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| ==Introduction== | | ==Introduction== |
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| ==Major Pathogens== | | ==Section 2== |
| <b><i>Mycobacterium tuberculosis</i></b><br>
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| Genetic evidence of <i>Mycobacterium tuberculosis</i>, the causative agent of tuberculosis, has been found as early as 5000 years ago <ref name=Fuchs>[http://journals.sagepub.com/doi/10.1177/0959683619857230 Fuchs, Katharina, Christoph Rinne, Clara Drummer, Alexander Immel, Ben Krause-Kyora, and Almut Nebel. “Infectious Diseases and Neolithic Transformations: Evaluating Biological and Archaeological Proxies in the German Loess Zone between 5500 and 2500 BCE.” 2019. The Holocene 29 (10): 1545–57.]</ref>. It is most often identified as a <i>Mycobacterium tuberculosis</i> complex, a larger group that is recognized by standard DNA probes <ref name=Rothschild>[https://doi.org/10.1086/321886 Rothschild, Bruce M., Larry D. Martin, Galit Lev, Helen Bercovier, Gila Kahila Bar‐Gal, Charles Greenblatt, Helen Donoghue, Mark Spigelman, and David Brittain. “Mycobacterium Tuberculosis Complex DNA from an Extinct Bison Dated 17,000 Years before the Present.” 2001. Clinical Infectious Diseases 33 (3): 305–11.]</ref>The complex includes <i>M. tuberculosis, M. bovis, M. africanum,</i> and <i>M. microti</i> <ref name=Rothschild/>. <i>M. tuberculosis</i> is one of the most common causes of tuberculosis, but <i>M. bovis</i> and <i>M. africanum</i> can result in similar symptoms in humans<ref name=Rothschild/>. Of these, <i>M. bovis</i> mostly affects cattle but can infect humans if infected meat and dairy products are ingested, while <i>M. africanum</i> is responsible for the majority of tuberculosis cases in Africa <ref name=Rothschild/>. <i>M. microti</i> specifically affects mice and voles<ref name=Rothschild/>.
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| Cases of tuberculosis are often recorded in Neolithic burials. It is among the diseases most commonly reported in the archaeological record because it leaves diagnostic changes on human bone, often in the form of lesions and spinal collapse <ref name=Fuchs/><ref name=Buikstra>[https://doi.org/10.1016/B978-0-12-809738-0.00011-9 Buikstra, J.E. ed. "Ortner's identification of pathological conditions in human skeletal remains." 2019.]</ref>. Calcifications in organs can also be indicative of previous tuberculosis infections <ref name=Sabin>[https://doi.org/10.1186/s13059-020-02112-1 Sabin et al. “A Seventeenth-Century Mycobacterium Tuberculosis Genome Supports a Neolithic Emergence of the Mycobacterium Tuberculosis Complex.” 2020. Genome Biology 21 (1): 201.]</ref>.Individual burials in the Near East and Europe from early domestication phases in approximately 8800-7250 BCE are some of the earliest recorded cases of tuberculosis among humans <ref name=Fuchs/>. In Europe, the earliest cases of skeletal tuberculosis date to about 5400-4800 BCE in Germany<ref name=Fuchs/>(Figure 1).
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| [[Image:Tuberculosis of Spine Buikstra.png|thumb|300px|right|Figure 1: Lateral view of spine affected by tuberculosis, partly healed, affecting thoracic vertebrae 7 and 8 and first lumbar vertebra. Photo credit: [https://doi.org/10.1016/B978-0-12-809738-0.00011-9]]]
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| While these demonstrate that tuberculosis was present within the Neolithic period, they also suggest that microbes within the complex were capable of infecting humans before the shift away from a hunter-gatherer lifestyle. One school of thought suggests that the bacteria evolved within Pleistocene megafauna before crossing over to humans. This is partially supported by evidence of ancient M. tuberculosis complex DNA found in a North American bison from 17,830 years ago<ref name=Rothschild/><ref name=Minniken>[https://doi.org/10.1177/0959683619895572 Minnikin, David E, Oona Y-C Lee, Houdini Ht Wu, Gurdyal S Besra, and Helen D Donoghue. “Recognising the Broad Array of Approaches Available for the Diagnosis of Ancient Tuberculosis: Comment on ‘Infectious Diseases and Neolithic Transformations’ (Fuchs et al. 2019 The Holocene 29: 1545–1557).” 2020. The Holocene 30 (5): 781–83.]</ref>. Others, however, suggest that the complex emerged during the Neolithic, and not before. Recently, DNA extracted from a Swedish mummy showing signs of tuberculosis contributed to a molecular clock phylogeny that placed a common ancestor to the <i>M. tuberculosis</i> complex as late as 2000-6000 years before present<ref name=Sabin/>. If this is the case, it would suggest that the emergence of human tuberculosis was correlated with the Neolithic revolution.
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| Regardless of its origin before or during the Neolithic, tuberculosis and its associated complex were likely more active once people began practicing agriculture. In a model aiming to characterize the maintenance of tuberculosis over time, researchers reinforced the claim that tuberculosis growth rates were higher in the Neolithic (0.1%/year) than they had been previously (0.003%/year)<ref name=Cardona>[https://doi.org/10.3390/pathogens11030366 Cardona, Pere-Joan, Martí Català, and Clara Prats. “The Origin and Maintenance of Tuberculosis Is Explained by the Induction of Smear-Negative Disease in the Paleolithic.” 2020. Pathogens 11 (3): 366]</ref>
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| . This trend may be tied to worsening living conditions that correspond with a shift to a sedentary lifestyle.
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| <b><i>Treponema</i></b><br>
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| Treponematoses, describing several diseases caused by bacteria of the genus <i>Treponema</i>, have been identified in individuals from Northern Vietnam in 2000 BCE <ref name=Vlok>[https://doi.org/10.5744/bi.2020.1000 Vlok, Melandri, Marc Oxenham, Kate Domett, Tran Thi Minh, Thi Mai Huong Nguyen, Hirofumi Matsumura, Hiep Hoang Trinh, et al. “Two Probable Cases of Infection with Treponema Pallidum during the Neolithic Period in Northern Vietnam (ca. 2000–1500 B.C.).” 2020. Bioarchaeology International 4 (1): 15–36.]</ref>. Treponematoses manifests in several commonly known diseases: yaws, from <i>T. pallidum pertenue</i>, pinta, from <i>T. carateum</i>, venerial syphilis, from <i>T. pallidum pallidum</i>, and endemic syphilis, from <i>T. pallidum endemicum</i><ref name=Vlok/>. These diseases, like tuberculosis, can be surmised from the archaeological record because late stages can leave lesions in bone<ref name=Vlok/><ref name=Buikstra/>. This method is particularly important because identification of ancient <i>Treponema</i> DNA is relatively lacking.
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| Soft, tumor-like growths and lesions called gumma can develop on the face and extracranial bone and are considered diagnostic for treponematoses VLOK. Tibia deformation, called saber shin, and evidence of swelling in the digits point specifically to yaws in the two Vietnamese individuals<ref name=Vlok/>. Five additional individuals had symptoms suggesting treponematoses, but could not be confirmed as infected VLOK. Because the individuals at the site were mostly juveniles, yaws may be the most likely candidate for infection at the site. Notably, the diagnostic lesions only occur in about 1% of patients with yaws, and they mostly occur in childhood<ref name=Buikstra/>. Therefore, the presence of yaws in the archaeological record, and treponematoses as a whole, is likely underrespresentative of the actual presence of infection throughout the Neolithic (Figure 2).
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| <b><i>Salmonella enterica</i></b><br>
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| </b>
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| Evidence of <i>Salmonella enterica</i> affecting Neolithic populations has been found in several agrarian communities throughout Eurasia. Unlike <i>M. tuberculosis</i> and <i>Treponema</i>, <i>Salmonella</i> does not usually leave distinctive marks in human skeletons<ref name=Key>[https://doi.org/10.1038/s41559-020-1106-9 Key, Felix M., Cosimo Posth, Luis R. Esquivel-Gomez, Ron Hübler, Maria A. Spyrou, Gunnar U. Neumann, Anja Furtwängler, et al. “Emergence of Human-Adapted Salmonella Enterica Is Linked to the Neolithization Process.” 2020. Nature Ecology & Evolution 4 (3): 324–33.]</ref>. Instead, it is often identified via ancient DNA analysis. This method often relies on metagenomic samples from the environment. In the case of <i>Salmonella,</i> however, ancient microbial DNA is collected from teeth. Teeth are often highly preserved in the archaeological record and seem to preserve bacterial DNA better than other types of bone, with reports of high microbial diversity recorded from teeth<ref name=Bergfeldt>[https://doi.org/10.1038/s41598-024-56096-0 Bergfeldt, Nora, Emrah Kırdök, Nikolay Oskolkov, Claudio Mirabello, Per Unneberg, Helena Malmström, Magdalena Fraser, et al. “Identification of Microbial Pathogens in Neolithic Scandinavian Humans.” 2024.Scientific Reports 14 (1): 5630.]</ref><ref name=Margaryan>[https://doi.org/10.1002/ece3.3924 Margaryan, Ashot, Henrik B. Hansen, Simon Rasmussen, Martin Sikora, Vyacheslav Moiseyev, Alexandr Khoklov, Andrey Epimakhov, et al. “Ancient Pathogen DNA in Human Teeth and Petrous Bones.” 2018. Ecology and Evolution 8 (6): 3534–42.]</ref>. Because teeth are vascularized – or contain blood vessels – in life, retrieval of microbial DNA from the teeth suggests that the microbe in question was present in high levels of an individual at the time of death<ref name=Key/>. In 2020, a study reported that eight <i>Salmonella enterica</i> genomes were collected from human teeth that were up to 6,500 years old<ref name=Key/>. With these data, it is clear that <i>S. enterica</i> in one form or another has been infecting human populations for thousands of years, well within the Neolithic. However, until 3,000 years ago, <i>S. enterica</i> strains may have been generalists, affecting a variety of mammals, until Neolithization made specifically infecting humans advantageous for some strains of the bacteria<ref name=Key/>. Similarity of ancient <i>S. enterica</i> genomes to those infecting pigs suggests some spillover or coevolution between strains infecting pigs and humans several thousand years ago<ref name=Key/>.
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| Notably, <i>S. enterica</i> genomes have also been found in Bronze Age Crete with limited host adaptation to humans<ref name=Neumann>[https://doi.org/10.1016/j.cub.2022.06.094 Neumann, Gunnar U., Eirini Skourtanioti, Marta Burri, Elizabeth A. Nelson, Megan Michel, Alina N. Hiss, Photini J.P. McGeorge, et al. “Ancient Yersinia Pestis and Salmonella Enterica Genomes from Bronze Age Crete.” 2022. Current Biology 32 (16): 3641-3649.e8.]</ref>. Presence of generalist strains after the Neolithic indicate that the Neolithic may not have affected <i>S. enterica</i> evolution as much as some other pathogens. While the bacteria could certainly infect humans, it may not have been advantageous to do so exclusively. That said, salmonellosis was likely still a serious concern for Neolithic people. DNA extraction from Stone Age Scandinavian farmers revealed <i>S. enterica</i>in two individuals<ref name=Bergfeldt/>. Because these two individuals were buried in the same grave, it is possible that salmonellosis was their cause of death<ref name=Bergfeldt/>. Regardless, people infected with <i>S. enterica</i> could expect symptoms like stomach cramps, fever, and diarrhea, which would seriously reduce quality of life<ref name=Bergfeldt/>.
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| ==Section 2== | | ==Section 2== |
