Relationship between a toll-like receptor-4 gene polymorphism, bacterial vaginosis-related flora and vaginal cytokine responses in pregnant women
ABSTRACT The relationship between a single nucleotide polymorphism (TLR4 896 A > G) in the toll-like receptor-4 (TLR4) gene, qualitative and quantitative changes in vaginal micro-flora and vaginal interleukin (IL)-1beta and IL-1 receptor antagonist (IL-1ra) concentrations in pregnant women were evaluated.
Qualitative and quantitative microbial methods were used to characterize vaginal micro-flora of 238 women at 18-22 weeks gestation. Polymerase chain reaction was used to determine TLR4 genotype. IL-1beta and IL-1ra concentrations in vaginal lavage samples were measured by ELISA.
The TLR4 variant was identified in 10.3% of women. Carriage of this variant was associated with a median increase in vaginal pH (P = 0.05), a greater than 10-fold increase in vaginal Gardnerella vaginalis levels (P < 0.0001) and a 10-fold increase in the vaginal concentration of three species of anaerobic Gram-negative rods, Prevotella, Bacteroides, and Porphyromonas (P = 0.08 ). Colonization with G. vaginalis and/or the anaerobic Gram-negative rods resulted in elevated vaginal IL-1 (P = 0.01) and IL-1ra (P < 0.0002) concentrations in women who were TLR4 896A homozygotes, but not in TLR4 896G carriers.
The TLR4 896 A > G polymorphism contributes to inter-individual differences in the vaginal immune defense against G. vaginalis and anaerobic Gram-negative rods.
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ABSTRACT: PURPOSE: To develop spray dried mucoadhesive and pH-sensitive microspheres (MS) based on polymethacrylate salt intended for vaginal delivery of tenofovir (a model HIV microbicide) and assess their critical biological responses. METHODS: The formulation variables and process parameters are screened and optimized using a 2(4-1) fractional factorial design. The MS are characterized for size, zeta potential, yield, encapsulation efficiency, Carr's index, drug loading, in vitro release, cytotoxicity, inflammatory responses and mucoadhesion. RESULTS: The optimal MS formulation has an average size of 4.73 μm, Zeta potential of -26.3 mV, 68.9% yield, encapsulation efficiency of 88.7%, Carr's index of 28.3 and drug loading of 2% (w/w). The MS formulation can release 90% of its payload in the presence of simulated human semen. At a concentration of 1 mg/ml, the MS are noncytotoxic to vaginal endocervical/epithelial cells and Lactobacillus crispatus when compared to control media. There is also no statistically significant level of inflammatory cytokine (IL1-α, IL-1β, IL-6, IL-8, and IP-10) release triggered by MS. The mucoadhesive property of MS formulation is 2-fold higher than that of 1% HEC gel formulation. CONCLUSION: These data suggest the promise of using such MS as an alternative controlled microbicide delivery template by intravaginal route for HIV prevention.Antiviral research 12/2012; 97(3). DOI:10.1016/j.antiviral.2012.12.019 · 3.43 Impact Factor
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ABSTRACT: Bacterial vaginosis (BV) is a common vaginal disorder in women of reproductive age, especially among women with HIV-1 infection. Several bacterial products including lipopolysaccharides (LPS), lipoteichoic acids (LTA), and peptidoglycans (PGN) are stimulatory ligands for Toll-like receptors (TLRs), and recent evidence indicates the important role of variation in TLR genes for permitting overgrowth of gram negative and BV-type flora. We assessed whether genetic polymorphisms in five TLR genes (TLR1, TLR2, TLR4, TLR6, and TLR9) could be determinants of differential host immune responses to BV in 159 HIV-1-positive African American adolescents enrolled in the Reaching for Excellence in Adolescent Care and Health (REACH) study. BV was assessed biannually and diagnosed either by a Nugent score of at least 7 of 10, or using the Amsel criteria. Cox-proportional hazards regression models, adjusted for concurrent Chlamydia and Gonorrhea infections, douching, and absolute CD4 cell count, were used to identify host genetic factors associated with BV. Two SNPs were associated with BV as diagnosed by the Nugent score and the combined criteria: a minor allele G of rs4986790 (frequency=0.07), which encodes a His to Tyr substitution in TLR4 (HR=1.47, 95% CI 1.15-1.87) and rs187084 (frequency=0.24) on TLR9. The minor allele of rs1898830 (frequency=0.13) was associated with an increased hazard of BV defined by the Amsel criteria (HR=1.86, 95% CI 1.17-2.95). Further studies are warranted to confirm the associations of TLR gene variants and also to understand the underlying pathways and immunogenetic correlates in the context of HIV-1 infection.Journal of Reproductive Immunology 09/2012; 96(1-2). DOI:10.1016/j.jri.2012.08.002 · 2.37 Impact Factor
- Preterm Birth - Mother and Child, 01/2012; , ISBN: 978-953-307-828-1