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，与男性发生性关系的男人的性传播率更高2-4倍 感染（性传播感染）和艾滋病毒比一般男性人群。在我们在肯尼亚Kisumu的700 MSM的队列中， 尿道和肛门直肠梭状芽胞庭（CT）和/或淋病（NG）的发生率为每100人19.8 年（PY）一年。这些速率是我们在异性恋肯尼亚人中测量的事件的2-3倍 男人。我们对Kisumu和Nairobi的MSM的研究确定了特定的直肠细菌社区结构 与炎症性粘膜免疫特征有关的。炎症直肠微生物组轮廓可以 通过倾斜全身性T细胞种群增加感染收购和干扰疫苗效率的风险 提高记忆/幼稚的淋巴细胞比和较高的基本免疫状态 激活，正如我们的初步研究所支持的那样。因此，炎症可能会破坏部分 STI疫苗能力的保护效率能够使最佳免疫性所需的幼稚淋巴细胞产生 降低幼稚淋巴细胞的频率，并通过降低其余幼稚的效率 T细胞被启动。目的：在一年的时间内，在Kisumu（n = 250）和内罗毕的500 msm样本中 （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 结构因子以及尿道和厌食性传播疾病的入射（CT，NG）。在AIM 1中，我们将表征 从检测时间到治疗时间到治疗时间到治疗和清除的临床感染的临床病史。 将从基线时，6个月和12个月的所有男人收集样品，以表征阴茎和直肠 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，炎症和抗炎细胞因子和趋化因子以及上皮措施 屏障完整性），并通过核酸扩增测定法进行STI。考虑到后续行动的损失，我们 预期70-90事件CT和/或NG感染，对于这些男性，微生物组成分，粘膜 免疫学和细菌功能将在出现抗生素治疗时再次评估，4 治疗后的几周。在AIM 2中，我们将量化阴茎和直肠微生物组成分的 分别与出现尿道和直肠性传播感染的风险有关。作为次要结果，我们将确定 主要的粘膜免疫学特征并检查它们与微生物组有关的时间变化 作品。在AIM 3中，我们将在STI中确定与直肠微生物组联系起来的自适应免疫组机制， 宿主免疫，有症状或无症状的性传播性传播感染感染。治疗和预防性 含义：STI治疗对阴茎和直肠微生物组组成和细菌功能的影响 是未知的，表征感染临床病史的这一方面可以识别新的治疗方法 预防途径。了解可能破坏受保护性传播疾病的因素可能是至关重要的 通知设计实现STI控制所需的更有效的疫苗。