Identification of Protective Innate Immune Memory Responses Against HIV Acquisition in the Human Female Genital Tract

人类女性生殖道中针对 HIV 感染的保护性先天免疫记忆反应的鉴定

• 批准号: 10954383
• 负责人: Marta Rodriguez Garcia
• 金额: $ 19.25万
• 依托单位: WAYNE STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-25 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10954383
• 关键词: Identification; Protective; Innate; Immune; Memory

PROJECT SUMMARY The main route for HIV acquisition in women of worldwide is sexual transmission. The low rate of HIV transmission per sexual act (0.08%) in women indicates that local innate immune mechanisms contribute to protection. Yet, the mucosal events that lead to the prevention or acquisition of HIV in the female genital tract (FGT) are largely unknown. Thus, it is critical to identify the early mucosal mechanisms that prevent HIV infection of target cells, in order to develop effective preventive approaches for women. Trained immunity is the functional modification of innate immune cells after initial stimulation that generates heightened innate immune responses to heterologous secondary stimulations. It can be induced by bacterial, fungal, and viral components through infection or vaccination, and leads to long-lasting epigenetic modifications in hematopoietic stem cell progenitors. This implies that trained innate cells can reach mucosal surfaces by replenishment of tissue-resident cells with new trained cells from the bone marrow or be generated after exposure to the microbiome and mucosal infections. However, the contribution of trained immunity to immune protection in human mucosal surfaces, including the FGT, is completely unknown. The PI’s research group recently discovered that dendritic cells and neutrophils in the FGT, innate cells involved in HIV pathogenesis, express transcripts and secrete cytokines and antimicrobials characteristic of trained immune responses and with known anti-HIV activity. Based on these preliminary results, the hypothesis being tested here is that genital DCs and neutrophils protect against HIV acquisition through trained innate immune responses. The proposed project builds on the PI’s prior work, and now seeks to define the trained immune signatures of genital DCs and neutrophils and determine how innate trained immunity contributes to anti-HIV mucosal protection of women. Single-cell sequencing approaches to define the phenotypical, transcriptional, and epigenetic signatures of trained DCs and neutrophils will be combined with in vitro functional assays to directly determine anti-HIV activity. It is expected that these studies will define, for the first time, how trained immune cells in the FGT contribute to protection against HIV acquisition. The identification of an inducible/modifiable form of innate protection against HIV in the FGT would represent a breakthrough in our understanding of how HIV acquisition occurs in the mucosa. Equally important, these findings will have a positive translational impact, since the identification of targetable cells and mechanisms of trained immunity responsible for anti-HIV protection will serve as the foundation to develop novel prevention strategies against HIV acquisition in women worldwide.

项目摘要 全世界妇女感染艾滋病毒的主要途径是性传播。艾滋病毒感染率低 女性每次性行为的传播率（0.08%）表明，局部先天免疫机制有助于 保护然而，导致女性生殖道预防或获得艾滋病毒的粘膜事件 (FGT)大部分都是未知的。因此，确定预防HIV感染的早期粘膜机制至关重要 目标细胞，以便为妇女制定有效的预防方法。 训练免疫是先天免疫细胞在初始刺激后的功能修饰， 增强对异源次级刺激的先天免疫应答。它可以由细菌， 真菌和病毒成分，并导致持久的表观遗传修饰 在造血干细胞祖细胞中。这意味着经过训练的先天细胞可以通过以下方式到达粘膜表面： 用来自骨髓的新的训练细胞补充组织驻留细胞，或者在 暴露于微生物组和粘膜感染。然而，训练的免疫力对免疫的贡献 对包括FGT在内的人粘膜表面的保护是完全未知的。PI的研究小组 最近发现FGT中的树突状细胞和中性粒细胞，参与HIV发病机制的先天细胞， 表达转录物并分泌细胞因子和抗微生物剂，这些是训练免疫应答的特征， 已知有抗艾滋病毒活性根据这些初步结果，这里正在测试的假设是，生殖器 树突状细胞和中性粒细胞通过训练的先天免疫反应防止HIV感染。拟议 该项目以PI之前的工作为基础，现在寻求定义生殖器DC的训练免疫特征， 中性粒细胞，并确定先天训练的免疫力如何有助于妇女的抗HIV粘膜保护。 单细胞测序方法，以确定表型，转录，和表观遗传签名， 将训练的DC和中性粒细胞与体外功能测定组合以直接测定抗HIV活性。 预计这些研究将首次定义FGT中经过训练的免疫细胞如何有助于 预防艾滋病毒感染。鉴定一种可诱导/可改变的先天保护形式， FGT中的HIV将代表我们对HIV获得如何在FGT中发生的理解的突破。 粘膜同样重要的是，这些发现将产生积极的转化影响，因为 负责抗HIV保护的可靶向细胞和经过训练的免疫机制将作为 该基金会致力于制定新的预防战略，防止全球妇女感染艾滋病毒。