The source of the Black Death in fourteenth-century central Eurasia.

The origin of the medieval Black Death pandemic (AD 1346-1353) has been a topic of continuous investigation because of the pandemic's extensive demographic impact and long-lasting consequences1,2. Until now, the most debated archaeological evidence potentially associated with the pandemic's initiation derives from cemeteries located near Lake Issyk-Kul of modern-day Kyrgyzstan1,3-9. These sites are thought to have housed victims of a fourteenth-century epidemic as tombstone inscriptions directly dated to 1338-1339 state 'pestilence' as the cause of death for the buried individuals9. Here we report ancient DNA data from seven individuals exhumed from two of these cemeteries, Kara-Djigach and Burana. Our synthesis of archaeological, historical and ancient genomic data shows a clear involvement of the plague bacterium Yersinia pestis in this epidemic event. Two reconstructed ancient Y. pestis genomes represent a single strain and are identified as the most recent common ancestor of a major diversification commonly associated with the pandemic's emergence, here dated to the first half of the fourteenth century. Comparisons with present-day diversity from Y. pestis reservoirs in the extended Tian Shan region support a local emergence of the recovered ancient strain. Through multiple lines of evidence, our data support an early fourteenth-century source of the second plague pandemic in central Eurasia.

Uncovering the genomic toll of the Black Death.

The Black Death, a notorious devastating pandemic caused by Yersinia pestis infection during the 14th century, posed a formidable challenge to human immune defenses. A new article by Klunk et al. reports that a variant in an antigen-processing gene may have favored survival during the plague and may have undergone genomic selection in Europeans at unprecedented speed.

14th century Yersinia pestis genomes support emergence of pestis secunda within Europe.

Pestis secunda (1356-1366 CE) is the first of a series of plague outbreaks in Europe that followed the Black Death (1346-1353 CE). Collectively this period is called the Second Pandemic. From a genomic perspective, the majority of post-Black Death strains of Yersinia pestis thus far identified in Europe display diversity accumulated over a period of centuries that form a terminal sub-branch of the Y. pestis phylogeny. It has been debated if these strains arose from local evolution of Y. pestis or if the disease was repeatedly reintroduced from an external source. Plague lineages descended from the pestis secunda, however, are thought to have persisted in non-human reservoirs outside Europe, where they eventually gave rise to the Third Pandemic (19th and 20th centuries). Resolution of competing hypotheses on the origins of the many post-Black Death outbreaks has been hindered in part by the low representation of Y. pestis genomes in archaeological specimens, especially for the pestis secunda. Here we report on five individuals from Germany that were infected with lineages of plague associated with the pestis secunda. For the two genomes of high coverage, one groups within the known diversity of genotypes associated with the pestis secunda, while the second carries an ancestral genotype that places it earlier. Through consideration of historical sources that explore first documentation of the pandemic in today's Central Germany, we argue that these data provide robust evidence to support a post-Black Death evolution of the pathogen within Europe rather than a re-introduction from outside. Additionally, we demonstrate retrievability of Y. pestis DNA in post-cranial remains and highlight the importance of hypothesis-free pathogen screening approaches in evaluations of archaeological samples.

Analytical framework to evaluate and optimize the use of imperfect diagnostics to inform outbreak response: Application to the 2017 plague epidemic in Madagascar.

During outbreaks, the lack of diagnostic "gold standard" can mask the true burden of infection in the population and hamper the allocation of resources required for control. Here, we present an analytical framework to evaluate and optimize the use of diagnostics when multiple yet imperfect diagnostic tests are available. We apply it to laboratory results of 2,136 samples, analyzed with 3 diagnostic tests (based on up to 7 diagnostic outcomes), collected during the 2017 pneumonic (PP) and bubonic plague (BP) outbreak in Madagascar, which was unprecedented both in the number of notified cases, clinical presentation, and spatial distribution. The extent of these outbreaks has however remained unclear due to nonoptimal assays. Using latent class methods, we estimate that 7% to 15% of notified cases were Yersinia pestis-infected. Overreporting was highest during the peak of the outbreak and lowest in the rural settings endemic to Y. pestis. Molecular biology methods offered the best compromise between sensitivity and specificity. The specificity of the rapid diagnostic test was relatively low (PP: 82%, BP: 85%), particularly for use in contexts with large quantities of misclassified cases. Comparison with data from a subsequent seasonal Y. pestis outbreak in 2018 reveal better test performance (BP: specificity 99%, sensitivity: 91%), indicating that factors related to the response to a large, explosive outbreak may well have affected test performance. We used our framework to optimize the case classification and derive consolidated epidemic trends. Our approach may help reduce uncertainties in other outbreaks where diagnostics are imperfect.

No evidence for persistent natural plague reservoirs in historical and modern Europe.

Caused by Yersinia pestis, plague ravaged the world through three known pandemics: the First or the Justinianic (6th-8th century); the Second (beginning with the Black Death during c.1338-1353 and lasting until the 19th century); and the Third (which became global in 1894). It is debatable whether Y. pestis persisted in European wildlife reservoirs or was repeatedly introduced from outside Europe (as covered by European Union and the British Isles). Here, we analyze environmental data (soil characteristics and climate) from active Chinese plague reservoirs to assess whether such environmental conditions in Europe had ever supported "natural plague reservoirs". We have used new statistical methods which are validated through predicting the presence of modern plague reservoirs in the western United States. We find no support for persistent natural plague reservoirs in either historical or modern Europe. Two factors make Europe unfavorable for long-term plague reservoirs: 1) Soil texture and biochemistry and 2) low rodent diversity. By comparing rodent communities in Europe with those in China and the United States, we conclude that a lack of suitable host species might be the main reason for the absence of plague reservoirs in Europe today. These findings support the hypothesis that long-term plague reservoirs did not exist in Europe and therefore question the importance of wildlife rodent species as the primary plague hosts in Europe.

Stone Age Yersinia pestis genomes shed light on the early evolution, diversity, and ecology of plague.

The bacterial pathogen Yersinia pestis gave rise to devastating outbreaks throughout human history, and ancient DNA evidence has shown it afflicted human populations as far back as the Neolithic. Y. pestis genomes recovered from the Eurasian Late Neolithic/Early Bronze Age (LNBA) period have uncovered key evolutionary steps that led to its emergence from a Yersinia pseudotuberculosis-like progenitor; however, the number of reconstructed LNBA genomes are too few to explore its diversity during this critical period of development. Here, we present 17 Y. pestis genomes dating to 5,000 to 2,500 y BP from a wide geographic expanse across Eurasia. This increased dataset enabled us to explore correlations between temporal, geographical, and genetic distance. Our results suggest a nonflea-adapted and potentially extinct single lineage that persisted over millennia without significant parallel diversification, accompanied by rapid dispersal across continents throughout this period, a trend not observed in other pathogens for which ancient genomes are available. A stepwise pattern of gene loss provides further clues on its early evolution and potential adaptation. We also discover the presence of the flea-adapted form of Y. pestis in Bronze Age Iberia, previously only identified in in the Caucasus and the Volga regions, suggesting a much wider geographic spread of this form of Y. pestis. Together, these data reveal the dynamic nature of plague's formative years in terms of its early evolution and ecology.

Multiple Introductions of Yersinia pestis during Urban Pneumonic Plague Epidemic, Madagascar, 2017.

Pneumonic plague (PP) is characterized by high infection rate, person-to-person transmission, and rapid progression to severe disease. In 2017, a PP epidemic occurred in 2 Madagascar urban areas, Antananarivo and Toamasina. We used epidemiologic data and Yersinia pestis genomic characterization to determine the sources of this epidemic. Human plague emerged independently from environmental reservoirs in rural endemic foci >20 times during August-November 2017. Confirmed cases from 5 emergences, including 4 PP cases, were documented in urban areas. Epidemiologic and genetic analyses of cases associated with the first emergence event to reach urban areas confirmed that transmission started in August; spread to Antananarivo, Toamasina, and other locations; and persisted in Antananarivo until at least mid-November. Two other Y. pestis lineages may have caused persistent PP transmission chains in Antananarivo. Multiple Y. pestis lineages were independently introduced to urban areas from several rural foci via travel of infected persons during the epidemic.

Assessing the origins of the European Plagues following the Black Death: A synthesis of genomic, historical, and ecological information.

The second plague pandemic started in Europe with the Black Death in 1346 and lasted until the 19th century. Based on ancient DNA studies, there is a scientific disagreement over whether the bacterium, Yersinia pestis, came into Europe once (Hypothesis 1) or repeatedly over the following four centuries (Hypothesis 2). Here, we synthesize the most updated phylogeny together with historical, archeological, evolutionary, and ecological information. On the basis of this holistic view, we conclude that Hypothesis 2 is the most plausible. We also suggest that Y. pestis lineages might have developed attenuated virulence during transmission, which can explain the convergent evolutionary signals, including pla decay, that appeared at the end of the pandemics.

Immunogenetics, sylvatic plague and its vectors: insights from the pathogen reservoir Mastomys natalensis in Tanzania.

Yersinia pestis is a historically important vector-borne pathogen causing plague in humans and other mammals. Contemporary zoonotic infections with Y. pestis still occur in sub-Saharan Africa, including Tanzania and Madagascar, but receive relatively little attention. Thus, the role of wildlife reservoirs in maintaining sylvatic plague and spillover risks to humans is largely unknown. The multimammate rodent Mastomys natalensis is the most abundant and widespread rodent in peri-domestic areas in Tanzania, where it plays a major role as a Y. pestis reservoir in endemic foci. Yet, how M. natalensis' immunogenetics contributes to the maintenance of plague has not been investigated to date. Here, we surveyed wild M. natalensis for Y. pestis vectors, i.e., fleas, and tested for the presence of antibodies against Y. pestis using enzyme-linked immunosorbent assays (ELISA) in areas known to be endemic or without previous records of Y. pestis in Tanzania. We characterized the allelic and functional (i.e., supertype) diversity of the major histocompatibility complex (MHC class II) of M. natalensis and investigated links to Y. pestis vectors and infections. We detected antibodies against Y. pestis in rodents inhabiting both endemic areas and areas considered non-endemic. Of the 111 nucleotide MHC alleles, only DRB*016 was associated with an increased infestation with the flea Xenopsylla. Surprisingly, we found no link between MHC alleles or supertypes and antibodies of Y. pestis. Our findings hint, however, at local adaptations towards Y. pestis vectors, an observation that more exhaustive sampling could unwind in the future.

Ancient Yersinia pestis genomes lack the virulence-associated YpfΦ prophage present in modern pandemic strains.

Yersinia pestis is the causative agent of at least three major plague pandemics (Justinianic, Medieval and Modern). Previous studies on ancient Y. pestis genomes revealed that several genomic alterations had occurred approximately 5000-3000 years ago and contributed to the remarkable virulence of this pathogen. How a subset of strains evolved to cause the Modern pandemic is less well-understood. Here, we examined the virulence-associated prophage (YpfΦ), which had been postulated to be exclusively present in the genomes of strains associated with the Modern pandemic. The analysis of two new Y. pestis genomes from medieval/early modern Denmark confirmed that the phage is absent from the genome of strains dating to this time period. An extended comparative genome analysis of over 300 strains spanning more than 5000 years showed that the prophage is found in the genomes of modern strains only and suggests an integration into the genome during recent Y. pestis evolution. The phage-encoded Zot protein showed structural homology to a virulence factor of Vibrio cholerae. Similar to modern Y. pestis, we observed phages with a common origin to YpfΦ in individual strains of other bacterial species. Our findings present an updated view on the prevalence of YpfΦ, which might contribute to our understanding of the host spectrum, geographical spread and virulence of Y. pestis responsible for the Modern pandemic.

Disease and weather induce rapid shifts in a rangeland ecosystem mediated by a keystone species (Cynomys ludovicianus).

Habitat loss and changing climate have direct impacts on native species but can also interact with disease pathogens to influence wildlife communities. In the North American Great Plains, black-tailed prairie dogs (Cynomys ludovicianus) are a keystone species that create important grassland habitat for numerous species and serve as prey for predators, but lethal control driven by agricultural conflict has severely reduced their abundance. Novel disease dynamics caused by epizootic plague (Yersinia pestis) within prairie dog colonies have further reduced prairie dog abundances, in turn destabilizing associated wildlife communities. We capitalized on a natural experiment, collecting data on prairie dog distributions, vegetation structure, avian abundance, and mesocarnivore and ungulate occupancy before (2015-2017) and after (2018-2019) a plague event in northeastern Wyoming, USA. Plague decimated black-tailed prairie dog populations in what was then the largest extant colony complex, reducing colony cover in the focal area from more than 10,000 ha to less than 50 ha. We documented dramatic declines in mesocarnivore occupancy and raptor abundance post-plague, with probability of occupancy or abundance approaching zero in species that rely on prairie dogs for a high proportion of their diet (e.g., ferruginous hawk [Buteo regalis], American badger [Taxidea taxus], and swift fox [Vulpes velox]). Following the plague outbreak, abnormally high precipitation in 2018 hastened vegetation recovery from prairie dog disturbance on colonies in which constant herbivory had formerly maintained shortgrass structure necessary for certain colony-associates. As a result, we observed large shifts in avian communities on former prairie dog colonies, including near-disappearance of mountain plovers (Charadrius montanus) and increases in mid-grass associated songbirds (e.g., lark bunting [Calamospiza melanocorys]). Our research highlights how precipitation can interact with disease-induced loss of a keystone species to induce drastic and rapid shifts in wildlife communities. Although grassland taxa have co-evolved with high spatiotemporal variation, fragmentation of the remaining North American rangelands paired with higher-than-historical variability in climate and disease dynamics are likely to destabilize these systems in the future.

Acceleration of plague outbreaks in the second pandemic.

Historical records reveal the temporal patterns of a sequence of plague epidemics in London, United Kingdom, from the 14th to 17th centuries. Analysis of these records shows that later epidemics spread significantly faster ("accelerated"). Between the Black Death of 1348 and the later epidemics that culminated with the Great Plague of 1665, we estimate that the epidemic growth rate increased fourfold. Currently available data do not provide enough information to infer the mode of plague transmission in any given epidemic; nevertheless, order-of-magnitude estimates of epidemic parameters suggest that the observed slow growth rates in the 14th century are inconsistent with direct (pneumonic) transmission. We discuss the potential roles of demographic and ecological factors, such as climate change or human or rat population density, in driving the observed acceleration.

Colonial rodent control in Tanganyika and the application of ecological frameworks.

ABSTRACTAt the end of the 1920s, Tanganyika Territory experienced several serious rodent outbreaks that threatened cotton and other grain production. At the same time, regular reports of pneumonic and bubonic plague occurred in the northern areas of Tanganyika. These events led the British colonial administration to dispatch several studies into rodent taxonomy and ecology in 1931 to determine the causes of rodent outbreaks and plague disease, and to control future outbreaks. The application of ecological frameworks to the control of rodent outbreaks and plague disease transmission in colonial Tanganyika Territory gradually moved from a view that prioritised 'ecological interrelations' among rodents, fleas and people to one where those interrelations required studies into population dynamics, endemicity and social organisation in order to mitigate pests and pestilence. This shift in Tanganyika anticipated later population ecology approaches on the African continent. Drawing on sources from the Tanzania National Archives, this article offers an important case study of the application of ecological frameworks in a colonial setting that anticipated later global scientific interest in studies of rodent populations and rodent-borne disease ecologies.

Transmission of Antimicrobial Resistant Yersinia pestis During a Pneumonic Plague Outbreak.

BACKGROUND: Pneumonic plague (PP), caused by Yersinia pestis, is the most feared clinical form of plague due to its rapid lethality and potential to cause outbreaks. PP outbreaks are now rare due to antimicrobial therapy. METHODS: A PP outbreak in Madagascar involving transmission of a Y. pestis strain resistant to streptomycin, the current recommended first-line treatment in Madagascar, was retrospectively characterized using epidemiology, clinical diagnostics, molecular characterization, and animal studies. RESULTS: The outbreak occurred in February 2013 in the Faratsiho district of Madagascar and involved 22 cases, including 3 untreated fatalities. The 19 other cases participated in funeral practices for the fatal cases and fully recovered after combination antimicrobial therapy: intramuscular streptomycin followed by oral co-trimoxazole. The Y. pestis strain that circulated during this outbreak is resistant to streptomycin resulting from a spontaneous point mutation in the 30S ribosomal protein S12 (rpsL) gene. This same mutation causes streptomycin resistance in 2 unrelated Y. pestis strains, one isolated from a fatal PP case in a different region of Madagascar in 1987 and another isolated from a fatal PP case in China in 1996, documenting this mutation has occurred independently at least 3 times in Y. pestis. Laboratory experiments revealed this mutation has no detectable impact on fitness or virulence, and revertants to wild-type are rare in other species containing it, suggesting Y. pestis strains containing it could persist in the environment. CONCLUSIONS: Unique antimicrobial resistant (AMR) strains of Y. pestis continue to arise in Madagascar and can be transmitted during PP outbreaks.

Antimicrobial Treatment and Prophylaxis of Plague: Recommendations for Naturally Acquired Infections and Bioterrorism Response.

This report provides CDC recommendations to U.S. health care providers regarding treatment, pre-exposure prophylaxis, and postexposure prophylaxis of plague. Yersinia pestis, the bacterium that causes plague, leads to naturally occurring disease in the United States and other regions worldwide and is recognized as a potential bioterrorism weapon. A bioweapon attack with Y. pestis could potentially infect thousands, requiring rapid and informed decision making by clinicians and public health agencies. The U.S. government stockpiles a variety of medical countermeasures to mitigate the effects of a bioterrorism attack (e.g., antimicrobials, antitoxins, and vaccines) for which the 21st Century Cures Act mandates the development of evidence-based guidelines on appropriate use. Guidelines for treatment and postexposure prophylaxis of plague were published in 2000 by a nongovernmental work group; since then, new human clinical data, animal study data, and U.S. Food and Drug Administration approvals of additional countermeasures have become available. To develop a comprehensive set of updated guidelines, CDC conducted a series of systematic literature reviews on human treatment of plague and other relevant topics to collect a broad evidence base for the recommendations in this report. Evidence from CDC reviews and additional sources were presented to subject matter experts during a series of forums. CDC considered individual expert input while developing these guidelines, which provide recommended best practices for treatment and prophylaxis of human plague for both naturally occurring disease and following a bioterrorism attack. The guidelines do not include information on diagnostic testing, triage decisions, or logistics involved in dispensing medical countermeasures. Clinicians and public health officials can use these guidelines to prepare their organizations, hospitals, and communities to respond to a plague mass-casualty event and as a guide for treating patients affected by plague.

Plague risk in the western United States over seven decades of environmental change.

After several pandemics over the last two millennia, the wildlife reservoirs of plague (Yersinia pestis) now persist around the world, including in the western United States. Routine surveillance in this region has generated comprehensive records of human cases and animal seroprevalence, creating a unique opportunity to test how plague reservoirs are responding to environmental change. Here, we test whether animal and human data suggest that plague reservoirs and spillover risk have shifted since 1950. To do so, we develop a new method for detecting the impact of climate change on infectious disease distributions, capable of disentangling long-term trends (signal) and interannual variation in both weather and sampling (noise). We find that plague foci are associated with high-elevation rodent communities, and soil biochemistry may play a key role in the geography of long-term persistence. In addition, we find that human cases are concentrated only in a small subset of endemic areas, and that spillover events are driven by higher rodent species richness (the amplification hypothesis) and climatic anomalies (the trophic cascade hypothesis). Using our detection model, we find that due to the changing climate, rodent communities at high elevations have become more conducive to the establishment of plague reservoirs-with suitability increasing up to 40% in some places-and that spillover risk to humans at mid-elevations has increased as well, although more gradually. These results highlight opportunities for deeper investigation of plague ecology, the value of integrative surveillance for infectious disease geography, and the need for further research into ongoing climate change impacts.

Ancient Yersinia pestis genomes from across Western Europe reveal early diversification during the First Pandemic (541-750).

The first historically documented pandemic caused by Yersinia pestis began as the Justinianic Plague in 541 within the Roman Empire and continued as the so-called First Pandemic until 750. Although paleogenomic studies have previously identified the causative agent as Y. pestis, little is known about the bacterium's spread, diversity, and genetic history over the course of the pandemic. To elucidate the microevolution of the bacterium during this time period, we screened human remains from 21 sites in Austria, Britain, Germany, France, and Spain for Y. pestis DNA and reconstructed eight genomes. We present a methodological approach assessing single-nucleotide polymorphisms (SNPs) in ancient bacterial genomes, facilitating qualitative analyses of low coverage genomes from a metagenomic background. Phylogenetic analysis on the eight reconstructed genomes reveals the existence of previously undocumented Y. pestis diversity during the sixth to eighth centuries, and provides evidence for the presence of multiple distinct Y. pestis strains in Europe. We offer genetic evidence for the presence of the Justinianic Plague in the British Isles, previously only hypothesized from ambiguous documentary accounts, as well as the parallel occurrence of multiple derived strains in central and southern France, Spain, and southern Germany. Four of the reported strains form a polytomy similar to others seen across the Y. pestis phylogeny, associated with the Second and Third Pandemics. We identified a deletion of a 45-kb genomic region in the most recent First Pandemic strains affecting two virulence factors, intriguingly overlapping with a deletion found in 17th- to 18th-century genomes of the Second Pandemic.

Living with plague: Lessons from the Soviet Union's antiplague system.

Zoonoses, such as plague, are primarily animal diseases that spill over into human populations. While the goal of eradicating such diseases is enticing, historical experience validates abandoning eradication in favor of ecologically based control strategies (which reduce morbidity and mortality to a locally accepted risk level). During the 20th century, one of the most extensive plague-eradication efforts in recorded history was undertaken to enable large-scale changes in land use in the former Soviet Union (including vast areas of central Asia). Despite expending tremendous resources in its attempt to eradicate plague, the Soviet antiplague response gradually abandoned the goal of eradication in favor of plague control linked with developing basic knowledge of plague ecology. Drawing from this experience, we combine new gray-literature sources, historical and recent research, and fieldwork to outline best practices for the control of spillover from zoonoses while minimally disrupting wildlife ecosystems, and we briefly compare the Soviet case with that of endemic plague in the western United States. We argue for the allocation of sufficient resources to maintain ongoing local surveillance, education, and targeted control measures; to incorporate novel technologies selectively; and to use ecological research to inform developing landscape-based models for transmission interruption. We conclude that living with emergent and reemergent zoonotic diseases-switching to control-opens wider possibilities for interrupting spillover while preserving natural ecosystems, encouraging adaptation to local conditions, and using technological tools judiciously and in a cost-effective way.

Pandemic realism as the indispensable political precondition for global disease eradication.

This article examines the politico-scientific mechanism, which leads nations to declare an epidemic or a pandemic finished, irrespective of the actual epidemiological situation at a given time. A historical comparison is made with the famous behavior of Emperor Justinian I (482-565 CE) during the plague pandemic named after him (part of the first plague pandemic). Finally, a reference to the importance of the multidisciplinary study of the history of medicine and the intersection between pandemics and wars is made.