TB or not TB: that is no longer the question

Tuberculosis (TB) remains a devastating infectious disease and, with the emergence of multidrug-resistant forms, represents a major global threat. Much of our understanding of pathogenic and immunologic mechanisms in TB has derived from studies in experimental animals. However, it is becoming increasingly clear in TB as well as in other inflammatory diseases that there are substantial differences in immunological responses of humans not found or predicted by animal studies. Thus, it is critically important to understand mechanisms of pathogenesis and immunological protection in humans. In this review, we will address the key immunological question: What are the necessary and sufficient immune responses required for protection against TB infection and disease in people-specifically protection against infection, protection against the establishment of latency or persistence, and protection against transitioning from latent infection to active disease.