Abstract
BackgroundCoronal sulcus (CS) anaerobe abundance and IL-8 levels are linked to HIV acquisition, and are dramatically reduced after penile circumcision (PC). The distal urethra may be the site of some HIV acquisition before PC, and presumably most acquisition post PC. We describe the immune milieu and microbiome of the distal urethra in uncircumcised Ugandan men, and define the impact of PC. Participants consisted of HIV-negative, genital symptom-free adult Ugandan men undergoing PC (n = 51). Urethral and coronal sulcus swabs were collected at baseline and at 6- and 12-months post-PC. Soluble immune factors were quantified by multiplex ELISA, and bacterial abundance assessed by 16S rRNA qPCR and sequencing.ResultsAt baseline, the urethra was enriched compared to the CS for most cytokines (including IL-8 and MIP-1β) and soluble E-cadherin (sE-cadherin, an epithelial disruption marker), although CS levels of IL-1α and IL-1β were higher. Baseline total bacterial abundance was ≥ 20-fold higher in the CS than the urethra (median 27,100 vs. 1200 gene copies/swab, p = 0.001), and anaerobes comprised 58% of CS bacteria vs. 42% of urethral bacteria. PC did not alter urethral IL-8 (median 806 at baseline vs. 1130 pg/ml at 12 months; p = 0.062) and urethral sE-cadherin increased (113,223 vs. 158,385 pg/ml, p = 0.009), despite five- and sevenfold drops in total bacterial and anaerobe abundance after PC, respectively. However, PC dramatically reduced CS levels of sE-cadherin (15,843 vs. 837 pg/ml, p < 0.001) and most cytokines (IL-8; 34 vs. 3 pg/ml, p < 0.001), while reducing total bacterial and anaerobe abundance by 13-fold and 60-fold, respectively (both P ≤ 0.004).ConclusionsThe urethra is immunologically rich with characteristics of an HIV-susceptible tissue site. However, PC had no impact on urethral immunology and may have reduced epithelial integrity, despite modest reductions in total bacteria and anaerobes, suggesting that HIV protection from PC is not mediated via immune or microbiome alterations in the urethra.6PgEasmsZ9wG1E4iwYa-kCVideo abstract
Highlights
Coronal sulcus (CS) anaerobe abundance and interleukin 8 (IL-8) levels are linked to human immunodeficiency virus type 1 (HIV) acquisition, and are dramatically reduced after penile circumcision (PC)
The total bacterial load and the proportion of anaerobes is dramatically reduced in the CS after PC, with a shift from anaerobes typically associated with bacterial vaginosis (e.g., Gardnerella, Prevotella, and Peptostreptococcus) toward facultative anaerobic bacteria generally considered to be normal skin flora (e.g., Staphylococcus and Corynebacteria)
The distal urethra was significantly enriched for multiple cytokines and other immune factors compared to the CS, including IL-8, matrix metallopeptidase 9 (MMP-9), macrophage inflammatory protein (MIP)-1β, resistin and tissue inhibitor of metalloproteinases (TIMP)-1
Summary
Coronal sulcus (CS) anaerobe abundance and IL-8 levels are linked to HIV acquisition, and are dramatically reduced after penile circumcision (PC). Foreskin removal obliterates the subpreputial space, where HIV-containing genital fluids may be retained between the glans penis and inner foreskin after sex, thereby prolonging virus-tissue contact In addition to these physical alterations, surgical obliteration of the subpreputial space via PC exposes the coronal sulcus (CS) to air, profoundly altering both the penile microbiome composition and immune milieu. There are substantial reductions in the levels of the chemoattractant cytokine interleukin (IL)-8 [9,10,11], a chemokine which has been directly linked to the increased density of anaerobes in the prepuce, to an increased density of foreskin HIV target cells, and to an increased risk of HIV acquisition risk [9] This suggests that the microenvironment of the subpreputial space in an uncircumcised man sustains an anaerobic microbiome that induces host tissue inflammation and thereby increases HIV susceptibility [12]
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