Controlled fire use in early humans might have triggered the evolutionary emergence of tuberculosis

The Evolutionary Origins of TB.

The age of the association between humans and MTBC remains controversial: some studies estimate the most recent common ancestor (MRCA) of MTCB existed less than 6,000 y ago (17⇓–19), whereas others have obtained a figure of around 70,000 y ago (20⇓–22). Regardless of which estimate is more accurate, TB is likely to be older in humans than these inferred ages. These coalescent estimates are based on extant lineages and do not necessarily provide the age of the first strain to infect humans; selective sweeps, population bottlenecks, and simply genetic drift can all make the MRCA younger than the origin of a species (23). It is unlikely, however, that TB was a transmissible disease before the separation of the human lineage from other apes. Although other mammals, including chimpanzees, can be infected with TB, there is no evidence of any cospeciation between nonhuman primates and mycobacteria (24).

The archaeological and molecular evidence taken together favors an early emergence of MTBC originating in Africa and a long-term association with modern humans on this continent. For instance, all strains adapted to animal hosts are derived from human strains (23), ruling out the possibility that TB was first a bovine disease which crossed over to humans during the Neolithic period. Whole-genome draft sequencing has identified deep lineages in Africa that are excellent candidates for representing the original ecotype of the MTBC (25) and African lineages show high diversity compared with other regions (26). Cases of MTBC in pre-Columbian human remains from Peru (27) and Chile (28) and in a 17,500 y old Bison bone discovered in the United States (29) further suggest that MTBC is ancient and crossed the Bering Strait during the Late Pleistocene. Contrasting evidence from MTBC genomes isolated from Peruvian human remains suggests that sea mammals were a source of TB in the Americas (18), although this evidence does not preclude the possibility of preexisting MTBC strains. Further support for ancient origins of TB is found in the form of characteristic lesions on Paleolithic human remains (30) and from ancient DNA isolates (31).

Nontuberculous mycobacteria are ubiquitous in the environment and account for the majority of species within the genus Mycobacterium (32). Such organisms can infect humans opportunistically, particularly in immunocompromised individuals and patients with inflammatory lung diseases (33, 34). For instance, Mycobacterium abscessus is a major respiratory pathogen in patients with cystic fibrosis who have profoundly impaired local immune protective mechanisms (35). Although they are not generally thought to establish person-to-person chains of transmission, clusters of closely related strains of M. abscessus have been isolated from patients with cystic fibrosis, suggesting such transmission can occur, although the mechanism may be indirect (34, 36).

Comparative analysis indicates that MTBC diverged from a related nontuberculous mycobacterial species before arising as a clonal expansion from a generalist ancestral mycobacterial population shared by the smooth tubercle bacilli Mycobacterium canettii (37, 38). This ancestor of MTBC, which might have resembled Mycobacterium kansasii (38), presumably lived in the environment and caused sporadic disease before it acquired the ability to transmit between hosts (22, 38). Patients infected with M. kansasii present very similarly to TB and respond to antituberculous antibiotics (39), although M. kansasii is not transmissible in humans and has significantly reduced in vivo fitness (38).

Conditions for Evolutionary Emergence.

For an environmental species to become an endemic human pathogen, the species must undergo a series of evolutionary transformations (5, 6). Exposure of a host to a microbe requires sufficient overlap of their habitats. Evolutionary transformations then allow more complex interactions to arise where the potential pathogen becomes capable of infecting humans and then of transmitting between hosts. Endemic persistence, however, requires the basic reproduction number R0 in human populations (the expected number of secondary cases produced by a typical case in a completely susceptible host population) to be greater than unity. The emergence of transmissible TB, therefore, would have been a rare and unlucky event in which an opportunistic and poorly transmitting environmental Mycobacterium evolved the ability to transmit over short chains of infection until its R0 reached the critical value of unity (40).

Today, MTBC causes mostly latent infection in human hosts, although a small fraction of these latent infections reactivate to the disease state before the hosts die (41). It is not known whether the MTBC precursor also caused latent infection or whether latency evolved subsequent to its emergence (42). Either way, for TB to emerge as a transmissible disease, its etiological agent had to overcome the obstacle of a low R0. The occurrence of any of the risk factors for infectious disease emergence (see Introduction) brought about by a transition in human culture or behavior would have facilitated this process (5, 6). Such a transition would necessarily have occurred well before the existence of the MRCA of MTBC and affected the rate of pathogen exposure or the extent of human susceptibility to infection. The transition might also have provided novel opportunities for between-host transmission events and/or supported within-host adaptation of the pathogen (40). The prehistoric transition of controlling fire, we argue, satisfies these criteria for influencing the emergence of MTBC in human populations.

Cultural Impact of Fire Use.

The earliest convincing evidence for human control of fire predates both estimates for the MRCA of MTBC (21), as well as the oldest molecular dates (43), and fossil remains for anatomically modern humans (44) by considerable margins. The current consensus is that fire was first made by Homo heidelbergensis (8), a species widely regarded to be the last common ancestor of the Neanderthals and anatomically modern humans (45). The regular use of fire would have constructed a new cultural niche for hominins with potentially profound implications for the evolution of H. heidelbergensis and, ultimately, anatomically modern humans through genetic and ecological inheritance (12⇓⇓–15, 46).

One important change experienced by these early fire-makers that, we argue, influenced the sporadic transmission of and susceptibility to pulmonary mycobacterial infection, would have been the addition of new contexts for human social interactions. For instance, fire would have provided light to allow social and subsistence activities to occur beyond daylight hours and food being brought to a central site for cooking and preservation, and fire maintenance would all have increased interactions and physical contacts among individuals (16, 47). Early humans in these new contexts would necessarily have had greatly increased inhalation of smoke from fires used for these purposes but also by fires used to repel insects and other pests and possibly even for communication (48). Indeed, the presence of small microcharcoal fragments in 300,000- to 400,000-y-old dental calculus samples taken from human remains at Qesem Cave is suggestive of accidental smoke inhalation from hearth fires (49).

Although fire must also have been used at open-air sites, most Pleistocene evidence for controlled fire use from the archaeological record derives from caves (8, 9). The biased record of fire use results, in large part, from geological and taphonomic factors, with cave sediments being more conducive to the preservation of charcoal, ash, and burnt bone. Temporary shelters were also built by hunter–gatherers across the globe and were undoubtedly one of the keys to the successful occupation of wide-ranging environments by modern humans. Sheltered spaces such as caves and built structures are inherently social spaces (16, 47), and camp fires act as a natural focal point for social gatherings (11). Therefore, early fire makers occupying poorly ventilated spaces were likely to have been especially vulnerable to inhalation of smoke from fires.

Physiological Impact of Fire Use.

A large proportion of biomass smoke constituents are in the inhalable size range (e.g., carbon monoxide, aldehydes, nitric oxide, and particulate matter), and many of these constituents incite chronic inflammatory and destructive changes in the respiratory system (50). Early hunter–gatherer communities burning biomass fuels in poorly ventilated spaces were, therefore, vulnerable to a wide range of unprecedented adverse health effects (51).

Metaanalysis has revealed positive associations between smoking tobacco and domestic use of biomass fuels with increased risk of MTBC infection and TB disease (52). Possible mechanisms suggested for these associations include the impairment of respiratory defenses against mycobacteria, because even a brief exposure of animals to wood smoke can alter bacterial clearance and macrophage-mediated local immunity (53). This association is likely to be attributable to the critical role played by the local immune response (both innate and adaptive) in protective immunity against MTBC infection, much more so than humoral adaptive immunity (54). The process of developing protective immunity against MTBC infection is largely coordinated within the lungs and lymphatics through, for instance, the mucociliary escalator and macrophage function, processes that may be particularly impaired by smoke exposure and in patients with inflammatory lung diseases (53⇓–55).

Several respiratory diseases associated with tissue destruction and impaired local immunity are also well-established to be associated with TB and other mycobacterial infections (56⇓⇓⇓–60). The best characterized of these conditions include chronic obstructive pulmonary disease (COPD), bronchiectasis, and silicosis, whereas the association between nontuberculous mycobacterial disease and cystic fibrosis is discussed above in The Evolutionary Origins of TB. The high risk of TB and other mycobacterial infections in patients with COPD is particularly well characterized because of the high prevalence of smoking in modern societies (56, 57), although indoor biomass burning remains a major causative factor globally (52, 61, 62). Bronchiectasis is another obstructive lung disease that is significantly more common in populations exposed to wood smoke (63) and is similarly associated with an increased risk of mycobacterial infection (58). Meanwhile, mycobacterial infection is also a risk factor for the development and progression of these diseases (64), indicating that there is likely to be a feedback mechanism supporting the persistence of all three conditions in humans.

The pathogenesis of smoke exposure is closely related to that of silicosis, which is caused by the inhalation of silica particles that damage alveolar macrophages and cause inflammation and fibrogenesis (65). Individuals exposed to aerosolized silica, even without silicosis, have a dramatically increased risk of mycobacterial infection (59). The individual-level relative risk for silicosis and silica-associated TB also persists after exposure has ceased and is dose-dependent (60, 66). Although biomass burning is not predominantly silica exposure, these principles may apply to other inorganic inhaled particles.

Model of TB Emergence.

To test the logic in our hypothesis that the advent of the controlled use of fire could have significantly affected the probability of TB emergence, we considered quantitatively the rise in the risk of the evolutionary emergence of TB attributable to the use of fire. We developed a mathematical model, building on existing theory of the evolutionary emergence of pathogens (40), to ask how the ancestor of MTBC could evolve such that its basic reproductive number R0 reached unity. The model assumes that R0 can increase because of two mechanisms: (i) by adaptive evolution during chains of transmission and (ii) by the effects of habitual fire use, namely increased host-susceptibility attributable to biomass smoke-induced lung damage and greater between-host transmission opportunities brought about by a developing human social culture. The model also assumes that host-susceptibility remains otherwise unchanged through time (this assumption is relaxed in an extended model presented in SI Appendix) and allows slow exponential growth of early human populations before expansion out of Africa (67), although the effect of this assumption on the results was minor.

We calculated the cumulative probability over time of TB emergence as an endemic human pathogen. This quantity increases with time and the rate of infections attributable to host exposure to MTBC’s ancestral natural reservoir. The cumulative probability also depends on the probability that a chain of transmission evolves an R0 greater than unity, and the probability that an evolved pathogen does not undergo stochastic extinction.

Under our model, controlled fire use increased the cumulative probability that TB emerged by several orders of magnitude compared with the case where TB emerges without fire (Fig. 2). This result holds when we consider the cumulative probability of TB emerging up to and including both estimates for the time since the MRCA of MTBC of 70,000 y ago (Fig. 2) and 6,000 y ago (SI Appendix, Fig. S2) and is robust to variation in model parameters including the number of mutations required for the ancestor of MTBC to evolve an R0 greater than unity from the characteristic R0 of the natural reservoir (Fig. 3). As the number of mutations required for R0 to exceed unity increases, so too does the influence controlled fire use has on the probability of emergence, whereas the cumulative probability quickly decreases with and without fire use. Nevertheless, it is likely that only a few mutations were needed before TB could emerge, because as few as three mutations can significantly attenuate the virulence of Mycobacterium tuberculosis in human cells (68) and recombination at one locus can increase the virulence of M. canettii in cellular and animal infection models (69). Although unrelated to mycobacteria, it is also noteworthy that five mutations are required for avian influenza to acquire the ability of airborne transmission in ferrets (70).

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Fig. 2.

Model results of the change in the cumulative probability of TB emergence attributable to the advent of controlled use of fire 400,000 y ago. Here, we assume that two mutations are required for the environmental mycobacteria to evolve to have an R0>1. For more details, see SI Appendix, Figs. S1 and S2 and Table S1.

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Fig. 3.

Sensitivity analysis of the cumulative probability of TB emergence 70,000 y ago attributable to the advent of controlled use of fire. The varied input parameters include the characteristic R0 of the environmental reservoir of the MTBC precursor, the factor L that R0 was increased because of fire use, the time tf of onset of controlled fire use, the time te of onset of human population growth, and the rate α of population growth and the early human population size N0. (A–C) The frequency distributions of the absolute cumulative probabilities of TB emergence by 70,000 y ago with fire Pf (orange) and without fire P (blue). (D) Frequency distribution of the ratio of cumulative probabilities of the emergence of TB by 70,000 y ago Pf/P. The three alternative scenarios shown here represent the cases where one (m=1), two (m=2), and three (m=3) mutations are required for the environmental mycobacteria to evolve to have an R0>1. For more details and additional results, see SI Appendix, Figs. S3 and S4 and Table S2.