing Mtb that suppress mycobacterial survival. Recently, we have discovered that HIV infection of macrophages, similar to Mtb, inhibits autophagy, while induction of autophagy inhibits HIV replication. Of note, our preliminary data suggest that calcitriol the active form of vitamin D3, long associated with possible activity against Mtb, also promotes autophagy and the antimicrobial peptide cathelicidin both of which inhibit HIV infection. This R21 application is based on the premise that induction of autophagy and cathelicidin by vitamin D3 in persons coinfected with HIV and Mtb will augment standard treatment of both infections and improve outcome. The specific aims of this proposal are to: 1. Establish the ability of vitamin D3 (calcitriol) to improve Mtb killing and inhibit HIV infection in coinfected monocyte-derived-macrophages (MDM)); and 2. Identify the mechanism(s) of vitamin D3 mediated inhibition of Mtb and HIV in coinfected macrophages. The laboratory experiments proposed will establish the scientific justification for a clinical study of calcitriol designed to treat persons coinfected with both pathogens. Additionally, this research will demonstrate the potential benefit of enhancing innate immunity to control microbial infections including Mtb/HIV coinfection. PUBLIC HEALTH RELEVANCE: 7. It is expected that the studies outlined in this grant will establish the ability of calcitriol (the active form of vitamin D3) to induce autophagy and the antimicrobial peptide cathelicidin sufficiently to promote intracellular killing of HIV and Mycobacterium tuberculosis.

描述（由申请人提供）：人类免疫缺陷病毒类型1（HIV）和结核分枝杆菌（MTB）是全世界死亡的主要原因之一，与死亡率增加和MTB多重耐药性选择的可能性更大相关。与HIV感染相关的免疫抑制以及用于治疗两种病原体的药物之间的药理相互作用，在存在HIV/AIDS的情况下对MTB的治疗变得复杂。需要进行新的治疗方法，以抑制MTB，允许在没有复杂的药物相互作用的情况下对HIV进行治疗，并且在发展中国家负担得起。 MTB是一种细胞内病原体，它通过干扰吞噬吞噬体生物发生在巨噬细胞吞噬体中。越来越多的证据表明，自噬的诱导促进了含有抑制分枝杆菌存活的MTB的吞噬体的成熟。最近，我们发现巨噬细胞的HIV感染类似于MTB，抑制自噬，而自噬的诱导抑制了HIV的复制。值得注意的是，我们的初步数据表明，骨化维生素D3的活性形式与对MTB的可能活性长期相关，还促进自噬和抗菌肽cathelicidin均抑制HIV感染。该R21应用是基于以下前提：与HIV和MTB共感染的人中，维生素D3对自噬和cathelicidin诱导将增强两种感染的标准治疗并改善预后。该提案的具体目的是：1。建立维生素D3（钙三醇）改善MTB杀伤和抑制HIV感染的能力。和2。确定维生素D3的机制介导的巨噬细胞中MTB和HIV的抑制作用。提出的实验室实验将建立旨在治疗与两种病原体共同感染的人的骨化临床研究的科学依据。此外，这项研究将证明增强先天免疫以控制包括MTB/HIV共感染在内的微生物感染的潜在益处。公共卫生相关性：7。预计该赠款中概述的研究将确定骨化三醇（维生素D3的活性形式）能够诱导自噬和充分促进抗菌肽cateelicidin的能力，足以促进细胞内HIV和肺结核的细胞内杀死。