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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 human history did indeed occur during the Neolithic Transition around 10,000 years ago, but not because of the arrival of human MTBC, which had been implanted many thousands of years before, but because of growing increases in population size and population density. Here again is where hunter-gatherers re-enter the picture as they began the switch from nomadic pursuits to a settled life of animal domestication and agriculture. The Neolithic Revolution took a few thousand years to implement all its dramatic changes – one of which, as emphasized in this first chapter, was the onset of warfare, a never-ending process that continues to kill and ravage today. Another derivative of the acceleration in growth of human populations and increasingly crowded surroundings with resultant multiplication of susceptible hosts was that human MTBC adapted to this stimulus by switching from a low-density infectious disease to a modern “crowd” disease; furthermore, a corollary consequence of an increasing number of potential victims unfailingly leads to higher virulence and shorter latency [36]. But crowd diseases (i.e., teeming people) caused by TB, as discussed later, do not really show up until around the 17th century.

Remember that the Holocene epoch, or current geologic period, began approximately 11,700 years ago, which is about the time humans had almost migrated from Africa into Europe, India, and China, and as Gagneux [30] correctly assumes, “human exploration, trade, and conquest” further broadened the distribution of people and increased the density of the growing populations. We are following the gospel that during the last 70,000 years humans became newly infected with M. tuberculosis and some must have become sick and died, but the accompanying long latency period, in theory, allowed people with hidden infection to migrate for many years and long distances before clinical signs of reactivation disease appeared; but bear in mind that the shortened human life expectancies during those hazardous years must have cut off TB latencies as well as lives. This leads to 2 important questions: when did humans migrate from Eurasia to the Americas, and did TB accompany those prehistoric migrations or did the disease recur much later through European contact?

Paulsen [39] concludes in his 1987 review that the evidence for the presence of TB in Native Americans and Alaskans in prehistoric North America remains inconclusive. And it looks like the jury is still out on that question. What remains unsettled, of course, is whether or not the heightened susceptibility of Native Americans to TB should have decimated the vulnerable inhabitants once virulent M. tuberculosis was brought along with the incoming migrants: which does not appear to have happened. Another Paulsen conclusion is that the evidence for the presence of TB in prehistoric South America has been “fairly well established.” Both conclusions, therefore, have stood the test of time, except to advance the current South American verdict from “fairly well” to “well established.”

North America: The melting of the giant ice caps of northern Canada opened up pathways to North America around 15,000 years ago. Several possible routes through or around (by boat) the remaining massive ice deposits towards the end of the Pleistocene epoch allowed humans to migrate from eastern Siberia to Alaska, then further southward. An early site at Clovis, New Mexico, for example, attracted considerable attention in the 1920s to 1930s, and is still a major reference center [40]. But several other locations have also gained archaeological importance: near Calgary, Canada, in south-central Oregon, Texas, and the Channel Islands of California. New evidence from the Wally’s Beach site in Canada, using improved radiocarbon dating and supplemented by data from Clovis, New Mexico, provides a more comprehensive understanding of the contribution of the 2,000-year hunting spree by humans in the extinction of at least 6 genera of megafauna, including mammoths, mastodons, gomphotheres, sloths, horses, and camels [41]. The extinction of these giant mammals was mainly caused by dramatic changes in climate and habitat; nevertheless, even though the human population at the time was small and its weapons primitive, hunting must have played a role. First solitary then groups of animals are believed to have been hunted from roughly “15,000–13,300 years ago.” But apparently no pre-Columbian European Contact with TB occurred in North America and Mexico, and throughout Mesoamerica, which comprises central Mexico south to the Central America isthmus countries that link North and South America.

Naturally, studies are underway to compare the genomes of modern Native Americans and Siberians. Findings by Dryomov et al. [42] and associates of the mitochondrial genome diversity support the hypotheses that there were “multiple streams of expansions to northern North America from northeastern Eurasia in late Pleistocene- early Holocene.” More definitive information about genomic dispersal in the Americas should soon be available.

South America: An early case of TB in pre-Columbian Peru was reported in 1973 in a child 8–10 years old with radiographic features of Pott’s disease plus lung, pleural and kidney disease [43]. Ziehl-Neelsen staining revealed many clumps of acid-fast bacilli and radiocarbon dating estimated death at approximately 700 A.D. Another Peruvian mummy with a radiocarbon age of 1,040 ± 4 years had pulmonary lesions with DNA unique to M. tuberculosis, as shown by extraction and identification techniques [44]. Another vertebral lesion was similarly identified from a pre-Columbian mummy from Arica, Chile [45]. These abnormalities provided circumstantial evidence for the presence of TB in pre-Columbian specimens, but given the lengthy differential diagnosis, definitive proof was impossible [46].

The still open question concerning the presence or absence of pre-Columbian TB seems to have been convincingly answered affirmatively in 2014 by Bos et al. [47]. Their excavations of 3 Peruvian mummies revealed mycobacterial genomes that proved that this particular and most unusual cause of human TB originated from seals and sea lions and evolved from a well-known ancient strain of non-human MTBC, which clearly differed from modern M. tuberculosis. All 3 specimens derived from the same period of historic Peruvian culture and had radiocarbon dates between 1028 and 1280 A.D. In addition, based on extensive genomic analyses, instead of clustering with other human strains, the Peruvian samples clustered with animal lineages, particularly M. pinnipedii – and provide “unequivocal evidence of human infection” by an animal – adapted strain of MTBC [47].

One possible sequence – there are not many others to go by – postulates that M. pinnipedii-infected seals and sea lions crossed the southern Atlantic Ocean, probably from Spain, where they colonized costal South American and (later) Australian waters. Because shore-based Peruvian and other neighboring humans had presumably been hunting and eating seals for thousands or more years, sooner or later the newly arrived seals liberated sufficient air-borne pathogen passengers to infect local humans and complete the zoonotic transfer of TB from seals to coastal humans, then from coastal humans to inland humans [47]. Previous observations have reported presumed air-borne M. pinnipedii transmission from seals to other mammals, including human animal keepers in a Netherland zoo [48].

Human Contact: Christopher Columbus certainly made human contact with indigenous natives in or near one of the present day Bahama Islands during his first voyage to the New World in 1492; he returned to Spain with a few gold nuggets, Indian captives, and 2 greatly unwanted gifts for the Old World: tobacco and syphilis (as many believe, but remains debatable). There is no evidence either his sailors or the aboriginal people he contacted had TB. In 1497, John Cabot landed in North America and ships from other countries soon followed. European contacts from Spain returned to South America and Mexico as conquistadores in the early 1500s, conquering and plundering the Aztec, Mayan, Toltec, Inca, and other native populations, seeking gold and other treasures. Decades later, Spanish soldiers, priests, explorers, and opportunists, whose number had increased dramatically by then, made their way north to what is now the United States. These newcomers may have brought cases of TB with them, specifically from the Euro-American lineage (the predominant lineage in North and South America), who then spread the disease to the Aboriginal populations of North America.

The arrival of European contacts from different sources harboring M. tuberculosis, did not lead to an instant, widespread epidemic of TB among susceptible Native Americans and Canadians: there was too much country and too few invaders. When nascent colonies started to enlarge, and Europeans began to mix with the Natives, smallpox and measles were far more frequent and deadly than TB.

An interesting study by Pepperell et al. [49] documents an unfamiliar sequence of low-level spread of TB from incoming migrants. These authors observed that a single Euro-American lineage M. tuberculosis – with a characteristic DS6^Quebec genomic deletion – was at its highest circulating frequency in both Aboriginal populations in Ontario, Saskatchewan, and Alberta, and in French Canadian residents in Quebec. In addition, substantial contact among these populations occurred during a defined historical period of fur trading from 1710 to 1870. The results of historical and genetic analyses show that for around 100 years, small, widely scattered indigenous groups became infected by M. tuberculosis, thanks to an infrequent number of human migrants who were infected with low numbers of tubercle bacilli. Furthermore, large-scale TB epidemics did not appear in these communities before the late 19th and 20th centuries [49].

New Observations: Knowledge about susceptibility to the development of TB after exposure to M. tuberculosis includes several risk factors, most of which have been recognized for decades: malnutrition, inadequate ventilation, and overcrowding; once TB infection has occurred mental and/or physical stress, and impaired immunity exacerbate the likelihood that disease will occur. To a greater or lesser extent, all of these factors are related to warfare. Much more recently, whole genome sequencing and phylogenetic analyses have demonstrated more genetic diversity of human-adapted MTBC than previously believed [50]. As already described, 7 lineages, each having a number of sublineages, have been shown to govern intrinsic bacterial forces that affect the pathogenicity of tubercle bacilli. These new factors have increasing public health importance.

The East-Asian lineage, which includes the famous Beijing strain, has spread in successive global waves during the last 200 years, first during the Industrial Revolution, later during World War I (WWI), and lastly associated with the epidemic of HIV infection [51]. According to some, Beijing strains are allegedly endowed with “selective advantages,” including enhanced pathogenicity and/or virulence, and increased progression from infection to disease. Recent studies showing considerable variation among different Euro-American sublineages in the frequency of transmission of contacts to TB among index patients – from 15.7% in RD145 to 1.8% in RD219 – clearly indicate that further studies are needed to document the impact of “bacterial factors on transmissibility and pathogenicity” of human MTBC [52].