MODIFYING THE LUNG TO INDUCE STERILE VACCINE-INDUCED PROTECTION AGAINST MTB INFECTION

改造肺部以诱导无菌疫苗诱导的针对 MTB 感染的保护

• 批准号: 9298567
• 负责人: Shabaana A Khader
• 金额: $ 22.88万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-06-16 至 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9298567
• 关键词: Adolescence; Agonist; Animals; BCG Vaccine; CD4 Positive T Lymphocytes; Cell Differentiation process; Cells; Cessation of life; Childhood; Consequences of HIV; Data; Dendritic Cells; Development; Diagnosis; Disease; Epidemic; Exhibits; Future; Generations; Genes; Goals; Granulocyte-Macrophage Colony-Stimulating Factor; HIV; Human; Immunity; Incidence; Individual; Interferon Type II; Interleukins; Ligands; Lung; Mediating; Messenger RNA; Modeling; Modernization; Mus; Mycobacterium bovis; Mycobacterium tuberculosis; Mycobacterium tuberculosis antigens; Pathway interactions; Physiologic pulse; Play; Population; Primary Infection; Public Health; Pulmonary Tuberculosis; Role; Signal Pathway; Sterility; T cell response; T-Lymphocyte; TNFRSF5 gene; Testing; Th1 Cells; Therapeutic; Translating; Tuberculosis; Tuberculosis Vaccines; Uncertainty; Up-Regulation; Vaccinated; Vaccination; Vaccines; Work; cytokine; design; genetic signature; improved; killings; mouse model; nanoparticle; novel; novel strategies; novel therapeutics; novel vaccines; response; transcription factor; transcriptome sequencing; tuberculosis immunity; vaccine response; vaccine-induced immunity

PROJECT ABSTRACT Mycobacterium tuberculosis (Mtb) and human immunodeficiency virus (HIV) together represent the world's biggest killers. There are an estimated nine million new cases of tuberculosis (TB) diagnosed each year, resulting in 1.4 million deaths annually. It is therefore of paramount importance that we develop novel strategies for controlling Mtb infection. The only currently-licensed vaccine for TB, M.bovis Bacille Calmette Guerin (BCG), is effective against childhood forms of TB, but has limited efficacy against pulmonary TB after adolescence. Thus, development of novel vaccines and therapeutics for TB that will provide improved protection upon Mtb exposure are urgently required. Modern candidate TB vaccines under development have focussed on induction of strong T cell responses, primarily CD4+ T cells producing the cytokine interferon gamma (IFN-γ, Th1 cells). More recently, a key role for mucosal interleukin 17A (IL-17) in vaccine-induced protection against TB disease has also been shown. Thus, induction of lung-resident IL- 17-producing CD4+ T cell populations (Th17 cells) by mucosal TB vaccines is also being explored. However, most TB vaccines do not confer sterilizing immunity, instead, inducing a reduction of only ~0.5 to 1.5 logs in lung Mtb burden in animal challenge models. Our new data presented here, show that the lack of sterilizing vaccine-induced immunity to TB vaccines is not due to poor function of vaccine-induced CD4+ T cells, but due to delayed activation and accumulation of recall CD4+ T cell responses in the lung following Mtb infection. Using novel strategies, we show that this bottleneck can be overcome by delivery of activated Mtb antigen (Ag)-pulsed dendritic cells (DCs) into the lungs of vaccinated Mtb-infected mice. DC transfer substantially accelerates the timing of CD4+ T cell accumulation in the lungs, and leads to superior vaccine- induced immunity in Mtb-infected vaccinated mice. Using RNASeq analysis, we have further generated a gene signature in vaccinated mice receiving DC transfer, that is associated with the superior vaccine immunity induced upon Mtb infection. This gene signature reflects upregulation of pathways associated with rapid and effective activation of lung DCs and T cell pathways. Specifically, we found genes associated with activation of CD103+ DC and CD40 pathways upregulated in DC transfer-recipient vaccinated Mtb-infected mice, exhibiting superior Mtb control. In this exploratory proposal, using mouse models of vaccination and Mtb infection, we will investigate whether targeting host lung CD103+ DCs and the CD40 pathway with novel host-directed therapeutics (HDTs) can induce sterilizing vaccine- induced immunity following Mtb infection. These studies will functionally determine the mechanisms that mediate rapid activation of vaccine-induced T cell recall responses to TB. Importantly, these studies will also provide novel HDTs to enhance vaccine responses to either control Mtb burden in infected hosts, or delay TB reactivation in latently-infected individuals.

项目摘要 结核分枝杆菌（Mtb）和人类免疫缺陷病毒（HIV）共同代表了 世界上最大的杀手据估计，每年有900万新的结核病确诊病例， 每年造成140万人死亡。因此，我们开发新的 控制结核分枝杆菌感染的策略。目前唯一获得许可的结核病疫苗是牛分枝杆菌 卡介苗（BCG）对儿童结核病有效，但对肺结核疗效有限 在青春期之后。因此，开发新的结核病疫苗和治疗剂， 迫切需要对Mtb暴露的保护。正在开发的新型结核病候选疫苗 已经专注于诱导强烈的T细胞应答，主要是产生细胞因子的CD 4 + T细胞 干扰素γ（IFN-γ，Th 1细胞）。最近，粘膜白细胞介素17 A（IL-17）在 疫苗诱导的对结核病的保护作用也已显示出来。因此，诱导肺驻留IL- 17-还在探索通过粘膜TB疫苗产生CD 4 + T细胞群（Th 17细胞）。 然而，大多数TB疫苗不赋予杀菌免疫，相反，诱导仅约0.5至约1.5的减少。 1.5在动物激发模型中记录肺Mtb负荷。我们在这里提出的新数据表明，缺乏 疫苗诱导的免疫力对结核疫苗的杀灭不是由于疫苗诱导的CD 4+功能低下 T细胞，但由于延迟激活和积累的回忆CD 4 + T细胞反应在肺以下 结核病感染。使用新的策略，我们表明，这一瓶颈可以克服交付激活 Mtb抗原（Ag）脉冲的树突状细胞（DC）进入接种的Mtb感染的小鼠的肺中。直流传递 大大加速了肺中CD 4 + T细胞积累的时间，并导致上级疫苗- 在Mtb感染的接种小鼠中诱导免疫。使用RNASeq分析，我们进一步生成了一个 接受DC转移的接种小鼠中的基因特征，其与上级疫苗相关 Mtb感染后诱导的免疫力。该基因标记反映了与细胞凋亡相关的通路的上调。 快速有效地激活肺树突状细胞和T细胞通路。具体来说，我们发现了 与DC转移受体中上调的CD 103 + DC和CD 40通路的活化相关 免疫接种的Mtb感染的小鼠，表现出上级的Mtb控制。在这个探索性的建议中，使用鼠标 免疫接种和Mtb感染模型，我们将研究靶向宿主肺CD 103 + DCs是否 和CD 40途径与新的宿主定向治疗（HDTs）可以诱导杀菌疫苗- 结核杆菌感染后诱导免疫力。这些研究将从功能上确定 介导疫苗诱导的T细胞对TB的回忆反应的快速激活。重要的是，这些研究 还提供了新的HDT，以增强疫苗对控制感染宿主中的Mtb负荷的应答， 延迟潜伏感染者的结核病复发。