Bubonic Plague Research Articles

Medicine, illness and disease in the lordship of Ireland, 1177 to 1541 A.D.

The lordship of Ireland existed for 364 years from 1177 to 1541. Inhabited mostly by the English-of-Ireland, its medical infrastructure resembled contemporary England rather than Gaelic Ireland. The medical marketplace comprised physicians, surgeons, barber-surgeons, apothecaries and midwives, some organised into societies and guilds. Monastic infirmaries and hospitals, including leper hospitals, provided institutional care. Medical practice was rooted in classical medicine and the few Hiberno-English medical texts that survive attest to the use of bleeding, herbs and charms as treatments. Among many ailments leprosy was common, but the arrival of the Black Death bubonic plague pandemic of 1348 decimated the population of the lordship and contributed to its eventual decline. Using historical, archaeological and literary sources this paper analyses the experience of medicine, illness and disease among the people of the lordship of Ireland from the twelfth to the sixteenth centuries.

Plasmonic-Enhanced Colorimetric Lateral Flow Immunoassays Using Bimetallic Silver-Coated Gold Nanostars.

The colorimetric lateral flow immunoassay (cLFIA) has gained widespread attention as a point-of-care testing (POCT) technique due to its low cost, short analysis time, portability, and capability of being performed by unskilled operators with minimal requirement of reagents. However, the low analytical sensitivity of conventional LFIA based on colloidal gold nanospheres limits their applications for sensitive detection of trace amounts of target analytes. In this study, we introduced a novel plasmonic-enhanced colorimetric LFIA (PE-cLFIA) platform featuring bimetallic silver-coated gold nanostars (BGNS) with exceptional optical properties, leading to ultrahigh visual color brightness. The BGNS-based PE-cLFIA was successfully applied to detect a model analyte, low-calcium response V (LcrV), a virulence protein factor found in Yersinia pestis, the causative agent of bubonic plague. The PE-cLFIA sensing using BGNS-3 composed of 45 nm silver thickness showed a high visual colorimetric sensitivity with a detection limit as low as 13.7 pg/mL, which was around 50 times more sensitive than that of a traditional gold nanoparticle-based LFIA. In addition, the antibody-conjugated BGNS-3 showed excellent stability over 6 months. To illustrate the potential for clinical applications, we demonstrated that our LFIA platform for detecting LcrV spiked in human serum without any sample preprocessing exhibited a detection limit of 22.8 pg/mL. These results open up new opportunities for developing hybrid nanoparticle systems for sensitive POCT PE-cLFIA screening for infectious disease detection.

The Need for Historical Fluency in Pandemic Law and Policy.

The primary claim of this essay is that historical fluency is required for effective work in crafting legal and policy interventions as a part of public health emergency preparedness and response (PHEPR). At a broad level, public health law is explicitly recognized as a key systems-level component of PHEPR practice.1 This essay therefore focuses on the extent to which historical fluency is necessary or at least useful to all aspects of PHEPR that draw on or deploy legal and policy mechanisms (e.g., design, planning, implementation, dissemination, monitoring and evaluation, etc.). The essay collectively refers to these legal and policy mechanisms as epidemic law and policy response (ELAPR). Part I explains the concept of historical fluency. Part II explores the foundations of public health law both as a way of highlighting key structural features of ELAPR and in supporting the claim that historical fluency is critical for ELAPR. Part III applies the previous arguments to a specific case study to highlight the promise and power of historical fluency - the outbreak of bubonic plague in San Francisco in 1900. Tracking this essay's pragmatic focus, part IV offers several recommendations for how specifically historical fluency in public health law and ethics can be operationalized in PHEPR practice and policy. Part V summarizes and concludes.

Title

During the fourteenth century, the bubonic plague or Black Death killed more than one third of Europe or 25 million people. Those afflicted died quickly and horribly from an unseen menace, spiking high fevers with suppurative buboes (swellings). Its causative agent is Yersinia pestis, creating recurrent plague cycles from the Bronze Age into modern-day California and Mongolia. Plague remains endemic in Madagascar, Congo, and Peru. This history of medicine review highlights plague events across the centuries. Transmission is by fleas carried on rats, although new theories include via human body lice and infected grain. We discuss symptomatology and treatment options. Pneumonic plague can be weaponized for bioterrorism, highlighting the importance of understanding its clinical syndromes. Carriers of recessive familial Mediterranean fever (FMF) mutations have natural immunity against Y. pestis. During the Black Death, Jews were blamed for the bubonic plague, perhaps because Jews carried FMF mutations and died at lower plague rates than Christians. Blaming minorities for epidemics echoes across history into our current coronavirus pandemic and provides insightful lessons for managing and improving its outcomes

Evaluation of human antibodies from vaccinated volunteers for protection against Yersinia pestis infection.

Yersinia pestis has a broad host range and has caused lethal bubonic and pneumonic plague in humans. With the emergence of multiple resistant strains and the potential for biothreat use, there is an urgent need for new therapeutic strategies that can protect populations from natural or deliberate infection. Targeting F1 has been proven to be the main strategy for developing vaccines and therapeutic antibodies, but data on anti-F1 antibodies, especially in humans, are scarce. To date, three human anti-F1 monoclonal antibodies (m252, αF1Ig2, and αF1Ig8) from naive populations have been reported. Here, we constructed an antibody library from vaccinees immunized with the plague subunit vaccine IIa by phage display. The genetic basis, epitopes, and biological functions of the obtained mAbs were assessed and evaluated in plague-challenged mice. Three human mAbs, namely, F3, F19, and F23, were identified. Their biolayer responses were 0.4, 0.6, and 0.6 nm, respectively. The dissociation constants (KD) of the F1 antigen were 1 pM, 0.165 nM, and 1 pM, respectively. Although derived from distinct Ab lineages, that is, VH3-30-D3-10-JH4 (F3&F23) and VH3-43-D6-19-JH4 (F19), these mAbs share similar binding sites in F1 with some overlap with αF1Ig8 but are distinct from αF1Ig2. Each of them provided a significant protective effect for Balb/c mice against a 100 median lethal dose (MLD) challenge of a virulent Y. pestis strain when administered at a dose of 100 µg. No synergistic or antagonistic effects were observed among them. These mAbs are novel and excellent candidates for further drug development and use in clinical practice.IMPORTANCEIn this study, we identified three human monoclonal antibodies with a high affinity to F1 protein of Yersinia pestis. We discovered that they have relatively lower somatic hypermutations compared with antibodies, m252, αF1Ig2, and αF1Ig8, derived from the naive library reported previously. We also observed that these mAbs share similar binding sites in F1 with some overlapping with αF1Ig8 but distinct from that of αF1Ig2. Furthermore, each of them could provide complete protection for mice against a lethal dose of Yersinia pestis challenge. Our data provided new insights into the anti-F1 Ab repertories and their associated epitopes during vaccination in humans. The findings support the additional novel protective human anti-F1Abs for potential therapeutics against plaque.

Differential pathogenicity and lethality of bubonic plague (1720-1945) by sex, age and place.

COVID-19 brought back to the attention of the scientific community that males are more susceptible to infectious diseases. What is clear for other infections-that sex and gender differences influence both risk of infection and mortality-is not yet fully elucidated for plague, particularly bubonic plague, although this knowledge can help find specific defences against a disease for which a vaccine is not yet available. To address this question, we analysed data on plague from hospitals in different parts of the world since the early eighteenth century, which provide demographic information on individual patients, diagnosis and course of the disease in the pre-antibiotic era. Assuming that the two sexes were equally represented, we observe a worldwide prevalence of male cases hospitalized at any age, a result which seems better explained by gender-biased (thus cultural) behaviours than biological sex-related factors. Conversely, case fatality rates differ among countries and geographic macro-areas, while globally, lethality appears slightly prevalent in young females and older adults (regardless of sex). Logistic regression models confirm that the main risk factor for bubonic plague death was the geographical location of the cases and being older than 50 years, whereas sex only showcased a slight trend.

Yersinia pestis and pneumonic plague: Insight into how a lethal pathogen interfaces with innate immune populations in the lung to cause severe disease

Yersinia pestis is the causative agent of bubonic, septicemic and pneumonic plague. The historical importance and potential of plague to re-emerge as a threat worldwide are indisputable. The most severe manifestion of plague is pneumonic plague, which results in disease that is 100% lethal without treatment. Y. pestis suppresses host immune responses early in the lung to establish infection. The later stages of infection see the rapid onset of hyperinflammatory responses that prove lethal. The study of Y. pestis host/pathogen interactions have largely been investigated during bubonic plague and with attenuated strains in cell culture models. There remains a somewhat limited understanding of the interactions between virulent Y. pestis and immune populations in the lung that drive severe disease. In this review we give a broad overview of the progression of pneumonic plague and highlighting how Y. pestis interfaces with host innate immune populations in the lung to cause lethal disease.

An open-label, randomized, non-inferiority trial of the efficacy and safety of ciprofloxacin versus an aminoglycoside + ciprofloxacin in the treatment of bubonic plague (IMASOY): study protocol for a randomized control trial—an update to the published protocol

This article reports an update to the protocol of the IMASOY trial, which was prospectively registered on clinicaltrials.gov (NCT04110340) in October 2019.

Segregation and plague: King William's Town and the plague outbreaks of 1900-1907

Studies in the history of bubonic plague in Cape Town and Port Elizabeth revealed the close connection between the Victorian obsession with sanitation and the development of urban segregation in South Africa. The response of the medical officials and local authorities in the cities was mirrored in King William's Town, where racial prejudges were compounded by the Town Council's incompetence and reluctance to incur any expenditure from its own coffers.

An overview of the first human case of Bubonic plague detected in Bugat settlement, Gobi-Altai province in Mongolia

On June 27th, 2023, Mongolia registered its first case of bubonic plague in the Bugat settlement, Gobi-Altai province. Cases in this outbreak are widespread throughout the country with multiple close contacts identified and monitored. Environmental surveillance, including the testing of marmots, picked up the presence of Yersinia Pestis in many samples prior to the beginning of the outbreak. Marmots are seen as a delicacy in Mongolia which presents a challenge when preventing animal to human transmission of bubonic plague via the consumption of raw undercooked marmot meat. Although bubonic plague is endemic in Mongolia, cases are often sporadic and mostly registered in the western provinces of the region however, one case was recorded in the capital city of Ulan Bator on the eastern side of the country. The nature of this outbreak highlights the importance of effective preventive measures such as, PPE, awareness campaigns, health literacy and safe food handling practices.

Creative infestation

The fourteenth-century outbreak of Bubonic Plague, known as the Black Death, exerted a transformative impact upon Western Europe, facilitating the development of more empirical and observational forms of medicine and science, weakening the hold of the Catholic Church, and dealing a major blow to the feudalistic state organization and manorial economies. Western society after the Black Death would never look the same again. The Black Death should thus be viewed as laying the foundations of, and a major catalyst for, the emergence of modernity in Western Europe.

Knowledge and practices related to plague persistence in plague-endemic foci, Mbulu District, Tanzania.

Plague continues to be a major public health concern in African countries. Several social practices and environmental conditions have been associated with the reoccurrence of bubonic plague, especially in places where the disease is prevalent. Therefore, it remains important to understand people knowledge, behavior and practices related to disease risks in order to identify factors that may hinder prevention and control strategies in the foci. A study survey of 100 households was conducted in Mbulu district to assess plague knowledge, factors that influence flea bite and measures used for rodent and flea control. Majority of participants (86%) were familiar with the plague disease and about (50%) mentioned swelling lymph nodes as a common symptom. Most of the participants (62%) claimed to observe human plague cases during the long rain season. The majority of participants (97%) reported to experience flea bite in their domestic settings, with most stating that they experienced more flea bites during the dry season. Houses with livestock had a greater likelihood of flea bite (OR = 2.7; 95% CI: 0.36-18.80, p = 0.267) compared to houses with no livestock. Furthermore, residents reported using both local and chemical methods to control rodents and flea inside houses. Most respondents preferred using local methods in flea control. Respondents stated that the efficacy of flea control methods being applied ranged from few days to several months. There was limited knowledge of the residual effects of the agricultural chemicals being used to control fleas among the surveyed community. Our study highlights the importance of raising awareness and adopting effective control methods for controlling fleas and lower the risk of plague transmission and other flea borne diseases in the local communities. Sensitization of the local community on the use of appropriate chemicals for flea control is urgent to avoid any potential long-term impacts of the residual effects on the health of the local communities.

LAS TRIACAS, AYER Y HOY

The history of theriaca reveals several attributes of humankind in their relation to medicine that enriches their present understanding. A compound of numerous simples, it reigned through twenty centuries as a panacea against diverse ailments, was a symbol of therapeutic progress, and sustained the interest and hope of learned and lay people of many cultures and civilizations. Its fame and commercial success drove the apparition of copies and falsifications that have persisted under the names of their creators, the city of origin, or some special char­acteristics. Most famous are mithridatium, theriaca magna of Andromachus, diatessaron or of the poor, and Venice theriaca. Of Greeks origin, it grew in fame mainly due to Galen and an unknown contemporary in Rome. Byzantine, Arab and Persian medical authors, and later others in Montpellier, Salerno and Padua, preserved the ancient writings and elaborated on them. The apparition of bubonic plague meant an enormous impulse to its use, augmented by the commercial strategy of Venice, and amplified by the printing of numerous pamphlets and books. The Scientific Revolution and the diffusion of its ideas marked the beginning of its decline, but it was still present in most European pharmacopeias until the end of the 19th cen­tury. We propose that fear, greed and credulity were seminal factors in its success, conditions still present today in medical marketing, quackery and falsifications, unnecessary care, medical consumerism, and unregulated alternative medicines and cosmetic industries.

Differentiation of Synanthropic Fleas from Andalusia (Spain) through Geometric Morphometrics Analysis.

Fleas (Siphonaptera) are ectoparasitic hematophagous insects responsible for causing bites and itchy skin conditions in both humans and animals. Furthermore, they can act as vectors of different pathogens of a wide variety of diseases worldwide, including bartonellosis, rickettsiosis, and bubonic plague. Accurate identification of fleas is necessary for the study of their epidemiology, prevention, and control. In addition to traditional morphological classification approaches and molecular biology techniques, geometric morphometrics is increasingly proving to be a useful complementary tool for discriminating between Siphonaptera taxa. With the objective of determining the capacity of this technique to identify and differentiate synanthropic fleas, a principal component analysis was carried out on populations of Ctenocephalides felis, Pulex irritans, and Archaeopsylla erinacei collected in distinct regions of Andalusia (Spain). The analysis carried out on 81 male and female specimens revealed factorial maps that allowed the differentiation of the populations under study, with only partial overlaps that did not prevent their correct identification. Global size differences were also detected, with a slightly larger size in P. irritans males and a bigger size in A. erinacei females. Therefore, the present study emphasizes the role of geometric morphometrics as a useful complementary technique in taxonomic studies of arthropods, especially in the case of flea specimens lacking representative morphological features.

Past anthropogenic impacts revealed by trace elements in cave guano

Natural and human-induced toxic elements can accumulate in the environment, posing significant risks to human health and ecosystems. This study explores cave bat guano, an unconventional and relatively under-researched environmental repository, to reveal historical pollution trends and sources. Through trace elements analysis of a 1.5-m-thick guano deposit from Zidită Cave (Romania), we track changes in mining and metallurgy from 1000 CE–2012. We identified substantial pollution primarily from porphyry copper and Au–Ag–Te mines, but also impacts from usage of leaded gasoline and agricultural practices. Our record shows disruptions caused by the Bubonic plague around 1250 CE and a major surge ∼ 1500 CE. After the decline triggered by the European silver market collapse in 1525 CE, our study reveals a brief mining revival. This resurgence was followed by a continuous decline lasting until the early 1800s, driven by socio-economic upheavals and recurrent outbreaks of the bubonic plagues. The Industrial Revolution sparked prolonged growth that lasted until 1989 CE, only briefly interrupted by the Great Depression and World War II. Consequently, cave bat guano proves to be a critical resource for understanding spatial pollution patterns, both locally and regionally, and for identifying specific pollution sources.

Sex differences in immune protection in mice conferred by heterologous vaccines for pneumonic plague.

Yersinia pestis is the etiological agent of plague, which can manifest as bubonic, septicemic, and/or pneumonic disease. Plague is a severe and rapidly progressing illness that can only be successfully treated with antibiotics initiated early after infection. There are no FDA-approved vaccines for plague, and some vaccine candidates may be less effective against pneumonic plague than bubonic plague. Y. pestis is not known to impact males and females differently in mechanisms of pathogenesis or severity of infection. However, one previous study reported sex-biased vaccine effectiveness after intranasal Y. pestis challenge. As part of developing a safe and effective vaccine, it is essential that potential sex differences are characterized. In this study we evaluated novel vaccines in male and female BALB/c mice using a heterologous prime-boost approach and monitored survival, bacterial load in organs, and immunological correlates. Our vaccine strategy consisted of two subcutaneous immunizations, followed by challenge with aerosolized virulent nonencapsulated Y. pestis. Mice were immunized with a combination of live Y. pestis pgm- pPst-Δcaf1, live Y. pestis pgm- pPst-Δcaf1/ΔyopD, or recombinant F1-V (rF1-V) combined with adjuvants. The most effective vaccine regimen was initial priming with rF1-V, followed by boost with either of the live attenuated strains. However, this and other strategies were more protective in female mice. Males had higher bacterial burden and differing patterns of cytokine expression and serum antibody titers. Male mice did not demonstrate synergy between vaccination and antibiotic treatment as repeatedly observed in female mice. This study provides new knowledge about heterologous vaccine strategies, sex differences in plague-vaccine efficacy, and the immunological factors that differ between male and female mice.

Prime-boost vaccination combining rF1-V subunit and novel live attenuated bacterial strains protects mice from virulent aerosolized nonencapsulated Yersinia pestis

Abstract Yersinia pestis (Yp) is a security concern since it can be aerosolized and cause pneumonic plague, a rapidly progressing illness that is fatal if not treated promptly with antibiotics. There are no FDA-approved vaccines, and candidate vaccines are less effective against pneumonic than bubonic plague. The major protective vaccine antigen has been the F1 capsule protein; protection against nonencapsulated strains has been elusive. We constructed two novel live attenuated vaccine (LAV) strains on the pgm-pPst- background, which is excluded from the CDC select agent list due to established safety. These strains, Δcaf1 and ΔyopD/Δcaf1, lack F1 and may be more effective at inducing immunity against nonencapsulated strains like C12. Female BALB/c mice were immunized with a heterologous prime-boost strategy combining one subcutaneous injection of novel LAV and one of recombinant F1-V (rF1-V) subunit, then challenged with aerosolized virulent Yp C12 and monitored for survival, bacterial load, and immunological factors. Priming with rF1-V and boosting with LAV was more protective than the reverse strategy. Protection was accompanied by high antibody titers against rF1-V and rV. rF1-V prime and LAV boost also led to a higher IgG2a/IgG1 antibody ratio than the reverse, suggesting a balanced Th1/Th2 response. These data support rF1-V prime and pgm-pPst-Δcaf1 LAV boost as a promising strategy for a safe and effective vaccine against both encapsulated and nonencapsulated Yp.

Decrypting the multi-genome data for chimeric vaccine designing against the antibiotic resistant Yersinia pestis

Yersinia pestis, the causative agent of plague, is a gram-negative bacterium that can be fatal if not treated properly. Three types of plague are currently known: bubonic, septicemic, and pneumonic plague, among which the fatality rate of septicemic and pneumonic plague is very high. Bubonic plague can be treated, but only if antibiotics are used at the initial stage of the infection. But unfortunately, Y. pestis has also shown resistance to certain antibiotics such as kanamycin, minocycline, tetracycline, streptomycin, sulfonamides, spectinomycin, and chloramphenicol. Despite tremendous progress in vaccine development against Y. pestis, there is no proper FDA-approved vaccine available to protect people from its infections. Therefore, effective broad-spectrum vaccine development against Y. pestis is indispensable. In this study, vaccinomics-assisted immunoinformatics techniques were used to find possible vaccine candidates by utilizing the core proteome prepared from 58 complete genomes of Y. pestis. Human non-homologous, pathogen-essential, virulent, and extracellular and membrane proteins are potential vaccine targets. Two antigenic proteins were prioritized for the prediction of lead epitopes by utilizing reverse vaccinology approaches. Four vaccine designs were formulated using the selected B- and T-cell epitopes coupled with appropriate linkers and adjuvant sequences capable of inducing potent immune responses. The HLA allele population coverage of the T-cell epitopes selected for vaccine construction was also analyzed. The V2 constructs were top-ranked and selected for further analysis on the basis of immunological, physicochemical, and immune-receptor docking interactions and scores. Docking and molecular dynamic simulations confirmed the stability of construct V2 interactions with the host immune receptors. Immune simulation analysis anticipated the strong immune profile of the prioritized construct. In silico restriction cloning ensured the feasible cloning ability of the V2 construct in the expression system of E. coli strain K12. It is anticipated that the designed vaccine construct may be safe, effective, and able to elicit strong immune responses against Y. pestis infections and may, therefore, merit investigation using in vitro and in vivo assays.

Socio-ecological risk factors associated with human flea infestations of rural household in plague-endemic areas of Madagascar.

Plague is a flea-borne fatal disease caused by the bacterium Yersinia pestis, which persists in rural Madagascar. Although fleas parasitizing rats are considered the primary vectors of Y. pestis, the human flea, Pulex irritans, is abundant in human habitations in Madagascar, and has been found naturally infected by the plague bacterium during outbreaks. While P. irritans may therefore play a role in plague transmission if present in plague endemic areas, the factors associated with infestation and human exposure within such regions are little explored. To determine the socio-ecological risk factors associated with P. irritans infestation in rural households in plague-endemic areas of Madagascar, we used a mixed-methods approach, integrating results from P. irritans sampling, a household survey instrument, and an observational checklist. Using previously published vectorial capacity data, the minimal P. irritans index required for interhuman bubonic plague transmission was modeled to determine whether household infestations were enough to pose a plague transmission risk. Socio-ecological risk factors associated with a high P. irritans index were then identified for enrolled households using generalized linear models. Household flea abundance was also modeled using the same set of predictors. A high P. irritans index occurred in approximately one third of households and was primarily associated with having a traditional dirt floor covered with a plant fiber mat. Interventions targeting home improvement and livestock housing management may alleviate flea abundance and plague risk in rural villages experiencing high P. irritans infestation. As plague-control resources are limited in developing countries such as Madagascar, identifying the household parameters and human behaviors favoring flea abundance, such as those identified in this study, are key to developing preventive measures that can be implemented at the community level.

‘Unpaused’ - Naya Safar - Navigating through Life During the COVID-19 Pandemic

Life changed after the first nationwide lockdown was announced by Prime Minister Shri Narendra Modi on 24th March,2020 and the series of lockdowns that were announced later, in India. What ensued, has gone down in history. The COVID-19 virus had steadily gained a steady footing and was a force to reckon with. The middle-aged population in India and specifically Bombay (now Mumbai) had heard narratives of the Bubonic Plague epidemic, which affected people well into the 1950s, from the septuagenarian population, which were woven around plague deaths and had left an indelible mark. The COVID-19 pandemic provided first-hand experience across the spectrum, of a pandemic. Solitary confinement or lockdowns forced families to huddle together in the narrow confines of their homes, which was a challenge, especially in metro cities, that are plagued with space constraints. This resulted in unwittingly kicking ‘a can of worms’ for many, as a result of coming face-to-face with unacknowledged emotions. Emotions that ranged from grief over loss of employment, the sorrow, due to the inability to connect with loved ones to feelings of helplessness faced while fighting with the demons within, and many such unsavoury feelings, which raised their ugly head. At such times, Over-The-Top (OTT) platforms provided the much-required succour in the form of anthologies that dealt with myriad sentiments that people felt during the pandemic. This paper intends to analyse the digitised literary representation as captured in Unpaused- Naya Safar- Season 1, which is streaming on Amazon Prime, capturing the highs and lows experienced by individuals during the COVID-19 pandemic.