Abstract
Recent epidemiological studies link Periodontal disease(PD) to age-related macular degeneration (AMD). We documented earlier that Porphyromonas gingivalis(Pg), keystone oral-pathobiont, causative of PD, efficiently invades human gingival epithelial and blood-dendritic cells. Here, we investigated the ability of dysbiotic Pg-strains to invade human-retinal pigment epithelial cells(ARPE-19), their survival, intracellular localization, and the pathological effects, as dysfunction of RPEs leads to AMD. We show that live, but not heat-killed Pg-strains adhere to and invade ARPEs. This involves early adhesion to ARPE cell membrane, internalization and localization of Pg within single-membrane vacuoles or cytosol, with some nuclear localization apparent. No degradation of Pg or localization inside double-membrane autophagosomes was evident, with dividing Pg suggesting a metabolically active state during invasion. We found significant downregulation of autophagy-related genes particularly, autophagosome complex. Antibiotic protection-based recovery assay further confirmed distinct processes of adhesion, invasion and amplification of Pg within ARPE cells. This is the first study to demonstrate invasion of human-RPEs, begin to characterize intracellular localization and survival of Pg within these cells. Collectively, invasion of RPE by Pg and its prolonged survival by autophagy evasion within these cells suggest a strong rationale for studying the link between oral infection and AMD pathogenesis in individuals with periodontitis.
Highlights
P. gingivalis[16,17], an effective late colonizer of oral tissues and a red complex bacterium is highly associated with PD
To determine whether P. gingivalis invades human retinal pigment epithelial (RPE), ARPE-19 cells were cocultured with Carboxyfluorescein diacetate succinimidyl ester (CFSE)-labeled Pg381 at 1, 10 and 100 multiplicity of infection (MOI) (Fig. 1B–D) and uptake quantified (Fig. 1E), compared with uninfected control (Fig. 1A) after 24 hours
It was interesting to note that Pg381 is capable of invading ARPE cells even at 1 MOI (Fig. 1B), which can be clearly observed in the cytosol and around the cell nuclei
Summary
P. gingivalis[16,17], an effective late colonizer of oral tissues and a red complex bacterium is highly associated with PD. Specific microbiota of human nasopharynx is linked to AMD31 Despite these observations, a limited understanding exists about the role of dysbiotic oral pathobionts in AMD pathology indicating a critical knowledge gap and an imperative need to probe the underlying molecular mechanisms. The dissemination of oral microbes to the eye structure and their interactions that could contribute to the development of AMD have not been investigated yet This may represent a novel opportunity to understand the mechanisms underlying the pathological association of AMD in coexisting chronic oral inflammation. Breakdown of the inner endothelial BRB is reported in diabetic retinopathy and that of outer BRB in case of AMD38
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