for his discovery of tuberculin. Although initially he misjudged its value as treatment for TB, the subsequent use of tuberculin by skin testing as an indicator of the presence of either active disease or latent infection of both M. tuberculosis and M. bovis “led to the virtual eradication of TB-ridden cattle and other domesticated animals in industrialized countries” [27].
Fig. 2. Changes in mortality from presumed tuberculosis in the city of London, England, between 1631 and 1901 [54], with permission from Oxford University Press.
Fig. 3. Schematic model of the trend of mortality from tuberculosis in Western Europe from 1740 to 1985. Modified from [18] and using data from [57], with permission from the American Thoracic Society.
Fig. 4. Fragment from the Stele of Vultures. Victory stele of King Eannutum of Lagash over Umma, showing the first extant evidence of an ancient army equipped with helmets, shields and spears. Limestone, circa 2450 BC, Summerian archaic dynasties. Found in 1881 in Girsu (now Tello, Iraq), Mesopotamia, by Edourad de Sarzec. Currently in Louvre Museum, Paris, France. Eric Gaba, July 15, 2005, with permission from Sting.
Fig. 5. Tuberculosis death rates in Great Britain, Belgium, the Netherlands, and Denmark during Fifty Year Period, 1885–1935, with permission from Sheridan Content Solutions, Sheridan, PA, on behalf of The American Public Health Association.
Population Genomics
The former prevailing, now obsolete, view of the evolutionary history of TB had long concluded that M. bovis was an ancient cause of the disease in cows, bison, and other bovines and that M. tuberculosis became a human pathogen much later during the Neolithic Demographic Transition, around 10,000 years ago: a supposition now being revisited, thanks to comparative genomic evidence. Cole et al. [28] first showed that M. bovis and its animal partners have a genome that is around 60,000 base pairs smaller than that of “human-adapted M. tuberculosis.” Accordingly, it looks increasingly evident that M. tuberculosis and M. bovis both share a common ancestor, but that the ancient genomic regions present in M. tuberculosis predated those of M. bovis [29].
TB is not caused by a single bacterium but by a group of phylogenetically related bacterial cousins called the M. tuberculosis complex (MTBC) [30]. Human TB is most often caused by M. tuberculosis but Mycobacterium africanum is also a cause in West Africa. By far the most important animal-adapted member of the MTBC is M. bovis, which was previously a common cause of milk-borne TB in children before being largely controlled by pasteurization. Other MTBC species affecting animals include Mycobacterium caprae in sheep and goats, Mycobacterium pinnipedii in seals and sea lions, and Mycobacterium microti in voles [31]. Owing either to significant differences in communicability or to its complete absence among various human and animal contacts, MTBC species are usually found mainly in their preferred hosts. M. microti, for example, is not pathogenic for humans, and M. bovis is 6-times less virulent in humans than in cows.
Recent studies have amplified and considerably revised previous views about the origin and evolution of MTBC and its human predecessors. In 2002, for example, Brosch et al. [32] published the genomic analyses of 100 strains of MTBC, including M. tuberculosis, Mycobacterium canettii, M. microti, and M. bovis and concluded that the analysis of the regions of difference of MTBC strains can distinguish between “ancestral” and “modern” strains of human TB. In addition, all strains with TbD1 deletions appear to be derived from a single clone of human MTBC descent, which includes the major modern epidemic families, such as Beijing and Haarlem.
As reviewed at the beginning of this chapter, modern humans, H. sapiens, originated in Kenya and Tanzania towards the end of the Pleistocene epoch around 200,000 years ago. Descendant populations of hunter-gatherers remained small in number owing to the persistence of the last Ice Age and the accompanying lethality of its prevailing recurrent climatic changes. Survivors are thought to have collected in small bands of 25 or even fewer members, as judged from historical observations and the habits of current nomadic groups [33]. But then the climatic conditions presumably improved and humans started to migrate out of Africa: the great human expansion was underway.
In 2006, Gagneux et al. [34] and Firdessa et al. [35] first showed that human MTBC strains demonstrated a phylogeographic organization consisting of 7 different population lineages, each associated with particular geographic areas but all of which are found in Africa. Lineages 5 and 6, the most basal, often referred to as M. africanum, occur chiefly in West Africa. Later, Comas et al. [36] postulated that human-adapted MTBC originated in Africa and “has been infecting humans for at least the last 70,000 years,” after which viable tubercle bacilli were transmitted both by and to the migrating anatomically modern humans headed toward Eurasia. Based on their model of human whole-genome variation data, Rasmussen et al. [37] determined that H. sapiens spread from Africa in 2 major waves: the first dispersal took place around the Indian Ocean beginning between 62,000 and 75,000 years ago, and the second dispersal occurred 25,000–38,000 years ago into Eurasia. Interestingly, one of the evolutionary models of MTBC showed that the Indo-Oceanic lineage or lineage 1 (predominant in the Indian Ocean region) split 67,000 years ago, and the lineages 2 and 4 (East Asian and Euro-American, respectively) split between 30,000 and 46,000 years ago. This evolutionary model showed a striking correlation between the human migration events and the evolutionary split of MTBC [36, 37]. Note also that the lengthy overlap in Africa of both H. sapiens and each of the lineages of M. tuberculosis has established a reciprocal evolutionary partnership in which the 2 players have been coevolving for countless millenniums.
These observations reinforce the conclusion that all MTBC species shared a common ancestral origin around 70,000 years ago, but then diversified into 7 major lineages distributed in different regions throughout the world [34, 35]. But how far back does the ancestral MTBC lineage actually extend? The recently reported 500,000-year old fossil of H. erectus from Turkey showing characteristic lesions of TB, if confirmed, remarkably lengthens the historic evolution of TB [38].
The newly revised concepts that changed