Dichotomy of HIV-Sugar with Vaginal Microbes

HIV-糖与阴道微生物的二分法

基本信息

批准号：
10693740
负责人：
Johnson Mak
金额：
$ 14.85万
依托单位：
GRIFFITH UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-03-24 至 2025-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10693740
关键词：
Bacteria Bacterial Infections Bacterial Vaginosis Binding Biological Models Biology CCR5 gene CD4 Antigens Cell surface Cells Cervical Clinical Cytometry Data Dendritic Cells Development Electron Microscopy Electrostatics Epithelial Cells Epithelium Eukaryotic Cell Exhibits Genetic Genital Genitalia Glycoconjugates Glycoside Hydrolases HIV HIV Infections HIV Receptors HIV envelope protein Human Image Imaging Techniques Immune In Vitro Infection Inflammation Inflammatory Invaded Laboratories Lactobacillus Langerhans cell Language Lectin Life Liquid substance Male Circumcision Mannose Mannose Binding Lectin Mediating Microbe Microbial Biofilms Modeling Molecular Molecular Cloning Molecular Virology Monosaccharides Movement Neisseria gonorrhoeae Nutraceutical Oral Outcome Phenotype Polysaccharides Population Process Production Recombinants Reporter Resource-limited setting Risk Risk Reduction Role Route Services Sexual Transmission Sexually Transmitted Diseases South African Specificity Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization Surface Surface Plasmon Resonance T-Lymphocyte Techniques Tight Junctions Time Trauma Urethra Vagina Vaginal Douching Viral Virus biophysical analysis biophysical techniques cell killing cervicovaginal clinically relevant cohort follow-up glycosylation in vivo mass spectrometric imaging nanoluciferase neutrophil novel particle pathogenic virus penile microbiome preference receptor sexual HIV transmission sialoadhesin sugar tissue culture transmission process vaginal lactobacilli vaginal microbiome

项目摘要

PROJECT SUMMARY This proposal is built upon a novel discovery from the PI Mak laboratory showing that a ‘non-electrostatic, specific, manipulatable, sugar-sugar’ is an attachment factor for HIV. This interaction occurs between HIV oligomannose (oligoman) and cellular N-acetylglucosamine (GlcNAc) prior to receptor engagement. The conservation of glycan biology across domains of life and the non-living (viruses) has led to our current proposal to investigate whether this oligoman-GlcNAc (or oligoman-based) interaction may underpin some of the dynamic- interplays amongst: (i) vaginal microbes; (ii) HIV; and (iii) their human host. Our findings that HIV double up to use its oligoman enriched HIV envelope (Env) glycan shield as an attachment factor may offer a general principle to account, at least in part, for: (i) how vaginal lactobacillus offers protection from HIV transmission; and (ii) how vaginal Neisseria gonorrhoeae increases the risk of HIV transmission. As many vaginal microbes have mannose- binding proteins and GlcNAc on their bacterial surface, our hypothesis is that the enrichment of oligoman N- glycans on HIV Env acts as a molecular Velcro to interact with mannose-binding proteins and/or GlcNAc sugars on the surface of genital microbes. We further hypothesize that the biology of these genital microbes would either helps trap HIV to deny their access to infect the host or acts as a courier service to deliver HIV into the host. We will use a combination of ultrastructural imaging techniques, biophysical approaches, molecular virology techniques, cytometry by time of flight (CyTOF) -imaging, glycan matrix-assisted laser desorption ionization - mass spectrometry imaging (MALDI-MSI), and tissue culture-based epithelial cell model system to examine the transmission of HIV via oligoman-based binding via two specific aims. In Aim1, we will define whether vaginal lactobacillus limits HIV transmission via oligoman-based trapping. In Aim2, we will assess if HIV hitch-hike across sub-epithelial barrier via oligoman-mediated bindings with N.gonorrhoeae. Successful completion of this proposal may result in proof of concept data that a simple oligoman-based mechanism could account for the opposing abilities of how lactobacillus protect and how N.gonorrhoeae enhance HIV transmission, respectively. We will also use pre-set vaginal microbes reference population from ATCC to evaluate these glycan-based interaction at the population level. We will perform follow-up analyses with vaginal microbiomes derived from established and clinically relevant South African HIV cohort. Data showing oligoman-based interaction is a contributing factor to sexual transmission of HIV may offer new hope for the development of a practical, orally delivery self-administrated HIV mitigation strategy using optimised versions of GlcNAc or mannose, given these parental monosaccharides are widely available, non-toxic, off-the counter, nutraceuticals.

项目概要该提案基于 PI Mak 实验室的一项新发现，该发现表明“非静电、特定的、可操纵的、糖-糖”是艾滋病毒的附着因素，这种相互作用发生在艾滋病毒之间。受体结合之前的寡甘露糖（oligoman）和细胞 N-乙酰氨基葡萄糖（GlcNAc）。跨生命和非生命（病毒）领域的聚糖生物学保护导致了我们目前的提议研究这种寡聚体-GlcNAc（或基于寡聚体）的相互作用是否可能支持某些动态- (i) 阴道微生物；(ii) HIV；和 (iii) 人类宿主之间的相互作用。使用其富含寡聚体的 HIV 包膜 (Env) 聚糖屏蔽作为附着因子可能会提供一般原则至少部分地解释：(i) 阴道乳酸菌如何提供预防艾滋病毒传播的保护；以及 (ii) 如何预防艾滋病毒传播；阴道淋病奈瑟菌会增加艾滋病毒传播的风险，因为许多阴道微生物含有甘露糖。结合蛋白和 GlcNAc 在细菌表面，我们的假设是寡聚核苷酸 N-的富集 HIV Env 上的聚糖充当分子 Velcro 与甘露糖结合蛋白和/或 GlcNAc 糖相互作用我们进一步研究了这些生殖器微生物的生物学特性。要么帮助捕获艾滋病毒以阻止其感染宿主，要么充当快递服务将艾滋病毒传递到宿主体内我们将结合使用超微结构成像技术、生物物理方法、分子病毒学。技术、飞行时间细胞计数 (CyTOF) -成像、聚糖基质辅助激光解吸电离 - 质谱成像（MALDI-MSI）和基于组织培养的上皮细胞模型系统来检查 HIV 通过基于寡聚体的结合通过两个特定目标进行传播在 Aim1 中，我们将定义是否通过阴道。乳酸菌通过基于寡聚体的捕获来限制 HIV 传播。在 Aim2 中，我们将评估 HIV 是否会搭便车。通过寡糖介导的与淋病奈瑟菌的结合成功完成了上皮下屏障。提案可能会产生概念证明数据，一个简单的基于寡头的机制可以解释乳酸菌如何保护和淋病奈瑟菌如何增强艾滋病毒传播的能力分别相反。我们还将使用 ATCC 预设的阴道微生物参考群体来评估这些基于聚糖的微生物我们将对源自阴道的微生物组进行后续分析。已建立的且临床相关的南非艾滋病毒队列数据显示基于寡聚物的相互作用是一个。艾滋病毒性传播的促成因素可能为开发实用的口服药物带来新的希望使用 GlcNAc 或甘露糖的优化版本提供自我管理的 HIV 缓解策略，考虑到这些亲代单糖是广泛使用的、无毒的、非处方的营养保健品。