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In recent studies, the interleukin (IL)-36 cytokines were shown to be elevated in women with non-Lactobacillus-dominated vaginal microbiomes. In this study, we evaluated IL36G expression in clinical samples from women with and without bacterial vaginosis (BV) and a human 3-dimensional cervical epithelial cell model. IL36G expression was significantly elevated in cervicovaginal epithelial cells isolated from BV-positive women and corresponded with increased neutrophil counts relative to BV-negative women. In addition, specific BV-associated bacterial species as well as a polymicrobial cocktail significantly induced IL36G expression in vitro. These findings suggest that IL-36γ may exhibit an important function in the host response to BV and other sexually transmitted infections., (© The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Background: Pregnancy has been considered to be a time of relative immune compromise. Lower-genital-tract immune response appears to be influenced by pregnancy. The objective of this study was to compare, in pregnant versus nonpregnant women, endocervical proinflammatory-cytokine expression in response to bacterial vaginosis., Methods: Endocervical levels of interleukin (IL)-1 beta , IL-6, and IL-8 in 99 pregnant and 99 nonpregnant women, all with bacterial vaginosis and without concurrent sexually transmitted infections, were assessed by ELISA. Vaginal flora was characterized on the basis of quantitative vaginal cultures., Results: Women in the 2 groups differed with respect to smoking status and microbiological constituents responsible for bacterial vaginosis. When the data were stratified by these potential confounders, the levels of all 3 proinflammatory endocervical cytokines were significantly higher in pregnant women than in nonpregnant women., Conclusions: The proinflammatory cytokine milieu in the cervix is enhanced in pregnant women with bacterial vaginosis, compared with that in nonpregnant women. The notion of pregnancy as an immune-compromised state may be anatomically compartment specific.

Background: Bacterial vaginosis (BV) is associated with increased risk of obstetrical and gynecologic complications and acquisition of sexually transmitted diseases. Despite this, very little is known about the pathogenesis of this disease., Methods: Interleukin (IL)-1 beta , tumor necrosis factor- alpha , IL-6, and IL-8 concentrations in vaginal wash and serum samples from women with normal flora, intermediate flora, and BV (determined by Nugent criteria) were measured by enzyme-linked immunosorbent assay., Results: Cytokine levels were not different between women with intermediate flora and women with BV. Women with either intermediate flora or BV had significantly higher concentrations of IL-1 beta in vaginal wash samples than did women with normal flora. The presence of IL-1 beta in vaginal wash samples was associated with >30 Gardnerella or Prevotella morphotypes per high-power field, as detected by Gram staining of vaginal swab specimens. Variation in the numbers of Lactobacillus and Mobiluncus species did not influence local cytokine levels. Serum cytokine levels were not influenced by any changes in vaginal flora., Conclusions: Women with intermediate flora generate significant cytokine responses. It is possible that the risks associated with BV may also affect women with intermediate flora and that appropriate treatment may reduce such risk.

Background: Bacterial vaginosis (BV) is associated with complications of pregnancy and increased susceptibility to human immunodeficiency virus (HIV) sexual transmission., Methods: The ability of genital mucosal fluids from women with BV and of microbial flora associated with BV to induce tumor necrosis factor (TNF)- alpha secretion and Toll-like receptor (TLR) 2 and TLR4 mRNA expression was assessed., Results: Primary peripheral-blood mononuclear cells and THP-1 monocytic cells secreted TNF- alpha in response to cervicovaginal lavage (CVL) samples from women with BV. Mycoplasma hominis and Gardnerella vaginalis also stimulated TNF- alpha secretion. Strikingly, CVL samples from women with BV induced up to 60-fold increases in TLR4 mRNA expression, compared with CVL samples from women without BV and with bacteria not associated with BV. Anti-TNF- alpha antibody blocked increases in TLR4 mRNA expression induced by CVL samples from women with BV, indicating that TNF- alpha plays a critical role in induction of TLR4. Both TLR2 and TLR4 mRNA expression were approximately 60-fold higher in cells isolated from the lumen of the genital tract than in cervical mucosal tissue, but lumen TLR mRNA levels did not change significantly after BV treatment., Conclusions: These experiments show that genital mucosal fluids and certain bacteria from women with BV stimulate TNF- alpha secretion and TLR4 mRNA expression, suggesting mechanisms whereby BV affects pregnancy and HIV transmission.

Six strains of Prevotella bivia and 4 of Gardnerella vaginalis were examined for nutrient substrate utilization as part of ongoing studies on the pathogenesis of bacterial vaginosis. Addition of single amino acids to vaginal defined medium (VDM) was stimulatory to the growth of P. bivia but not to G. vaginalis. However, peptides significantly promoted the growth of both organisms. Growth of P. bivia in VDM and VDM supplemented with either amino acids or peptone was accompanied by net ammonia production, while growth of G. vaginalis under the same conditions resulted in net ammonia utilization. Ammonia-enriched supernatants from the growth of P. bivia in peptone-supplemented VDM were stimulatory to G. vaginalis growth. However, ammonia-reduced supernatants from G. vaginalis growth in peptone-supplemented VDM had a neutral effect on P. bivia growth. A commensal relationship between P. bivia to G. vaginalis is proposed, with ammonia flow as a mechanism to support this hypothesis.