The Clinical History of Rectal and Urethral STIs among MSM: characterizing microbiome host immune interactions for diagnostic and vaccine advances - In the United States, men are disproportionately affected by HIV and sexually transmitted infections (STI), accounting for 81% of all HIV diagnoses and with 30% higher rates of gonorrhea than women. Among American men who have sex with men (MSM), STIs can be 70% higher. Similarly, in sub-Saharan Africa, MSM have 2-4 times higher rates of STIs than the general male population, and several fold higher than the U.S. population. STIs are a clinical and public health problem because they contribute to male infertility, risk of HIV acquisition, and prostate cancer. In our cohort of 700 MSM in 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. Our studies of Kenyan men 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 therapeutic efficacy by skewing systemic T cell populations toward an increased memory/decreased naïve lymphocyte ratios, and a higher state of basal immune activation. 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 treatment and clearance. Samples will be collected 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, anti-inflammatory cytokines and chemokines, and measures of epithelial barrier integrity), and test for STI by nucleic acid amplification assay. 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 identify adaptive immune mechanisms that link microbiome, host immunity, and symptomatic or asymptomatic STI incident infections. Implications for Americans: STIs in men account for an estimated 10-15% of male infertility, and 10-20% of new HIV cases. Gonorrhea is one of seven global pathogens of highest threat to antimicrobial resistance. If we identify male genitourinary/anorectal taxa with even a 25% protective effect against STIs, as we are powered to do, this can lead to tens of thousands of averted STIs, reduced poor health outcomes (infertility, HIV, cancers, transmission to women), and reduce antimicrobial use. This study is being conducted in Kenyan MSM because of the hyperendemicity of STIs, which results in smaller sample size and shorter duration of study needed to achieve > 80% power to observe even modest effect sizes. The results will be directly relevant to American men due to similar biological pathways and similar health outcomes.
