It has been estimated that 2 billion people, equivalent to one-third of the world’s population, are currently infected with Mycobacterium tuberculosis (M.tb), the causative agent of tuberculosis (TB). M.tb is typically an aerosol infection that causes disease in the lungs. Most people develop protective immunity that effectively contains M.tb bacilli in a clinically silent form (latent TB) that is not contagious. However, in a proportion of individuals, latent TB progresses to contagious active disease (reactivation TB) due to complex environmental, genetic, and immunologic interactions that are incompletely defined. By accurately predicting TB disease outcome, at-risk patients could be specifically targeted for antibiotic and/or immunotherapeutic treatments to prevent active TB. This strategy is important because early aggressive therapies would prevent illness in predisposed individuals, and benefit society by eliminating those patients’ abilities to transmit M.tb to others.

This work used comparative murine models to identify immunologic correlates and mechanisms of M.tb susceptibility and TB disease progression that may be applicable to humans. Following a low dose M.tb aerosol infection of susceptible and relatively resistant mice, we identified three immune mediators that were associated with M.tb susceptibility. These mediators, therefore, could predict the outcome and timing of TB disease progression: antigen specific interferon-γ (IFN-γ), interleukin-10 (IL-10), and chemokine C-C ligand 5 (CCL5). Persistently low antigen specific IFN-γ and low CCL5 were biomarkers of M.tb susceptibility and predicted TB disease progression four to five months prior to disease onset in mice. The studies using antigen specific IFN-γ are particularly relevant to man (where access to lung samples is limited) because blood antigen specific IFN-γ accurately predicted lung responses.

In contrast to low IFN-γ and low CCL5, elevated levels of IL-10 in the lungs predicted reactivation TB approximately 4-8 weeks prior to disease onset in M.tb susceptible mice. Furthermore, IL-10 was shown to be a single cause of reactivation TB, as disease progression was delayed and protective immunity was enhanced by IL-10 blockade in vivo. Overall, these results indicate that single immune mediators may be used as biomarkers of TB disease progression in humans, and furthermore, that appropriately timed immunotherapeutic intervention may prevent the transition from controlled M.tb infection to active TB disease.