Penile viral and bacterial microbiome, inflammation and HIV susceptibility

阴茎病毒和细菌微生物组、炎症和艾滋病毒易感性

• 批准号: 10402631
• 负责人: Heather Beryl Jaspan
• 金额: $ 41.1万
• 依托单位: SEATTLE CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-15 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10402631
• 关键词: 16S ribosomal RNA sequencing; 3-Dimensional; AIDS prevention; Accounting; Acquired Immunodeficiency Syndrome; Address; Anaerobic Bacteria; Anti-Inflammatory Agents; Anti-Retroviral Agents; Area; Bacteria; Bacteriophages; Cell Density; Cell model; Cells; Collection; Communities; DNA; Data; Dendritic Cells; Dose; Enrollment; Epithelial; Eukaryota; Gene Expression; Genital; Genitalia; HIV; HIV Infections; High Risk Woman; IL8 gene; Immune; Immunity; Immunology; In Vitro; Incidence; Infection; Inflammation; Inflammatory; Knowledge; Laboratories; Lead; Link; Location; Male Circumcision; Metagenomics; Methods; Mucosal Immunity; Mucous Membrane; Oral; Parents; Pattern; Pharmaceutical Preparations; Placebos; Play; Population; Predisposition; Prevention; Probiotics; Proteins; Randomized; Research; Risk; Shotguns; Surface; Swab; Testing; Tissues; Urethra; Vagina; Viral; Virus; aged; bacterial community; bacteriome; cytokine; improved; in vivo; innovation; keratinocyte; male; microbiome; microbiota; penile microbiome; penile microbiota; penis; penis foreskin; pre-exposure prophylaxis; preventive intervention; vaginal microbiota; virology; virome; young man

The mucosal microbiome plays a key role in determining risk for HIV acquisition. Penile anaerobic bacterial abundance correlates with penile cytokine concentrations, and cytokines are associated with HIV target cell density in the foreskin. Furthermore, anaerobe abundance and penile cytokine concentrations are associated with increased incidence of HIV infection. Thus, it is plausible that alterations in the penile microbiome with resultant inflammatory changes may increase the risk of HIV. Similarly, vaginal microbial communities with high diversity or those dominated by anaerobic or facultative bacteria render women at higher risk of HIV acquisition and are associated with high genital inflammation, which is thought to attract or activate HIV target cells in the mucosa or alter mucosal integrity. In addition to bacteria, the mucosal microbiome also contains viruses, and shifts in one community may modulate shifts in the other. The gut bacteriome diversity is mirrored in the virome, the collection of pro- and eukaryote-infecting viruses, and that these patterns of diversity are driven by bacteriophages, not by eukaryotic viruses. Expansion of bacteriophage populations, viruses that infect bacteria, has been linked to immune cell expansion and increased inflammation in the gut. Viral communities can influence host immunity by direct activation, or indirectly by modifying the bacterial community. However, the impact of the penile virome on bacterial communities, immunity and HIV susceptibility are unknown. The CHAPS study, which is randomizing young men aged 13-24 years to placebo versus various oral doses of antiretrovirals prior to circumcision, affords us the unique opportunity to address some of these knowledge gaps. Enrolment is complete, and 144 foreskins and corresponding penile swabs have been stored, with valuable data including ex vivo HIV susceptibility and local tissue gene expression available. We will extend the study to test our hypothesis that there is an interlinkage between penile viral and bacterial microbiota, and that penile anaerobic bacteria relative abundance modulates epithelial inflammation and CD4 target cell availability, and therefore HIV susceptibility with the following Specific Aims: Aim 1: To assess inter-kingdom interactions at the penile mucosa. Hypothesis: The viral and bacterial microbiota of the penis are interrelated. Aim 2: To evaluate the interaction between the bacterial microbiome, epithelial inflammation, target cell availability and HIV susceptibility. Hypothesis Penile anaerobic bacterial relative abundance modulates epithelial inflammation, CD4 target cell availability, and hence HIV susceptibility. We propose a highly innovative, unique study to answer important questions regarding the penile microbiome and HIV susceptibility, that could lead to improved prevention interventions, such as probiotics or anti- inflammatories, for uncircumcised males.

粘膜微生物组在确定HIV感染风险方面起着关键作用。阴茎厌氧菌 丰度与阴茎细胞因子浓度相关，细胞因子与HIV靶细胞相关， 包皮的密度。此外，厌氧菌丰度和阴茎细胞因子浓度相关 艾滋病毒感染率上升。因此，这是合理的，在阴茎微生物组的改变， 由此产生的炎症变化可能会增加感染艾滋病毒的风险。同样，阴道微生物群落与 高度多样性或以厌氧或兼性细菌为主细菌使妇女感染艾滋病毒的风险更高 获得并与高生殖器炎症有关，这被认为是吸引或激活艾滋病毒的目标 粘膜中的细胞或改变粘膜完整性。除了细菌，粘膜微生物组还含有 病毒，一个社区的转变可能会调节另一个社区的转变。肠道细菌组多样性反映了 在病毒组中，亲和真核生物感染病毒的集合，这些多样性的模式是 由噬菌体驱动，而不是真核病毒噬菌体数量的扩张， 感染细菌，与免疫细胞扩张和肠道炎症增加有关。病毒 细菌群落可以通过直接激活或间接修饰细菌， 社区然而，阴茎病毒组对细菌群落，免疫和艾滋病毒的影响 敏感性未知。 CHAPS研究将13-24岁的年轻男性随机分为安慰剂组和各种口服剂量组。 在包皮环切术前使用抗逆转录病毒药物，为我们提供了独特的机会来解决这些知识， 差距。包皮环切完成，144个包皮和相应的阴茎拭子已被储存， 有价值的数据，包括离体HIV易感性和局部组织基因表达可用。我们将扩展 这项研究旨在验证我们的假设，即阴茎病毒和细菌之间存在相互联系， 微生物群，阴茎厌氧菌相对丰度调节上皮炎症 和CD 4靶细胞的可用性，因此HIV易感性具有以下特定目的： 目的1：评估阴茎粘膜的王国间相互作用。假设：病毒和细菌 微生物是相互关联的。 目的2：评估细菌微生物组、上皮炎症、靶点之间的相互作用 细胞可用性和HIV易感性。假设阴茎厌氧菌相对丰度 调节上皮炎症、CD 4靶细胞可用性，从而调节HIV易感性。 我们提出了一项高度创新，独特的研究，以回答有关阴茎微生物组的重要问题 和艾滋病毒易感性，这可能导致改善预防干预措施，如益生菌或抗- 炎症，对于未割包皮的男性。