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

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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.