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: 10646217
• 负责人: Heather Beryl Jaspan
• 金额: $ 11.1万
• 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 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10646217
• 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; Epithelium; Eukaryota; Gene Expression; Genital; Genitalia; HIV; HIV Infections; HIV risk; High Risk Woman; IL8 gene; Immune; Immunity; Immunology; In Vitro; Incidence; Infection; Inflammation; Inflammatory; Knowledge; Laboratories; 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艾滋病毒获取风险方面起着关键作用。阴茎厌氧细菌 丰度与阴茎细胞因子浓度相关，细胞因子与HIV靶细胞有关 包皮中的密度。此外，厌氧菌丰度和阴茎细胞因子浓度是相关的 随着HIV感染的发生率增加。因此，在阴茎微生物组的改变与 由此产生的炎症变化可能会增加艾滋病毒的风险。同样，阴道微生物群落具有 高度多样性或以厌氧或兼性细菌为主的多样性使妇女患有更高的艾滋病毒风险 获取并与高生殖器炎症有关，这被认为吸引或激活HIV靶标 粘膜中的细胞或改变粘膜完整性。除细菌外，粘膜微生物组还包含 病毒和一个社区的转变可能会调节另一个社区的转变。肠道细菌组的多样性镜像 在病毒瘤中，亲和真核生物感染病毒的收集，这些多样性的模式是 由噬菌体驱动，而不是由真核病毒驱动。噬菌体种群的扩展，病毒 感染细菌已与免疫细胞扩张和肠道炎症增加有关。病毒性的 社区可以通过直接激活或通过修饰细菌而间接影响宿主免疫力 社区。但是，阴茎病毒蛋白对细菌群落，免疫和艾滋病毒的影响 敏感性未知。 CHAPS研究是将13-24岁的年轻人随机化安慰剂与各种口服剂量 割礼前的抗逆转录病毒，为我们提供了一个独特的机会来解决其中一些知识 空白。入学率是完整的，已经存储了144个或相应的阴茎拭子，并有 有价值的数据，包括实体HIV敏感性和可用的局部组织基因表达。我们将扩展 这项研究测试了我们的假设，即阴茎病毒与细菌之间存在互链 微生物群和阴茎厌氧菌相对丰度调节上皮炎症 和CD4靶细胞的可用性，因此具有以下特定目的的HIV敏感性： 目的1：评估阴茎粘膜的昆神之间的相互作用。假设：病毒和细菌 阴茎的微生物群相互关联。 目标2：评估细菌微生物组，上皮炎症，靶标之间的相互作用 细胞的可用性和HIV敏感性。假设阴茎厌氧细菌相对丰度 调节上皮炎症，CD4靶细胞的可用性，从而调节HIV敏感性。 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HIV易感性，可能导致预防干预措施，例如益生菌或抗 炎症，适用于未割礼的雄性。

项目成果

Bacterial microbiome and host inflammatory gene expression in foreskin tissue.

• DOI: 10.1016/j.heliyon.2023.e22145
• 发表时间: 2023-11
• 期刊: HELIYON
• 影响因子: 4
• 作者: Maust, Brandon S.;Petkov, Stefan;Herrera, Carolina;Feng, Colin;Brown, Bryan P.;Lebina, Limakatso;Opoka, Daniel;Ssemata, Andrew;Pillay, Natasha;Serwanga, Jennifer;Seatlholo, Portia;Namubiru, Patricia;Odoch, Geoffrey;Mugaba, Susan;Seiphetlo, Thabiso;Gray, Clive M.;Kaleebu, Pontiano;Webb, Emily L.;Martinson, Neil;Chiodi, Francesca;Fox, Julie;Jaspan, Heather B.
• 通讯作者: Jaspan, Heather B.