| dc.description.abstract | Rationale: Mycobacterium tuberculosis (M.tb) remains one of the deadliest infectious pathogens globally. Amidst efforts to control the disease, challenges such as long treatment duration, drug toxicity, and resistance underscore the need for novel therapeutic strategies. Until recently, emerging evidence suggests that some individuals, referred to as TB resistors, despite intense and persistent exposure to the bacilli, never acquire TB infection or clear the pathogen, remaining persistently negative for TST and IGRA. This persistently IGRA-negative phenotype suggests either resistance to M.tb infection at the respiratory mucosa or restriction of M.tb replication. To date, mechanisms of immune resistance to M.tb remain unknown and, if fully elucidated, may
provide insight into novel therapeutic strategies. The airway microbiome has been implicated in the modulation of airway mucosal immunity and could play a significant role in mediating immune resistance against M.tb among resistors. It is plausible that the airway microbiome-immune crosstalk determines resistance to M.tb attachment and infection of the respiratory mucosa or restriction of M.tb replication within alveolar macrophages. Deciphering which microbiome signatures induce robust immune responses remains a significant area to undertake. Aims and methods: In this study, we set out to characterize airway microbiome signatures driving immune resistance to M.tb in a rural Ugandan cohort of IGRA-negative individuals. To achieve our objective, we first developed a novel airway microbiome-immune library using COPD as an unbiased chronic airway inflammation environment. We performed detailed airway microbiome profiling based on M.tb-specific IFNg responses by QuantiFERON-TB GOLD assay and M.tb burden by TB GeneXpert. Using the airway microbiome-immune library as a reference, we predicted and validated microbiome-immune pathways associated with M.tb-specific immune responses among QFT-negative individuals. Results: Using a chronic airway inflammation “model”, we successfully deciphered the airway-microbiome-immune crosstalk and underpinned top signatures driving the immune response. We successfully underpinned a novel airway microbiome signature, accurately discriminating active TB from LTBI and healthy controls. M.tb rather than IFNg response strongly influenced airway microbiome diversity. Using the airway microbiome immune library, we showed that the airway microbiome signatures enriched among IGRA-negative individuals likely “induce” a non-specific inflammatory response that “mobilizes” a mixed immune phenotype of innate and adaptive immune cells, such as DCs, B cells, Th1, Th2, Th17, and memory helper T cells, to orchestrate a robust immune response. Independent mass flow cytometric analysis supported these results. Further interrogation of anti-M.tb-immune responses among IGRA-negative versus positive individuals using airway transcriptomic analysis revealed TNF-a, type I, and II interferons as hallmark signaling pathways enriched among IGRApositive versus IGRA-negative individuals. Interestingly, airway cytokine profiling revealed a positive trend towards increased pro-inflammatory cytokines among the IGRA-negative versus IGRA-positive individuals despite a robust pro-inflammatory cytokine response among M.tbstimulated blood from IGRA-positive versus IGRA-negative individuals. Conclusions and Recommendations: These findings suggest that the airway microbiome could be critical in TB control. Furthermore, the local airway responses could differ from the systemic response and could be vital in containing M.tb. Further studies are warranted to explore these findings. | en_US |
