Human major infections: Tuberculosis, treponematoses, leprosy-A paleopathological perspective of their evolution.

The key to evolution is reproduction. Pathogens can either kill the human host or can invade the host without causing death, thus ensuring their own survival, reproduction and spread. Tuberculosis, treponematoses and leprosy are widespread chronic infectious diseases whereby the host is not immediately killed. These diseases are examples of the co-evolution of host and pathogen. They can be well studied as the paleopathological record is extensive, spanning over 200 human generations. The paleopathology of each disease has been well documented in the form of published synthetic analyses recording each known case and case frequencies in the samples they were derived from. Here the data from these synthetic analyses were re-analysed to show changes in the prevalence of each disease over time. A total of 69,379 skeletons are included in this study. There was ultimately a decline in the prevalence of each disease over time, this decline was statistically significant (Chi-squared, p<0.001). A trend may start with the increase in the disease's prevalence before the prevalence declines, in tuberculosis the decline is monotonic. Increase in skeletal changes resulting from the respective diseases appears in the initial period of host-disease contact, followed by a decline resulting from co-adaptation that is mutually beneficial for the disease (spread and maintenance of pathogen) and host (less pathological reactions to the infection). Eventually either the host may become immune or tolerant, or the pathogen tends to be commensalic rather than parasitic.

Revisiting the tuberculosis and leprosy cross-immunity hypothesis: Expanding the dialogue between immunology and paleopathology.

OBJECTIVE: Our primary objective is to re-visit the tuberculosis and leprosy cross-immunity. hypothesis through the careful integration of immunology and paleopathology. METHODS: Using an integrated theoretical analysis that evaluates clinical literature on human innate immunological responses, paleomicrobiology, bioarchaeology, and paleopathology, we develop a multifactorial model. RESULTS: Past populations do not represent homogeneous immunological landscapes, and therefore it is likely that leprosy in Medieval Europe did not uniformly decline due to cross-immunity. CONCLUSIONS: We recommend that bioarchaeological reconstructions of past disease experience take into consideration models that include variation in immune function based on past environments and social contexts. This provides a unique opportunity to conduct comprehensive analyses on complex immunological processes. SIGNIFICANCE: Extrapolating results from experimental immunology to larger populations elucidates complexities of disease cross-immunity and highlights the importance of synthesizing archaeological, social, paleopathological and biological data as a means of understanding disease in the past. LIMITATIONS: All extrapolations from data produced from in vitro studies to past populations, using living donors, pose significant limitations where, among other factors, the full reconstruction of past environmental and social contexts can frequently be sparse or incomplete. SUGGESTIONS FOR FUTURE RESEARCH: To reduce the limitations of integrating experimental immunology with bioarchaeological reconstructions (i.e. how to use skeletal samples to reconstruct inflammatory phenotypes), we propose that osteoimmunology, or the study of the interplay between immune cells and bone cells, should be considered a vital discipline and perhaps the foundation for the expansion of paleoimmunology.

Tuberculosis and leprosy associated with historical human population movements in Europe and beyond - an overview based on mycobacterial ancient DNA.

Context: Tuberculosis and leprosy are readily recognised in human remains due to their typical palaeopathology. Both Mycobacterium tuberculosis (MTB) and Mycobacterium leprae (ML) are obligate pathogens and have been detected in ancient human populations. Objective: To demonstrate historical tuberculosis and leprosy cases in Europe and beyond using molecular methods, as human populations are associated with different mycobacterial genotypes. Methods: MTB and ML ancient DNA (aDNA) has been detected by DNA amplification using PCR, or by whole genome sequencing. Mycobacterial cell wall lipids also provide specific markers for identification. Results: In 18th century Hungary, the European indigenous MTB genotype 4 strains have been found. However, many individuals were co-infected with up to three MTB sub-genotypes. In 8th-14th century Europe significant differences in ML genotypes were found between northwest Europe compared with central, southern, or eastern Europe. In addition, several co-infections of MTB and ML were detected in historical samples. Conclusion: Both MTB and ML strain types differ between geographically separate populations. This is associated with ancient human migration after an evolutionary bottleneck and clonal expansion. The absence of indigenous leprosy in Europe today may be due to the greater mortality of tuberculosis in individuals who are co-infected with both organisms.

Impact of urbanization on tuberculosis and leprosy prevalence in medieval Denmark.

The consequences of urbanization, such as increased exposure to pathogens, have long been considered detrimental to human health. During the first half of the Danish medieval period, towns were established and throughout the period population increased. The following study analyzes the relationship between urbanization and disease frequency - specifically leprosy and tuberculosis - in four skeletal samples from medieval Denmark using a paleoepidemiological approach. Skeletons from two urban sites (Ole Wormsgade and Ribe Grey Friary) and two rural sites (Øm Kloster and Sejet), all located in the Jutland region of Denmark, were selected for this analysis (n = 204). All skeletons included date to the middle part of the Danish medieval period (AD 1200-1400). Six skeletal leprosy indicators and six skeletal tuberculosis indicators were analyzed, and disease frequencies in the samples were estimated using a probabilistic approach based on lesion sensitivity and specificity. The effect of tuberculosis on survival in urban and rural samples was evaluated using Kaplan-Meier survival analyses. The frequency of leprosy at death varied between four and 19 percent among the four cemeteries with Ole Wormsgade having the highest frequency. The estimated frequency of tuberculosis at death varied between 39 and 69 percent. Here, Sejet cemetery had the highest frequency. There were significant differences in survival for those with and without tuberculosis-related lesions between sites, but there were no significant differences between urban and rural sites. The analyses presented in this paper suggest that disease prevalence in skeletal samples cannot be sufficiently explained by urbanization alone; rather, there are likely other biological and behavioral sources of heterogeneity that are contributing factors to past disease experience.

A clausura enferma: petições para a saída do Convento da Ajuda no Rio de Janeiro para tratamento de doenças contagiosas, c. 1750-1780 / Disease in the cloisters: requests to leave Convento da Ajuda, Rio de Janeiro, for the treatment of contagious diseases, c. 1750-1780

Resumo O artigo discute os pedidos de freiras do Convento da Ajuda para deixar a clausura a fim de curar doenças contagiosas. O padecimento dessas doenças era considerado uma das poucas exceções para permitir a saída das freiras. As ordens femininas guardavam estritamente a clausura, condição necessária para manter o recato de virgens consagradas a Cristo. A documentação contém detalhes sobre as causas e as formas de transmissão das doenças, bem como sobre os tipos de tratamento para combatê-las. Por fim, os processos esclarecem os procedimentos adotados fora da clausura para as freiras não colocarem em risco o recolhimento e a honra, quando iam buscar em locais distantes o tratamento adequado para aquelas doenças.

Abstract This article discusses the requests submitted by nuns from Convento da Ajuda (Ajuda Convent) to leave their life of enclosure to receive treatment for contagious diseases. Disease was one of the few cases in which nuns were granted permission to leave. The female orders were strictly cloistered in order to preserve their purity as virgins consecrated to Christ. Extant documents detail the causes of the diseases, the ways they were transmitted, and the treatments used to fight them. These processes shed light on the procedures adopted outside the cloisters so that the nuns did not jeopardize their reclusion and honor when they went to distant places in search of treatment.

[Disease in the cloisters: requests to leave Convento da Ajuda, Rio de Janeiro, for the treatment of contagious diseases, c.1750-1780]. / A clausura enferma: petições para a saída do Convento da Ajuda no Rio de Janeiro para tratamento de doenças contagiosas, c.1750-1780.

This article discusses the requests submitted by nuns from Convento da Ajuda (Ajuda Convent) to leave their life of enclosure to receive treatment for contagious diseases. Disease was one of the few cases in which nuns were granted permission to leave. The female orders were strictly cloistered in order to preserve their purity as virgins consecrated to Christ. Extant documents detail the causes of the diseases, the ways they were transmitted, and the treatments used to fight them. These processes shed light on the procedures adopted outside the cloisters so that the nuns did not jeopardize their reclusion and honor when they went to distant places in search of treatment.

Ancient DNA analysis - An established technique in charting the evolution of tuberculosis and leprosy.

Many tuberculosis and leprosy infections are latent or paucibacillary, suggesting a long time-scale for host and pathogen co-existence. Palaeopathology enables recognition of archaeological cases and PCR detects pathogen ancient DNA (aDNA). Mycobacterium tuberculosis and Mycobacterium leprae cell wall lipids are more stable than aDNA and restrict permeability, thereby possibly aiding long-term persistence of pathogen aDNA. Amplification of aDNA, using specific PCR primers designed for short fragments and linked to fluorescent probes, gives good results, especially when designed to target multi-copy loci. Such studies have confirmed tuberculosis and leprosy, including co-infections. Many tuberculosis cases have non-specific or no visible skeletal pathology, consistent with the natural history of this disease. M. tuberculosis and M. leprae are obligate parasites, closely associated with their human host following recent clonal distribution. Therefore genotyping based on single nucleotide polymorphisms (SNPs) can indicate their origins, spread and phylogeny. Knowledge of extant genetic lineages at particular times in past human populations can be obtained from well-preserved specimens where molecular typing is possible, using deletion analysis, microsatellite analysis and whole genome sequencing. Such studies have identified non-bovine tuberculosis from a Pleistocene bison from 17,500 years BP, human tuberculosis from 9000 years ago and leprosy from over 2000 years ago.

Tuberculosis and leprosy in Italy: new skeletal evidence.

Tuberculosis (TB) and leprosy are infections caused by Mycobacteria. This paper documents new skeletal evidence in Italy from the Iron Age site of Corvaro (Central Italy; 5th century BCE) and the Roman site of Palombara (Central Italy; 4th-5th century CE), and briefly reviews the extant evidence for these infections in Italy. The skeletal evidence for TB in Italy is more ancient than for leprosy, and is more common. The oldest evidence for both mycobacterial diseases is in the North of Italy, but this could be by chance, even if biomolecular models suggest a land route from the East to central Europe, especially for leprosy.

Insights into ancient leprosy and tuberculosis using metagenomics.

Leprosy and tuberculosis were widespread in the past and remain significant diseases today. Comparison of ancient and modern genomes of Mycobacterium leprae and Mycobacterium tuberculosis gives insight into their evolution and a calibration of the timescale for observed changes. Recently, whole genome sequencing has revealed genotypes and mixed-strain infections.

A tuberculose no Espírito Santo e as ações do Estado no combate à doença / Tuberculosis in the Espírito Santo and the State's actions in combating the disease

Discute a política pública com foco na análise nos serviços de saúde voltados para o combate à tuberculose, no estado do Espírito Santo, a partir da década de 1930, quando é criada a Liga Espírito-Santense contra a Tuberculose. Os autores mostram que houve uma efetiva parceria entre a iniciativa privada e o Estado, a partir do Governo Vargas, e descrevem o funcionamento dos principais organismos na luta contra a tuberculose no Espírito Santo: o Dispensário Dr. Antonio Cardoso Fontes, o Preventório Gustavo Capanema e o Sanatório Getúlio Vargas.

Ancient urbanization predicts genetic resistance to tuberculosis.

A link between urban living and disease is seen in recent and historical records, but the presence of this association in prehistory has been difficult to assess. If the transition to urban living does result in an increase in disease-based mortality, we might expect to see evidence of increased disease resistance in longer-term urbanized populations, as the result of natural selection. To test this, we determined the frequency of an allele (SLC11A1 1729 + 55del4) associated with natural resistance to intracellular pathogens such as tuberculosis and leprosy. We found a highly significantly correlation with duration of urban settlement-populations with a long history of living in towns are better adapted to resisting these infections. This correlation remains strong when we correct for autocorrelation in allele frequencies due to shared population history. Our results therefore support the interpretation that infectious disease loads became an increasingly important cause of human mortality after the advent of urbanization, highlighting the importance of population density in determining human health and the genetic structure of human populations.

A short history of dapsone, or an alternative model of drug development.

From 1936 until 1996, the drug dapsone treated a diverse array of diseases, including tuberculosis, leprosy, malaria, and AIDS-related pneumonia. This article explores how dapsone transformed from a cure for one disease into a treatment for a totally different malady. This process of reinvention in the clinic represents an alternative model of drug development that the historical literature, focused on success in the laboratory, has largely ignored. The core of the paper discusses the reinvention of dapsone as an antimalarial in the Vietnam War through trials led by Robert J. T. Joy, a physician and military officer. As a case study, it offers a fresh perspective on the clinic-as-laboratory approach that other scholars have addressed in a civilian context. Viewing the randomized clinical trial (RCT) through a military prism will demonstrate how a combat environment combined with the regimentation of the armed forces affected the standard methodology of the RCT.

Tuberculosis and leprosy in perspective.

Two of humankind's most socially and psychologically devastating diseases, tuberculosis and leprosy, have been the subject of intensive paleopathological research due to their antiquity, a presumed association with human settlement and subsistence patterns, and their propensity to leave characteristic lesions on skeletal and mummified remains. Despite a long history of medical research and the development of effective chemotherapy, these diseases remain global health threats even in the 21st century, and as such, their causative agents Mycobacterium tuberculosis and M. leprae, respectively, have recently been the subject of molecular genetics research. The new genome-level data for several mycobacterial species have informed extensive phylogenetic analyses that call into question previously accepted theories concerning the origins and antiquity of these diseases. Of special note is the fact that all new models are in broad agreement that human TB predated that in other animals, including cattle and other domesticates, and that this disease originated at least 35,000 years ago and probably closer to 2.6 million years ago. In this work, we review current phylogenetic and biogeographic models derived from molecular biology and explore their implications for the global development of TB and leprosy, past and present. In so doing, we also briefly review the skeletal evidence for TB and leprosy, explore the current status of these pathogens, critically consider current methods for identifying ancient mycobacterial DNA, and evaluate coevolutionary models.

A cidade de São Paulo e a saúde pública (1554-1954) / The city of São Paulo and public health (1554-1954)

Narra as transformações na Cidade de São Paulo que formam o cenário onde se desenrolam as preocupações do poder público com a saúde. Um dos reflexos dessas transformações aparece nas medidas tomadas pela Câmara para proteger a população das doenças e dos perigos dos miasmas, das habitações insalubres, das imundícies jogadas à rua, das inundações dos rios, das águas paradas, dos depósitos de lixo e da proliferação de moscas. (AU)

The impact of "ancient pathogen" studies on the practice of public health.

A new field of "ancient pathogens" is making an impact on our concepts of the evolution of infectious diseases, and it will eventually alter the practice of public health in their control. It has begun to answer important questions regarding past epidemics of influenza and tuberculosis by recovering the genetic sequences of the ancient causative agents. Vaccination strategics will have to study these microbial variants in order to develop tomorrow's vaccines. It may also be possible to examine the role of past and present reservoirs in the dynamics of emerging diseases. In unraveling the evolution of pathogens, insights into the mechanisms of drug and antibiotic resistance are possible. As "genome projects" of more and more pathogens are being completed. Targets for chemotherapy are being revealed which are totally different from the metabolic processes of the mammalian host. Signal molecules are being identified which alter the virulence of the microbe. Focussing on these mechanisms without attempting to kill the pathogen may in some cases drive it into a benign state. These and other aspects of the evolution of pathogens are discussed which may lead to innovative approaches to the control of infectious diseases.

Molecular analysis of ancient microbial infections.

The detection of ancient microbial DNA offers a new approach for the study of infectious diseases, their occurrence, frequency and host-pathogen interaction in historic times and populations. Moreover, data obtained from skeletal and mummified tissue may represent an important completion of contemporary phylogenetic analyses of pathogens. In the last few years, a variety of bacterial, protozoal and viral infections have been detected in ancient tissue samples by amplification and characterization of specific DNA fragments. This holds particularly true for the identification of the Mycobacterium tuberculosis complex, which seems to be more robust than other microbes due to its waxy, hydrophobic and lipid-rich cell wall. These observations provided useful information about the occurrence, but also the frequency of tuberculosis in former populations. Moreover, these studies suggest new evolutionary models and indicate the route of transmission between human and animals. Until now, other pathogens, such as Mycobacterium leprae, Yersinia pestis, Plasmodium falciparum and others, have occasionally been identified - mostly in single case studies or small sample sizes - as well, although much less information is available on these pathogens in ancient settings. The main reason therefore seems to be the degradation and modification of ancient DNA by progressive oxidative damage. Furthermore, the constant risk of contamination by recent DNA forces to take time and cost effective measures and renders the analysis of ancient microbes difficult. Nevertheless, the study of microbial ancient DNA significantly contributes to the understanding of transmission and spread of infectious diseases, and potentially to the evolution and phylogenetic pathways of pathogens.