GL12

The use of laboratory animals for experimental modelling in tuberculosis (TB) has been instrumental in understand its natural history. One essential question has been the understanding of the mechanisms of latent tuberculosis infection (LTBI). Murine strains (C57BL/6 and DBA/2) were instrumental in find a key cell, the foamy macrophage, to demonstrate the constant drainage of dormant bacilli towards the bronchial tree, and the possibility of endogenous reinfection of the parenchyma. This explains the usefulness of isoniazid in the chemoprophylaxis. On the other hand, large mammals like minipigs, provided evidence on the role of interlobular septa, crucial for respiration, and their capacity to rapidly encapsulate minimal granulomatous lesions. This process made it impossible to understand how the progression from LTBI to active TB could occur, as it requires a significant enlargement of the lesions. It was another murine strain (C3HeB/FeJ) which gave a clue on this, showing that a strong neutrophilic infiltration, extracellular bacillary growth, induction of daughter lesions and finally the coalescence of all of them were required for the progression towards active TB. This model has been recently validated using macaques as laboratory animals. All these mechanisms help to understand the difficulty in finding better diagnostic approaches, because a part from radiographic methods, it is difficult to find a biomarker that can indicate Mycobacterium tuberculosis infection in upper lobes, where the majority of active TB lesions take place.