Exploring the role of innate immune genetic variation in bacterial vaginosis and vaginal bacterial colonization

Abstract

Background. Bacterial vaginosis (BV) is a common, vaginal dysbiosis associated with adverse gynecological and reproductive health outcomes. BV-associated bacteria (BVAB) present microbe-associated molecular patterns to Toll-like receptors (TLRs), which modulate the innate immune response. However, the role of these TLRs in BV pathogenesis remains unclear. I hypothesized that individuals possessing single nucleotide polymorphism (SNP) genotypes associated with heightened innate immune responses (TLR1, TLR6, TLR4, and TLR5 “sufficiency”; TLR10, TOLLIP “deficiency”) are at decreased risk of BV and colonization with BV-associated bacteria (BVAB). Methods. Women were enrolled in independent discovery and validation cohorts and genotyped for common, functionally-characterized SNPs: TLR1 rs5743618, TLR6 rs3821985, TLR4 rs4986790, TLR4 rs4986791, TLR5 rs5744168, TLR10 rs11096955, TLR10 rs4129009, and TOLLIP rs5743854. Genotype models (“sufficient” versus “deficient”) were based on previously published data. As my primary analysis, I compared TLR/TOLLIP sufficient and deficient study participants on the following outcomes: risk of clinically-defined BV, risk of microbiologically-defined BV, colonization with lactobacilli, and colonization with BVAB. Results – Association with BV. In both the discovery and validation cohorts, TLR10 rs11096955 TG/GG (deficiency) associated with increased risk of clinically-defined BV. TOLLIP deficiency and TLR4 deficiency were both associated with increased risk of clinically-defined BV, but only in the discovery cohort. Results – Association with bacterial colonization. TLR4, TLR10, and TLR6 deficiencies were associated with lower Lactobacillus jensenii concentrations. TOLLIP deficiency was associated with higher concentrations of Megasphaera types 1 and 2, Gardnerella vaginalis, and Atopobium vaginae. TLR4 deficiency was correlated with higher concentrations of G. vaginalis, A. vaginae, and total bacterial load. TLR5 deficiency was associated with lower concentration of flagellated species, BV-associated bacterium 1, and Mobiluncus mulieris (but not Mobiluncus curtisii). Conclusions. Individuals possessing genotypes consistent with increased TLR-mediated responses—TLR10, TOLLIP deficiency—have increased risk of clinically-defined BV. The data presented here are consistent with TLR4 deficiency being realized as a deficiency of soluble TLR4 that affects concentrations of several Gram-positive bacteria. Finally, individuals with more robust TLR5 responses (TLR5 sufficiency) appear more susceptible to colonization with specific, flagellated BVAB, although no differences in overall risk of clinically- or microbiologically-defined BV appear to exist. The data presented here are consistent with a model whereby some BVAB benefit from host innate immune response.