The Clinical History of Rectal and Urethral STIs among MSM: characterizing microbiome host immune interactions for diagnostic and vaccine advances

MSM 中直肠和尿道 STI 的临床史：表征微生物组宿主免疫相互作用以促进诊断和疫苗进展

• 批准号: 10703680
• 负责人: Lyle McKinnon
• 金额: $ 66.51万
• 依托单位: RUSH UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-18 至 2028-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10703680
• 关键词: 16S ribosomal RNA sequencing; Accounting; Adjuvant Therapy; Africa South of the Sahara; Aftercare; Anti-Inflammatory Agents; Antibiotic Therapy; Antibody Response; B-Lymphocytes; Biological; Biological Assay; Biological Response Modifier Therapy; Chlamydia trachomatis; Climate; Clinical; Clonality; Country; Data; Detection; Diagnostic; Disease Progression; Epithelium; Frequencies; HIV; Heterosexuals; High Prevalence; Hot Spot; Immune; Immune response; Immunity; Immunologic Factors; Immunologics; Immunology; Incidence; Infection; Infection Control; Inflammation; Inflammatory; Integration Host Factors; Interferons; Intervention; Investigation; Kenya; Link; Lymphocyte; Measures; Mediating; Memory; Methods; Modality; Mucous Membrane; Neisseria gonorrhoeae; Nucleic Acids; Outcome; Pathway interactions; Persons; Phenotype; Politics; Population; Prevalence; Prevention; Preventive; Preventive vaccine; Prevotella; Production; Recording of previous events; Rectum; Risk; Sampling; Severity of illness; Sexually Transmitted Diseases; Shotguns; Social Behavior; Structure; T cell response; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Therapeutic; Time; Urethra; Vaccines; adaptive immune response; adaptive immunity; antigen-specific T cells; bacterial community; behavioral study; chemokine; cohort; complex data; cytokine; design; effective therapy; follow-up; gut inflammation; gut microbiota; host microbiome; immune activation; immunoregulation; longitudinal analysis; male; memory CD4 T lymphocyte; men; men who have sex with men; metagenomic sequencing; microbiome; microbiome composition; microbiota; morphogens; novel; pathogen; peer; penile microbiome; prevent; protective efficacy; recruit; rectal; rectal microbiome; response; secondary outcome; structural determinants; systemic inflammatory response; vaccine development; vaccine efficacy; vaccine strategy; vaccine-induced immunity

In sub-Saharan Africa, men who have sex with men (MSM) have 2-4 times higher rates of sexually transmitted infections (STIs) and HIV than the general male population. In our cohort of 700 MSM in Kisumu, Kenya, the incidence of urethral and anorectal C. trachomatis (CT) and/or N. gonorrhoeae (NG) was 19.8 per 100 person years (PY) over one year. These rates are 2-3 times the incidence we measured among heterosexual Kenyan men. Our studies of MSM in Kisumu and Nairobi have identified specific rectal bacterial community structures that are associated with inflammatory mucosal immune profiles. Inflammatory rectal microbiome profiles could increase risk of STI acquisition and interfere with vaccine efficacy by skewing systemic T cell populations toward an increased memory/decreased naïve lymphocyte ratios, and a higher state of basal immune activation, as supported by our preliminary investigations. Inflammation could therefore undermine the partial protective efficacy of STI vaccines ability to prime naïve lymphocytes required for optimal immunity, both by decreasing the frequency of naïve lymphocytes, and by decreasing the efficiency in which the remaining naïve T cells are primed. Objective: Over a one-year period, in a sample of 500 MSM in Kisumu (n=250) and Nairobi (n=250), we will measure the penile and rectal microbiomes, mucosal immune profiles, socio-behavioral and structural factors, and incidence of urethral and anorectal STIs (CT, NG). In Aim 1, we will characterize the clinical history of STI infection from time of detection  to time of treatment  to treatment and clearance. Samples will be collected from all men at baseline, 6- and 12- months to characterize penile and rectal microbiome composition (via high throughput amplicon sequencing), mucosal immunology (broad measure of pro-inflammatory, inflammatory, and anti-inflammatory cytokines and chemokines and measures of epithelial barrier integrity), and test for STI by nucleic acid amplification assay. Accounting for loss to follow-up, we expect 70-90 incident CT and/or NG infections, and for these men, microbiome composition, mucosal immunology, and bacterial function will be assessed again when they present for antibiotic treatment, and 4 weeks subsequent to treatment. In Aim 2, we will quantify how penile and rectal microbiome composition are associated with risk of incident urethral and rectal STIs, respectively. As a secondary outcome, we will identify dominant mucosal immune profiles and examine how they change over time in relation to microbiome composition. In Aim 3, we will in STI cases identify adaptive immune mechanisms that link rectal microbiome, host immunity, and symptomatic or asymptomatic STI incident infections. Therapeutic and preventive implications: The impact of STI treatment on penile and rectal microbiome composition and bacterial function is unknown and characterizing this aspect of clinical history of infection can identify novel treatment and prevention pathways. Understanding factors that might undermine protective immunity to STIs could be critical to informing the design of more effective vaccines that are required to achieve STI control.

在撒哈拉以南非洲地区，男男性行为者 (MSM) 的性传播感染率高出 2-4 倍 在我们位于肯尼亚基苏木的 700 名男男性行为者队列中，感染（性传播感染）和艾滋病毒感染率高于一般男性人群。 尿道和肛门直肠沙眼衣原体 (CT) 和/或淋病奈瑟菌 (NG) 的发病率为每 100 人 19.8 例 这些比率是我们在异性恋肯尼亚人中测量的发病率的 2-3 倍。 我们对基苏木和内罗毕的 MSM 研究确定了特定的直肠细菌群落结构。 与炎症粘膜免疫特征相关的炎症直肠微生物特征可能。 通过扭曲全身 T 细胞群来增加获得性传播感染的风险并干扰疫苗功效 提高记忆力/降低幼稚淋巴细胞比率，以及提高基础免疫状态 因此，根据我们的初步调查，炎症可能会破坏部分功能。 STI 疫苗的保护功效能够启动最佳免疫所需的幼稚淋巴细胞，两者都通过 降低初始淋巴细胞的频率，并降低剩余初始淋巴细胞的效率 目标：在一年的时间内，基苏木 (n=250) 和内罗毕的 500 个 MSM 样本中的 T 细胞被激活。 (n=250)，我们将测量阴茎和直肠微生物组、粘膜免疫特征、社会行为和 在目标 1 中，我们将描述结构因素以及尿道和肛门直肠 STI（CT、NG）的发病率。 STI 感染的临床病史，从检测时间 → 治疗时间 → 治疗和清除。 将在基线、6 个月和 12 个月时从所有男性身上采集样本，以表征阴茎和直肠的特征 微生物组组成（通过高通量扩增子测序）、粘膜免疫学（广泛测量 促炎、炎性和抗炎细胞因子和趋化因子以及上皮细胞的测量 屏障完整性），并通过核酸扩增测定来测试 STI，考虑到随访损失。 预计会发生 70-90 例 CT 和/或 NG 感染，对于这些男性，微生物组组成、粘膜 当他们接受抗生素治疗时，将再次评估免疫学和细菌功能，4 在治疗后几周，我们将量化阴茎和直肠微生物组的组成。 分别与尿道和直肠性传播感染事件的风险相关 作为次要结果，我们将确定。 粘膜免疫特征和显性检查它们与微生物组的关系如何随时间变化 在目标 3 中，我们将在 STI 病例中确定与直肠微生物组相关的适应性免疫机制， 宿主事件免疫以及有症状或无症状性传播感染的治疗和预防。 影响：性传播感染治疗对阴茎和直肠微生物组组成和细菌功能的影响 尚不清楚，描述感染临床病史的这一方面可以确定新的治疗方法和 了解可能破坏性传播感染保护性免疫力的因素可能至关重要。 为实现性传播感染控制所需的更有效疫苗的设计提供信息。