The local immune response in the airways and blood of contacts early after TB exposure determines outcome

Most individuals infected with Mycobacterium tuberculosis remain healthy, while a subset only progress to active tuberculosis (TB) disease. Early local immune events following infection in humans, determining the pattern of ensuing host immunity and risk of disease progression, are unknown. We defined a blood transcriptional signature of active TB, absent in the majority of latently exposed asymptomatic individuals and healthy controls, that reflected the extent of radiographic lung disease. I recently demonstrated immunological heterogeneity in the blood transcriptome of a cohort of recent TB contacts. A small proportion expressed a persistent TB signature and subsequently progressed to active TB disease, whereas 50% of contacts who were sensitized to M. tuberculosis infection but did not progress to disease, exhibited a similar, but not identical, transient blood signature, suggesting early local immune responses are critical determinants of outcome from infection. I will now lead a study of TB contacts, to detect changes in immune events in the airways early after TB exposure, comparing with TB patients, in a low TB burden setting.The findings I will generate on the local early response to M. tuberculosis infection are critical for developing novel approaches for effective TB control and prevention and the improvement of vaccines.