Evolution of immune genes is associated with the Black Death.

Infectious diseases are among the strongest selective pressures driving human evolution1,2. This includes the single greatest mortality event in recorded history, the first outbreak of the second pandemic of plague, commonly called the Black Death, which was caused by the bacterium Yersinia pestis3. This pandemic devastated Afro-Eurasia, killing up to 30-50% of the population4. To identify loci that may have been under selection during the Black Death, we characterized genetic variation around immune-related genes from 206 ancient DNA extracts, stemming from two different European populations before, during and after the Black Death. Immune loci are strongly enriched for highly differentiated sites relative to a set of non-immune loci, suggesting positive selection. We identify 245 variants that are highly differentiated within the London dataset, four of which were replicated in an independent cohort from Denmark, and represent the strongest candidates for positive selection. The selected allele for one of these variants, rs2549794, is associated with the production of a full-length (versus truncated) ERAP2 transcript, variation in cytokine response to Y. pestis and increased ability to control intracellular Y. pestis in macrophages. Finally, we show that protective variants overlap with alleles that are today associated with increased susceptibility to autoimmune diseases, providing empirical evidence for the role played by past pandemics in shaping present-day susceptibility to disease.

Complete Protection Against Yersinia pestis in BALB/c Mouse Model Elicited by Immunization With Inhalable Formulations of rF1-V10 Fusion Protein via Aerosolized Intratracheal Inoculation.

Pneumonic plague, caused by Yersinia pestis, is an infectious disease with high mortality rates unless treated early with antibiotics. Currently, no FDA-approved vaccine against plague is available for human use. The capsular antigen F1, the low-calcium-response V antigen (LcrV), and the recombinant fusion protein (rF1-LcrV) of Y. pestis are leading subunit vaccine candidates under intense investigation; however, the inability of recombinant antigens to provide complete protection against pneumonic plague in animal models remains a significant concern. In this study, we compared immunoprotection against pneumonic plague provided by rF1, rV10 (a truncation of LcrV), and rF1-V10, and vaccinations delivered via aerosolized intratracheal (i.t.) inoculation or subcutaneous (s.c.) injection. We further considered three vaccine formulations: conventional liquid, dry powder produced by spray freeze drying, or dry powder reconstituted in PBS. The main findings are: (i) rF1-V10 immunization with any formulation via i.t. or s.c. routes conferred 100% protection against Y. pestis i.t. infection; (ii) rF1 or rV10 immunization using i.t. delivery provided significantly stronger protection than rF1 or rV10 immunization via s.c. delivery; and (iii) powder formulations of subunit vaccines induced immune responses and provided protection equivalent to those elicited by unprocessed liquid formulations of vaccines. Our data indicate that immunization with a powder formulation of rF1-V10 vaccines via an i.t. route may be a promising vaccination strategy for providing protective immunity against pneumonic plague.

Differential mortality of infectious disease in Italian polities: COVID-19, past plague epidemics, and currently endemic respiratory disease.

Coronavirus disease 2019 (COVID-19) has harshly impacted Italy since its arrival in February 2020. In particular, provinces in Italy's Central and Northern macroregions have dealt with disproportionately greater case prevalence and mortality rates than those in the South. In this paper, we compare the morbidity and mortality dynamics of 16th and 17th century Plague outbreaks with those of the ongoing COVID-19 pandemic across Italian regions. We also include data on infectious respiratory diseases which are presently endemic to Italy in order to analyze the regional differences between epidemic and endemic disease. A Growth Curve Analysis allowed for the estimation of time-related intercepts and slopes across the 16th and 17th centuries. Those statistical parameters were later incorporated as criterion variables in multiple General Linear Models. These statistical examinations determined that the Northern macroregion had a higher intercept than the Southern macroregion. This indicated that provinces located in Northern Italy had historically experienced higher plague mortalities than Southern polities. The analyses also revealed that this geographical differential in morbidity and mortality persists to this day, as the Northern macroregion has experienced a substantially higher COVID-19 mortality than the Southern macroregion. These results are consistent with previously published analyses. The only other stable and significant predictor of epidemic disease mortality was foreign urban potential, a measure of the degree of interconnectedness between 16th and 17th century Italian cities. Foreign urban potential was negatively associated with plague slope and positively associated with plague intercept, COVID-19 mortality, GDP per capita, and immigration per capita. Its substantial contribution in predicting both past and present outcomes provides a temporal continuity not seen in any other measure tested here. Overall, this study provides compelling evidence that temporally stable geographical factors, impacting both historical and current foreign pathogen spread above and beyond other hypothesized predictors, underlie the disproportionate impact COVID-19 has had throughout Central and Northern Italian provinces.

Ayudas transatlánticas: la actuación de la Casa de la Misericordia de Sevilla ante la gran peste de 1649 / Ajuda transatlântica: a ação da Casa da Misericórdia de Sevilha diante da grande praga em 1649 / Transatlantic aid: the performance of the House of Mercy of Seville before the great plague of 1649

Los legados testamentarios destinados a dotar a doncellas de la Casa Pía de la Misericordiade Sevilla provenían de diferentes lugares, algunas de las Indias o América hispana. Algunosenviaban para dotar a jóvenes pobres y otros a parientes. Uno de los casos más interesantesencontrados en la documentación fue la de un sevillano que vivía en Lima, capital del Virreinatodel Perú, que envió dinero para fundar una dotación para dotar a doncellas pobres. Lo singular delcaso es que coincidió el ingreso de esta dotación con la gran peste de 1649 que causó la peormortandad que recuerde la ciudad. Este dinero se empleó no para la voluntad del testador, sinopara otros fines más necesarios en aquellos momentos.(AU)

The testamentary legacies were destined to endow the families of the Casa Pia de laMisericordia of Seville from different places, some of the Indies or Hispanic America. Some sentto provide poor young people and others with relatives. One of the most interesting cases found inthe documentation was a subservient living in Lima, Viceroyalty of Peru, who sent money to obtaina date to send poor maidens. The singular thing of the case is that it coincided with the entry ofthis stage with the great plague of 1649 that caused the worst mortality that the city remembers.This money was not used for the will of the testator, but for other purposes more in memorablemoments.(AU)

Os legados testamentários destinados a dotar as donzelas da Casa Pía de la Misericordia deSevilha vieram de diferentes lugares, alguns das Índias ou da América hispânica. Alguns enviadospara equipar jovens pobres e outros para parentes. Um dos casos mais interessantes encontradosna documentação foi o de um sevilhano que morava em Lima, capital do Vice-Reino do Peru, queenviou dinheiro para fundar uma doação para fornecer donzelas pobres. O que há de único no casoé que a entrada deste fundo patrimonial coincidiu com a grande praga de 1649 que causou a piormortalidade na cidade lembra. Esse dinheiro não foi usado para a vontade do testador, mas paraoutros fins mais necessários à época.(AU)

Are we Athens or Florence? COVID-19 in historical context.

We have been here before. In 430 BCE, a plague struck Athens, killing as much as 25% of the population. In 1347 CE, the bubonic plague afflicted western Europe for 4 years, killing as much as 50% of the population. The plague of Athens led to a collapse of their religion, cultural norms and democracy. In contrast, the bubonic plague led eventually to the Renaissance, a growth of art, science and humanism. As we contend with the COVID-19 global pandemic, will we become Athens or Florence?

Two fatal cases of plague after consumption of raw marmot organs.

Marmots are an important reservoir of Yersinia pestis and a source of human plague in Mongolia. We present two fatal cases of plague after consumption of raw marmot organs and discuss the distribution of natural foci of Y. pestis in Mongolia.

Survival analysis of the Black Death: Social inequality of women and the perils of life and death in Medieval London.

OBJECTIVES: Described as an indiscriminate killer by many chroniclers, the Black Death descended on London during the 14th century. To best understand the pattern of transmission among demographic groups, models should include multiple demographic and health covariates concurrently, something rarely done when examining Black Death, but implemented in this study to identify which demographic groups had a higher susceptibility. Female predisposition to the Black Death was also explored, focusing on whether social inequality added to vulnerability. MATERIALS AND METHODS: Three attritional cemeteries from the Wellcome Osteological Research Database were compared with the Black Death cemetery, East Smithfield. A Cox proportional hazards regression estimated hazards ratios of dying of the Black Death, using transition analysis ages-at-death as the time variable, and sex and frailty as covariates. Additionally, a binomial logistic regression generated odds ratios for age-at-death, sex, and frailty. RESULTS: The Cox model produced a significant hazards ratio for individuals deemed frail. Similarly, the logit model calculated significantly increased odds ratios for frail individuals, and decreased odds for individuals aged 65+. DISCUSSION: The older individuals were not undergoing growth during times of great stress in London pre-dating the Black Death epidemic, which may explain the decreased odds of contracting the Black Death. Further, although women dealt with social inequality, which partially led to the demographic puzzle of the Medieval "missing" women, women's susceptibility to infection by the Black Death was not increased. The phenomenon of the missing women may be due to a combination of factors, including infant and child mortality and preservation.

Mortality and demographic recovery in early post-black death epidemics: Role of recent emigrants in medieval Dijon.

OBJECTIVE AND METHODS: We analyze the influence of population movement on susceptibility to death and resilience during two epidemics occurring in Dijon soon after the Black Death. Using a specific program designed to propose links between entries in annual tax registers, we define tentative heads of household, the elapsed time since their first registration and their ties with other persons within the city. RESULTS: During the 1400 epidemic heads of household who were registered for 1-3 years die in large numbers, whereas during years without epidemics, their death rate is lower than that of heads of household who were registered longer. Recent registration is an epidemic vulnerability factor only in association with a low taxation status, which, when isolated, does not influence mortality. A lack of familial ties within Dijon is another vulnerability factor among the recently registered. This suggests that poor, recent emigrants are more affected by epidemic mortality. In contrast, the mortality of recently registered heads of household is indistinct during a later epidemic occurring after several years of major famine that may have selected the more resistant emigrants and/or excluded the more miserable of them from our analysis. In contrast to the first one, this second epidemic is followed by rapid demographic recovery. This latter recovery is fully explained by the contribution of poor, newly registered heads of household without ties in Dijon. CONCLUSION: Our results outline the interaction between population movement and low socioeconomic status on death susceptibility in historical plagues and show that poor recent emigrants may also be key players in the resilience of the population after an epidemic.

Sex differences in adult famine mortality in medieval London.

OBJECTIVES: Recurrent famine events during the medieval period might have contributed to excess mortality during the Black Death in London, England (c. 1349-1350). Previous research using conventional methods of age estimation revealed that adult males experienced lower risks of mortality under "normal" (attritional) but not famine mortality conditions following the Black Death. However, given the biases inherent in conventional age estimation methods, this study reassesses sex differences in risks of medieval adult famine mortality using ages estimated via transition analysis, which avoids some of the limitations of conventional age estimation methods. MATERIALS AND METHODS: We apply hazards analysis (the Gompertz model of adult mortality) to ages estimated for human skeletal remains (n = 1245) from London cemeteries dated to the pre-Black Death (c. 1000-1250 CE) and post-Black Death (c. 1350-1540 CE) periods. RESULTS: The results reveal no sex differences in risks of mortality before the Black Death but indicate that adult males faced lower risks of mortality after the Black Death during conditions of normal and famine mortality. CONCLUSIONS: These findings largely support those of our previous research, which suggested that selective mortality during the Black Death or sex-biased improvements in standard of living following the epidemic reduced risk of mortality for adult males in the post-Black Death period under normal mortality conditions. However, the use of transition analysis age estimates also revealed a reduced risk of mortality for post-Black Death adult males under famine conditions.

A Recombinant Attenuated Yersinia pseudotuberculosis Vaccine Delivering a Y. pestis YopENt138-LcrV Fusion Elicits Broad Protection against Plague and Yersiniosis in Mice.

In this study, a novel recombinant attenuated Yersinia pseudotuberculosis PB1+ strain (χ10069) engineered with ΔyopK ΔyopJ Δasd triple mutations was used to deliver a Y. pestis fusion protein, YopE amino acid 1 to 138-LcrV (YopENt138-LcrV), to Swiss Webster mice as a protective antigen against infections by yersiniae. χ10069 bacteria harboring the pYA5199 plasmid constitutively synthesized the YopENt138-LcrV fusion protein and secreted it via the type 3 secretion system (T3SS) at 37°C under calcium-deprived conditions. The attenuated strain χ10069(pYA5199) was manifested by the establishment of controlled infection in different tissues without developing conspicuous signs of disease in histopathological analysis of microtome sections. A single-dose oral immunization of χ10069(pYA5199) induced strong serum antibody titers (log10 mean value, 4.2), secretory IgA in bronchoalveolar lavage (BAL) fluid from immunized mice, and Yersinia-specific CD4+ and CD8+ T cells producing high levels of tumor necrosis factor alpha (TNF-α), gamma interferon (IFN-γ), and interleukin 2 (IL-2), as well as IL-17, in both lungs and spleens of immunized mice, conferring comprehensive Th1- and Th2-mediated immune responses and protection against bubonic and pneumonic plague challenges, with 80% and 90% survival, respectively. Mice immunized with χ10069(pYA5199) also exhibited complete protection against lethal oral infections by Yersinia enterocolitica WA and Y. pseudotuberculosis PB1+. These findings indicated that χ10069(pYA5199) as an oral vaccine induces protective immunity to prevent bubonic and pneumonic plague, as well as yersiniosis, in mice and would be a promising oral vaccine candidate for protection against plague and yersiniosis for human and veterinary applications.

Plague-Positive Mouse Fleas on Mice Before Plague Induced Die-Offs in Black-Tailed and White-Tailed Prairie Dogs.

Plague is a lethal zoonotic disease associated with rodents worldwide. In the western United States, plague outbreaks can decimate prairie dog (Cynomys spp.) colonies. However, it is unclear where the causative agent, Yersinia pestis, of this flea-borne disease is maintained between outbreaks, and what triggers plague-induced prairie dog die-offs. Less susceptible rodent hosts, such as mice, could serve to maintain the bacterium, transport infectious fleas across a colony, or introduce the pathogen to other colonies, possibly facilitating an outbreak. Here, we assess the potential role of two short-lived rodent species, North American deer mice (Peromyscus maniculatus) and Northern grasshopper mice (Onychomys leucogaster) in plague dynamics on prairie dog colonies. We live-trapped short-lived rodents and collected their fleas on black-tailed (Cynomys ludovicianus, Montana and South Dakota), white-tailed (Cynomys leucurus, Utah and Wyoming), and Utah prairie dog colonies (Cynomys parvidens, Utah) annually, from 2013 to 2016. Plague outbreaks occurred on colonies of all three species. In all study areas, deer mouse abundance was high the year before plague-induced prairie dog die-offs, but mouse abundance per colony was not predictive of plague die-offs in prairie dogs. We did not detect Y. pestis DNA in mouse fleas during prairie dog die-offs, but in three cases we found it beforehand. On one white-tailed prairie dog colony, we detected Y. pestis positive fleas on one grasshopper mouse and several prairie dogs live-trapped 10 days later, months before visible declines and plague-confirmed mortality of prairie dogs. On one black-tailed prairie dog colony, we detected Y. pestis positive fleas on two deer mice 3 months before evidence of plague was detected in prairie dogs or their fleas and also well before a plague-induced die-off. These observations of plague positive fleas on mice could represent early spillover events of Y. pestis from prairie dogs or an unknown reservoir, or possible movement of infectious fleas by mice.

Methods for calculating credible intervals for ratios of beta distributions with application to relative risks of death during the second plague pandemic.

Employing historical records we are able to estimate the risk of premature death during the second plague pandemic, and identify the Black Death and pestis secunda epidemics. We show a novel method of calculating Bayesian credible intervals for a ratio of beta distributed random variables and use this to quantify uncertainty of relative risk estimates for these two epidemics which we consider in a 2 × 2 contingency table framework.

A survival analysis of the last great European plagues: The case of Nonantola (Northern Italy) in 1630.

This paper develops the first survival analysis of a large-scale mortality crisis caused by plague. For the time-to-event analyses we used the Cox proportional hazards regression model. Our case study is the town of Nonantola during the 1630 plague, which was probably the worst to affect Italy since the Black Death. Individual risk of death did not depend on sex, grew with age (peaking at ages 40-60 and then declining), was not affected by socio-economic status, and was positively associated with household size. We discuss these findings in light of the historical-demographic and palaeo-demographic literature on medieval and early modern plagues. Our results are compatible with the debated idea that ancient plague was able to spread directly from human to human. Our methods could be replicated in other studies of European plagues to nuance and integrate the findings of recent palaeo-biological and palaeo-demographic research on plague.

Human ectoparasites and the spread of plague in Europe during the Second Pandemic.

Plague, caused by the bacterium Yersinia pestis, can spread through human populations by multiple transmission pathways. Today, most human plague cases are bubonic, caused by spillover of infected fleas from rodent epizootics, or pneumonic, caused by inhalation of infectious droplets. However, little is known about the historical spread of plague in Europe during the Second Pandemic (14-19th centuries), including the Black Death, which led to high mortality and recurrent epidemics for hundreds of years. Several studies have suggested that human ectoparasite vectors, such as human fleas (Pulex irritans) or body lice (Pediculus humanus humanus), caused the rapidly spreading epidemics. Here, we describe a compartmental model for plague transmission by a human ectoparasite vector. Using Bayesian inference, we found that this model fits mortality curves from nine outbreaks in Europe better than models for pneumonic or rodent transmission. Our results support that human ectoparasites were primary vectors for plague during the Second Pandemic, including the Black Death (1346-1353), ultimately challenging the assumption that plague in Europe was predominantly spread by rats.

Pneumonic plague epidemic in Northeast China in 1910-1911: Dr. Wu Lien-Teh's epidemic preventive system for plague control.

Pneumonic plague that originated in Russian Siberia broke out in Northeast China in October 1910-March 1911. On the basis of field visits, autopsy, bacteriological identification, and close collaboration with local authorities and international colleagues, Dr. Wu Lien-Teh implemented a series of efficient antiplague measures, which successfully controlled the development of an extraordinary epidemic plague. In his subsequent work, Dr. Wu demonstrated the respiratory transmission of pneumonic plague and tarbagans' role in this spread. Dr.Wu's academic and cultural contributions are valuable in the medical progress in China.