Mycobacterium tuberculosis pathogenicity viewed through the lens of molecular Koch's postulates

Thirty years ago Stanley Falkow formulated molecular Koch's postulates as a framework to help dissect the contribution of microbial genes to their pathogenicity (Box 1). Three years later, his advice led me to develop Mycobacterium marinum, a close genetic relative of Mycobacterium tuberculosis, as a model for tuberculosis pathogenesis. Here, I discuss insights into M. tuberculosis pathogenicity from studying M. marinum in the zebrafish, and frame them in terms of molecular Koch's postulates. The highly orchestrated life cycle of M. tuberculosis is achieved in substantial measure not by "traditional" pathogen-exclusive virulence genes acquired along its evolutionary history, but rather by genes that are shared with its environmental ancestors. Together, these genes support its tactics of subterfuge and exploitation to overcome host immunity so as to produce the transmissible disease that ensures the evolutionary survival of this obligate human pathogen.