Protection from Mycobacterium tuberculosis infection: Learning from exposed but uninfected children

Background: Children are more susceptible than adults to progression from infection to tuberculosis and development of severe forms of disease. However, most children exposed to Mycobacterium tuberculosis are able to effectively control the pathogen without becoming infected. A better understanding of effective paediatric immunity to tuberculosis infection and discovery of correlates of protection could help to develop a novel vaccine as part of the End TB Strategy. Methods: A matched case-control study was conducted in The Gambia recruiting pairs of children with discordant tuberculin skin test infection status but the same sleeping proximity to the same adult with sputum smear positive tuberculosis (Highly Exposed Infected [HEI] and Highly Exposed Uninfected [HEU] children). Whole blood samples were used in a novel assay with an autoluminescent strain of Bacillus Calmette-Guérin (BCG). Serial luminescence measurements were recorded and supernatants from baseline, 24 hours and 96 hours were analysed with a multiplex assay to detect cytokines and targeted mass spectrometry to detect eicosanoids. Results: 29 pairs of HEI and HEU children aged between 5 and 15 years old were enrolled. HEU children had higher levels of luminescence at 96 hours than HEI children, on the threshold of statistical significance. HEI children produced significantly more BCG-specific interferon-gamma than HEU children at 24 and 96 hours. At 24 hours, HEI children had significantly suppressed BCG-specific levels of 12-oxo-LTB4, a metabolite of the pro-inflammatory eicosanoid LTB4. BCG-specific levels of the prostacyclin metabolite, 6ketoPGF-1-alpha , were significantly higher in HEI children at baseline, but this pattern was reversed at 24 hours. Conclusions: In the functional luminescence assay, HEU children did not demonstrate superior control of mycobacterial growth than HEI children. BCG-specific interferon-gamma levels reflected the infection status of the children. A potential role of prostacyclin in paediatric immunity against Mycobacterium tuberculosis infection has been identified with implications for vaccine design and adjuvant host-directed therapy.