Cervicovaginal Immune Activation in Zambian Women With Female Genital Schistosomiasis

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.

Association of Female Genital Schistosomiasis With the Cervicovaginal Microbiota and Sexually Transmitted Infections in Zambian Women

“…Additionally, macrophage polarization can be influenced by the local immune environment, schistosomes, and T. vaginalis [ 53 , 54 ]. We have previously shown that, compared with FGS-negative women, high-burden FGS is associated with higher concentrations of cervicovaginal Th2 cytokines [ 32 ]. A mouse model of urogenital S. haematobium infection suggested that the Th2 immune environment may be associated with delayed pathogen clearance [ 55 ].…”

“…In this study, we employed various diagnostic tests to evaluate urinary schistosome infection (CAA and urine microscopy) and FGS (portable colposcopy and Schistosoma DNA on CVL and genital swabs). As previously described [ 32 ], participants were grouped by diagnostic test results into 3 mutually exclusive categories: FGS, at least 1 positive Schistosoma qPCR on a genital specimen (cervical swab, vaginal swab, and/or CVL); FGS negative, negative results on all diagnostic methods; probable FGS, genital Schistosoma qPCRs negative but urinary schistosomiasis positive (as defined above), in combination with 1 of 4 clinical findings suggestive of FGS on any colposcope-obtained photograph [ 25 ].…”

The Road to Elimination: Current State of Schistosomiasis Research and Progress Towards the End Game

“…Also, FGS has been associated with a higher frequency of systemic CD4 T-cells expressing the chemokine receptor CCR5 ( 268 ) resulting in increased HIV-1 target cell population. Furthermore, cervicovaginal immune activation has also been observed in women with FGS ( 269 ). Conceivably, FGS lesions may compromise cervicovaginal immune barriers and possibly result in increased vulnerability to HIV-1 infection.…”

Impact of a Group-Based Video and Interactive Group Session Addressing Diarrheal Disease, Helminthic and Schistosomiasis Infections, Hypertension and Diabetes on Short and Long-Term Improvement in Knowledge and Healthy Behaviors in Seroconcordant HIV-Negative Zambian Couples

“…We have recently shown that schistosomiasis is associated with HIV-1 transmission and death in Lusaka, possibly related to enhanced inflammatory responses caused by egg deposition in the lower genital tract [24,53]. A recent assessment based on literature review estimates nationwide prevalence of schistosome infection exceeding 30% with an adult prevalence of 54% [54].…”