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）：1 型人类免疫缺陷病毒 (HIV) 和结核分枝杆菌 (Mtb) 是全球范围内导致死亡的主要原因，同时感染与死亡率增加和 Mtb 多重耐药性选择的可能性更大有关。 HIV/AIDS 存在下的 Mtb 治疗因 HIV 感染相关的免疫抑制以及治疗两种病原体的药物之间的药理相互作用而变得复杂。需要新的治疗方法来抑制结核分枝杆菌，无需复杂的药物间相互作用即可治疗艾滋病毒，并且发展中国家可以负担得起。结核分枝杆菌是一种细胞内病原体，通过干扰吞噬溶酶体生物发生而在巨噬细胞吞噬体内持续存在。越来越多的证据表明，自噬的诱导会促进含有 Mtb 的吞噬体的成熟，从而抑制分枝杆菌的存活。最近，我们发现HIV感染巨噬细胞，与Mtb类似，会抑制自噬，而自噬的诱导会抑制HIV复制。值得注意的是，我们的初步数据表明，骨化三醇（维生素 D3 的活性形式）长期与可能的抗 Mtb 活性相关，也可促进自噬和抗菌肽导管素，两者均可抑制 HIV 感染。 R21 的应用基于这样的前提：维生素 D3 在 HIV 和 Mtb 合并感染者中诱导自噬和抗菌素将增强两种感染的标准治疗并改善预后。该提案的具体目标是： 1. 建立维生素 D3（骨化三醇）在共感染的单核细胞源性巨噬细胞 (MDM) 中提高 Mtb 杀灭率并抑制 HIV 感染的能力； 2. 确定维生素 D3 介导的在共感染巨噬细胞中抑制 Mtb 和 HIV 的机制。拟议的实验室实验将为旨在治疗同时感染两种病原体的人的骨化三醇临床研究建立科学依据。此外，这项研究将证明增强先天免疫对于控制微生物感染（包括结核分枝杆菌/艾滋病毒合并感染）的潜在益处。公共健康相关性： 7. 预计本次资助中概述的研究将确定骨化三醇（维生素 D3 的活性形式）诱导自噬的能力，以及抗菌肽导管素足以促进细胞内杀死 HIV 和结核分枝杆菌的能力。