Relationship between a toll-like receptor-4 gene polymorphism, bacterial vaginosis-related flora and vaginal cytokine responses in pregnant women
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.
Available from: PubMed Central
- "For example, TLR-4 genes have been implicated in BV, PD and IBD pathogenesis (98–100). Cytokine-producing genes such as IL-1β and IL-1RA have been involved in the pathogenesis of BV, PD, IBD and PS (43, 101–104). Levels of pro-inflammatory cytokines such as TNF-α are increased in CD, PD and PS (27, 105, 106). "
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ABSTRACT: Thousands of bacterial phylotypes colonise the human body and the host response to this bacterial challenge greatly influences our state of health or disease. The concept of infectogenomics highlights the importance of host genetic factors in determining the composition of human microbial biofilms and the response to this microbial challenge. We hereby introduce the term 'genetic dysbiosis' to highlight the role of human genetic variants affecting microbial recognition and host response in creating an environment conducive to changes in the normal microbiota. Such changes can, in turn, predispose to, and influence, diseases such as: cancer, inflammatory bowel disease, rheumatoid arthritis, psoriasis, bacterial vaginosis and periodontitis. This review presents the state of the evidence on host genetic factors affecting dysbiosis and microbial misrecognition (i.e. an aberrant response to the normal microbiota) and highlights the need for further research in this area.
Journal of Oral Microbiology 02/2014; 6(1). DOI:10.3402/jom.v6.22962
Available from: Tao Zhang
- "Figure 8 shows the level of inflammatory cytokine release on VK and Endo cell lines. These cytokines are chosen because of their extensive involvement in mucosa toxicity research both in vitro and in vivo (Fichorova et al., 2004; Fichorova et al., 2005; Genc et al., 2004). In case of IL-6, IL-8 and IP-10, the level of cytokine triggered by EuSNa-TFV MS is significantly lower compared to the positive control, suggesting its immunogenicity is transient. "
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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.
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.
The optimal MS formulation has an average size of 4.73μm, zeta potential of -26.3mV, 68.9% yield, encapsulation efficiency of 88.7%, Carr's index of 28.3 and drug loading of 2% (w/w). The MS formulation release 91.7% of its payload in the presence of simulated human semen. At a concentration of 1mg/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 these MS. Their percent mucoadhesion is 2-fold higher than that of 1% HEC gel formulation.
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 · 3.94 Impact Factor
Available from: Sadeep Shrestha
- "This same SNP has also been associated with pre-term birth as well as a number of clinically relevant outcomes including higher gram negative infections and gram-negative septic shock (Agnese et al., 2002; Lorenz et al., 2002a,b). Colonization of G. vaginalis and/or gram-negative rods are significantly higher among women with homozygote AA genotype at rs4986790 (Genc et al., 2004); on the other hand AG and GG genotypes have been associated with decreased responsiveness to inhaled LPS in humans (Arbour et al., 2000). Our findings support the hypothesis that TLR4 gene is important for the response to gram negative bacteria in the vaginal microenvironment. "
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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 · 2.82 Impact Factor
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