Mycobacteriumdormancy and antibiotic tolerance within the retinal pigment epithelium of ocular tuberculosis

Abstract

AbstractTuberculosis (TB) is a leading cause of death among infectious diseases worldwide due to latent TB infection, which is the critical step for the successful pathogenic cycle. In this stage,Mycobacterium tuberculosisresides inside the host in a dormant and antibiotic-tolerant state. Latent TB infection can lead to a multisystemic diseases becauseM. tuberculosisinvades virtually all organs, including ocular tissues. Ocular tuberculosis (OTB) occurs when the dormant bacilli within ocular tissues reactivate, originally seeded by hematogenous spread from pulmonary TB. Timely and accurate diagnosis as well as efficient chemotherapies are crucial in preventing poor visual outcomes of OTB patients. Histological evidence suggests that retinal pigment epithelium (RPE) cells play a central role in immune privilege and in the protection from the antibiotic effects, making them an anatomical niche for invadingM. tuberculosis. RPE cells exhibit high tolerance to environmental redox stresses, allowing phagocytosedM. tuberculosisbacilli to maintain viability in a dormant state. However, the microbiological and metabolic mechanisms determining the interaction between the RPE intracellular environment and phagocytosedM. tuberculosisare largely unknown. Here, liquid chromatography mass spectrometry (LC-MS) metabolomics was used to illuminate the metabolic state within RPE cells reprogrammed to harbor dormantM. tuberculosisbacilli and enhance the antibiotic tolerance. The results have led to propose a novel therapeutic option to synthetically kill the dormantM. tuberculosisinside the RPE cells by modulating the phenotypic state ofM. tuberculosis, thus laying the foundation for a new, innovative regimen for treating OTB.ImportanceUnderstanding the metabolic environment within the retinal pigment epithelium (RPE) cells altered by infection withM. tuberculosisand mycobacterial dormancy is crucial to identify new therapeutic methods to cure OTB. The present study showed that RPE cellular metabolism is altered to foster intracellular M. tuberculosis to enter into the dormant and drug tolerant state, thereby blunting the efficacy of anti-TB chemotherapy. RPE cells serve as an anatomical niche as the cells protect invading bacilli from antibiotic treatment. LC-MS metabolomics of RPE cells after co-treatment with H2O2 and M. tuberculosis infection showed that intracellular environment within RPE cells is enriched with greater level of oxidative stress. The antibiotic tolerance of intracellularM. tuberculosiswithin RPE cells can be restored by a metabolic manipulation strategy such as co-treatment of antibiotic with the most downstream glycolysis metabolite, phosphoenolpyruvate.