Several pieces of the puzzle of the natural history of tuberculosis are assembled in this review to illustrate the potential reservoirs and sources of the Mycobacterium tuberculosis complex (MTBC) mycobacteria, their transmission to animals and humans, and their fate in populations, in a co-evolutionary perspective. Millennia-old companions of mammalian and human populations, MTBC are detected in the soil, in which they infect and survive within vegetative amoebae and cysts, except for Mycobacterium canettii. Never detected in the sphere of plants, they are transmissible by transcutaneous, digestive and respiratory routes and cause an infection of the lymphatic system with secondary dissemination in most tissues, in which they determine a specific and non-pathognomonic granulomatous inflammatory reaction; in which MTBC survives in dormant form irrespective of MTBC species and mammalian species; indicating that the current epidemiology in mammalian populations is essentially governed by the probabilities of contact between mammalian species and MTBC species. Individual variabilities in clinical expression of tuberculosis are related to MTBC species, strain and inoculum; host genetic factors; acquired modulations of the inflammatory response; and probably human microbiota. This review of the literature suggests an evolutionary natural history of telluric environmental mycobacteria, satellites of unicellular eukaryotes, transmissible to mammals via the digestive and then respiratory tracts, in which they determine a fatal contagious infection that is primarily lymphatic and a quiescence-mimicking encysted form. This review opens perspectives for microbiological and translational medical research.
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