Cervicovaginal Immune Activation in Zambian Women With Female Genital Schistosomiasis.

Amy S Sturt,Isaiah Hansingo,Tobias Mweene,Piet Cools,Grace A Mccomsey,Suzanna C Francis,Joyce Mapani,Lisette Van Lieshout,Paul L A M Corstjens,Maina Mudenda,James Chipeta,Helen Ayles,Helena Helmby,Govert J Van Dam,Catriona Patterson,Amaya L Bustinduy,Emily L Webb,Comfort Rutty Phiri ,Mable Mutengo ,Richard Hayes ,Eyrun Floerecke Kjetland

doi:10.3389/fimmu.2021.620657

Abstract

HIV-1 infection disproportionately affects women in sub-Saharan Africa, where areas of high HIV-1 prevalence and Schistosoma haematobium endemicity largely overlap. Female genital schistosomiasis (FGS), an inflammatory disease caused by S. haematobium egg deposition in the genital tract, has been associated with prevalent HIV-1 infection. Elevated levels of the chemokines MIP-1α (CCL-3), MIP-1β (CCL-4), IP-10 (CXCL-10), and IL-8 (CXCL-8) in cervicovaginal lavage (CVL) have been associated with HIV-1 acquisition. We hypothesize that levels of cervicovaginal cytokines may be raised in FGS and could provide a causal mechanism for the association between FGS and HIV-1. In the cross-sectional BILHIV study, specimens were collected from 603 female participants who were aged 18–31 years, sexually active, not pregnant and participated in the HPTN 071 (PopART) HIV-1 prevention trial in Zambia. Participants self-collected urine, and vaginal and cervical swabs, while CVLs were clinically obtained. Microscopy and Schistosoma circulating anodic antigen (CAA) were performed on urine. Genital samples were examined for parasite-specific DNA by PCR. Women with FGS (n=28), defined as a positive Schistosoma PCR from any genital sample were frequency age-matched with 159 FGS negative (defined as negative Schistosoma PCR, urine CAA, urine microscopy, and colposcopy imaging) women. Participants with probable FGS (n=25) (defined as the presence of either urine CAA or microscopy in combination with one of four clinical findings suggestive of FGS on colposcope-obtained photographs) were also included, for a total sample size of 212. The concentrations of 17 soluble cytokines and chemokines were quantified by a multiplex bead-based immunoassay. There was no difference in the concentrations of cytokines or chemokines between participants with and without FGS. An exploratory analysis of those women with a higher FGS burden, defined by ≥2 genital specimens with detectable Schistosoma DNA (n=15) showed, after adjusting for potential confounders, a higher Th2 (IL-4, IL-5, and IL-13) and pro-inflammatory (IL-15) expression pattern in comparison to FGS negative women, with differences unlikely to be due to chance (p=0.037 for IL-4 and p<0.001 for IL-5 after adjusting for multiple testing). FGS may alter the female genital tract immune environment, but larger studies in areas of varying endemicity are needed to evaluate the association with HIV-1 vulnerability.

Highlights

HIV-1 infection disproportionately affects women in subSaharan Africa [1], where areas of high HIV-1 prevalence and Schistosoma haematobium endemicity largely overlap [2]
For the cytokines analyzed by logistic regression (IL-5, IL-13, IL-15, and TNFa), due to the relatively low number of participants with concentrations above the lower limit of quantification (LLOQ), these cytokines were adjusted for age and Sexually transmitted infection (STI)
Probable Female genital schistosomiasis (FGS) was detected in 25 women, and 61.1% (159/262) of the women who were negative on all diagnostic tests were randomly selected for inclusion in this study

Summary

Introduction

HIV-1 infection disproportionately affects women in subSaharan Africa [1], where areas of high HIV-1 prevalence and Schistosoma haematobium endemicity largely overlap [2]. Female genital schistosomiasis (FGS), caused most frequently by S. haematobium egg deposition in the genital tract, has been associated with prevalent HIV-1 infection in cross-sectional studies [3]. The presence of S. haematobium eggs in genital tissue is associated with vascularization [4] and the accumulation of CD4+ lymphocytes and macrophages [5], making the granuloma-associated environment a potential contributor to HIV-1 vulnerability. Tissue-entrapped eggs are associated with clinically visible FGS-associated manifestations in the cervicovaginal mucosa [7]. FGS lesions may breach the intact cervicovaginal immune barrier and are hypothesized to provide an entry point for HIV-1 infection [2, 3]. The underlying mechanism for potential HIV-1 vulnerability in FGS has not been fully characterized and requires further investigation

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Results

Conclusion