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）的性传播疾病发病率是其他人的2-4倍。 艾滋病毒感染（STI）和艾滋病毒感染率高于一般男性人口。在肯尼亚基苏穆的700名男男性行为者中， 尿道和肛门直肠C.沙眼衣原体（CT）和/或N.淋球菌感染率为19.8/100人 年（PY）超过一年。这些比率是我们在肯尼亚异性恋者中测量的发病率的2-3倍 男人我们对基苏穆和内罗毕MSM的研究已经确定了特定的直肠细菌群落结构 与炎症性粘膜免疫特征有关。炎症性直肠微生物组特征可能 增加感染STI风险，并通过使全身T细胞群偏斜而干扰疫苗效力 增加记忆/降低幼稚淋巴细胞比率，以及基础免疫状态更高。 根据我们的初步调查，因此，炎症可能会破坏部分 STI疫苗的保护效力能够引发最佳免疫所需的幼稚淋巴细胞， 降低幼稚淋巴细胞的频率，并通过降低剩余幼稚淋巴细胞的效率， T细胞被激活。目的：在为期一年的时间里，在基苏穆（n=250）和内罗毕的500名MSM样本中 （n=250），我们将测量阴茎和直肠微生物组，粘膜免疫概况，社会行为和 结构因素和尿道和肛门直肠性传播感染（CT，NG）的发病率。在目标1中，我们将描述 从检测到治疗到治疗和清除的STI感染临床史。 将在基线、6个月和12个月时从所有男性中采集样本，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 促炎性、炎性和抗炎性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法测试STI。考虑到失访，我们 预计70-90例CT和/或NG感染，对于这些男性，微生物组组成，粘膜 免疫学和细菌功能将再次评估，当他们出现抗生素治疗，和4 治疗后几周。在目标2中，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的风险相关。作为次要结果，我们将确定 占主导地位的粘膜免疫谱，并检查它们如何随时间变化与微生物组 混合物.在目标3中，我们将在STI病例中确定连接直肠微生物组的适应性免疫机制， 宿主免疫力和有症状或无症状的性传播感染事件感染。治疗和预防 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，表征感染临床史的这一方面可以确定新的治疗方法， 预防途径。了解可能破坏对性传播感染的保护性免疫的因素可能至关重要 为设计实现STI控制所需的更有效疫苗提供信息。