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

在撒哈拉以南非洲，男男性行为者(MSM)的性传播率是男性的2-4倍 性传播感染(STI)和艾滋病毒的发病率高于一般男性人口。在我们肯尼亚基苏木的700名男男性接触者队列中， 尿路和肛门直肠沙眼衣原体(CT)和/或淋球菌(NG)的发病率为19.8/100人 年(PY)超过一年。这些发病率是我们在肯尼亚异性恋人群中测量的发病率的2-3倍 男人。我们在基苏木和内罗毕对男男性接触者的研究发现了特定的直肠细菌群落结构 与炎性粘膜免疫特征相关的基因。炎症性直肠微生物组图谱可能 通过扭曲系统T细胞群增加性传播感染的风险并干扰疫苗效力 记忆力增强/幼稚淋巴细胞比率降低，基础免疫状态更高 激活，由我们的初步调查支持。因此，炎症可能会破坏部分 性传播感染疫苗对最佳免疫所需的幼稚淋巴细胞的保护作用 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细胞已经准备好了。目标：在一年的时间里，在基苏木(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群，粘膜免疫图谱，社会行为和 结构因素，以及尿路和肛门直肠感染的发生率(CT，NG)。在目标1中，我们将描述 性传播感染的临床病史从检测到治疗再到治疗和清除。 将在基线、6个月和12个月时从所有男性身上收集样本，以确定阴茎和直肠的特征 微生物组组成(通过高通量扩增序列测定)、粘膜免疫学(广义的 促炎症、炎症和抗炎细胞因子和趋化因子及上皮细胞的测量 屏障完整性)，并通过核酸扩增试验检测STI。考虑到后续的损失，我们 预计发生70-90次CT和/或NG感染，对于这些人来说，微生物组组成，粘膜 免疫学和细菌功能将在他们接受抗生素治疗时再次进行评估，以及4 治疗后几周。在目标2中，我们将量化阴茎和直肠微生物群的组成 分别与发生尿道性传播感染和直肠性传播感染的风险有关。作为次要结果，我们将确定 主要的粘膜免疫图谱，并研究它们如何随时间变化与微生物组的关系 组成。在目标3中，我们将在性传播感染病例中确定与直肠微生物群有关的获得性免疫机制， 宿主免疫，以及有症状或无症状性传播感染事件。治疗和预防 STI治疗对阴茎和直肠微生物群组成和细菌功能的影响 感染临床病史的这一方面的特征是未知的，可以确定新的治疗方法和 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是至关重要的 为设计更有效的疫苗提供信息，这些疫苗是实现性传播感染控制所需的。

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.