A self-amplifying RNA vaccine provides protection in a murine model of bubonic plague.

Mice were immunized with a combination of self-amplifying (sa) RNA constructs for the F1 and V antigens of Yersinia pestis at a dose level of 1 µg or 5 µg or with the respective protein sub-units as a reference vaccine. The immunization of outbred OF1 mice on day 0 and day 28 with the lowest dose used (1 µg) of each of the saRNA constructs in lipid nanoparticles protected 5/7 mice against subsequent sub-cutaneous challenge on day 56 with 180 cfu (2.8 MLD) of a 2021 clinical isolate of Y. pestis termed 10-21/S whilst 5/7 mice were protected against 1800cfu (28MLD) of the same bacteria on day 56. By comparison, only 1/8 or 1/7 negative control mice immunized with 10 µg of irrelevant haemagglutin RNA in lipid nanoparticles (LNP) survived the challenge with 2.8 MLD or 28 MLD Y. pestis 10-21/S, respectively. BALB/c mice were also immunized with the same saRNA constructs and responded with the secretion of specific IgG to F1 and V, neutralizing antibodies for the V antigen and developed a recall response to both F1 and V. These data represent the first report of an RNA vaccine approach using self-amplifying technology and encoding both of the essential virulence antigens, providing efficacy against Y. pestis. This saRNA vaccine for plague has the potential for further development, particularly since its amplifying nature can induce immunity with less boosting. It is also amenable to rapid manufacture with simpler downstream processing than protein sub-units, enabling rapid deployment and surge manufacture during disease outbreaks.

The efficacy, safety, and immunogenicity of plague vaccines: A systematic literature review.

Plague remains endemic in many parts of the world, and despite efforts, no preventative vaccine is available. We performed a systemic review of available randomised controlled trials (RCTs) of live, attenuated, or killed plague vaccines vs. placebo, no intervention, or other plague vaccine to evaluate their efficacy, safety, and immunogenicity. Data sources included MEDLINE, Embase, and the Cochrane Library; clinical trial registers; and reference lists of included studies. Primary outcomes were efficacy, safety, and immunogenicity. Risk of bias was assessed using the Cochrane Collaborations tool. Only 2 RCTs, both on subunit vaccines, were included out of the 75 screened articles. The 2 trials included 240 participants with a follow-up of 3 months and 60 participants with a follow-up of 13 months, respectively. Safety evidence was limited, but both vaccines were well tolerated, with only mild to moderate adverse events. Both vaccines were immunogenic in a dose-dependent manner. However, given the limited data identified in this systematic review, we are unable to quantify the efficacy of vaccines to prevent plague, as well as their long-term safety and immunogenicity. More trials of plague vaccines are needed to generate additional evidence of their long-term effects.

War on Rats: the architecture of the bubonic plague in Galveston.

Galveston, Texas is one of the oldest seaport cities in the Gulf of Mexico west of New Orleans, making it a historically prime location for disease outbreaks. The bubonic plague bacterium, Yersinia pestis, likely spread to Galveston via infected rats and fleas on steamboats. Known as the Black Death, the bubonic plague infected 17 Galvestonians from 1920 to 1921. This article examines the "War on Rats," the public health response to the Galveston bubonic plague outbreak in the 1920s. As part of public health practices at the time, the rat-proofing of buildings provides a glimpse into the intersection of public health and architecture. This exploration of the war on rats in Galveston offers insights into 20th-century examples of cross-disciplinary collaboration to promote human health in urban contexts.

Single-cell transcriptomics of immune cells in lymph nodes reveals their composition and alterations in functional dynamics during the early stages of bubonic plague.

Bubonic plague caused by Yersinia pestis is highly infectious and often fatal. Characterization of the host immune response and its subsequent suppression by Y. pestis is critical to understanding the pathogenesis of Y. pestis. Here, we utilized single-cell RNA sequencing to systematically profile the transcriptomes of immune cells in draining lymph nodes (dLNs) during the early stage of Y. pestis infection. Dendritic cells responded to Y. pestis within 2 h post-infection (hpi), followed by the activation of macrophages/monocytes (Mφs/Mons) and recruitment of polymorphonuclear neutrophils (PMNs) to dLNs at 24 hpi. Analysis of cell-to-cell communication suggests that PMNs may be recruited to lymph nodes following the secretion of CCL9 by Mφs/Mons stimulated through CCR1-CCL9 interaction. Significant functional suppression of all the three innate immune cell types occurred during the early stage of infection. In summary, we present a dynamic immune landscape, at single-cell resolution, of murine dLNs involved in the response to Y. pestis infection, which may facilitate the understanding of the plague pathogenesis of during the early stage of infection.

Plague in Disguise: The Discovery of Occult Buboes on Surgical Procedure or Autopsy.

Introduction: Bubonic plague classically manifests as a painful, swollen superficial lymph node (bubo) that is readily apparent on physical examination. However, patients occasionally present with buboes formed in deep lymph nodes, which are difficult to detect and can lead to delays in diagnosis and treatment. To better characterize this phenomenon, we conducted a review of the published literature to identify reports of occult buboes among patients with plague. Methods: Articles were identified from two sources: a systematic review on plague treatment, and a search of the PubMed Central database. Articles were eligible if they described a patient with plague who had (1) no evidence of lymphadenopathy on examination; and (2) at least one bubo discovered during surgery or autopsy. Results: Six patients with occult buboes were identified among 5120 articles screened. The majority were male (n = 4/6) and three were <15 years of age. Fever (n = 6/6), leukocytosis (n = 5/6), and abdominal pain or distention (n = 4/6) were the most common signs and symptoms. Initial diagnoses included other bacterial infections, appendicitis, or acute abdomen. Four patients received at least one antimicrobial effective against Yersinia pestis; however, some experienced delayed treatment due to late diagnosis of plague. Occult buboes were discovered in retroperitoneal (n = 2), inguinal/femoral (n = 2), mesenteric (n = 2), axillary (n = 1), and mediastinal (n = 1) regions. Four of the six patients died. Conclusions: Patients with occult buboes experienced delays in the diagnosis of plague and a high fatality rate. Clinicians in plague-endemic areas should consider the presence of occult buboes among patients with compatible symptoms and exposure history.

Entre la voluntad de Allah y las balas de los jnun la epidemia de peste de 1799 y 1800 en Marruecos / Between the will of Allah and the bullets of the jnun the plague epidemic of 1799 and 1800 in Morocco

La peste que golpeó Marruecos en 1799 y 1800 fue una epidemia sin precedentes. En este artículo, examino algunas observaciones hechas sobre la peste por el agente comercial británico James Grey Jackson, en particular sus ideas sobre las comprensiones islámicas locales de la agencia de los jnūn y de Dios (Allāh) en la aparición de esta enfermedad (AU)

Similitudes y diferencias entre el Diario del año de la peste y la enfermedad por COVID-19 / Similarities and differences between a Journal of the plague year and COVID-19

La literatura sobre enfermedad –particularmente, sobre epidemias- cuenta con numerosos recursos a la hora de permitirnos profundizar en el conocimiento de la noxa desde un punto de vista no sólo nosológico, sino también sociológico. El presente trabajo analiza éstos y otros aspectos relevantes que se pueden extraer de la lectura de «El Diario del año de la peste», en contraposición a la situación derivada de la pandemia por el Sars-Cov-2. Se han encontrado similitudes significativas entre ambos procesos, sobre todo en lo relativo a las medidas públicas adoptadas y la respuesta social, así como diferencias sustanciales que pueden tener su base en el desarrollo científico-tecnológico que ha culminado en la obtención de las vacunas frente a la Covid 19 en un tiempo récord. Si bien cada epidemia es única, su estudio comparado puede aportar una visión global que sirva de aprendizaje y guía para afrontar posibles crisis sanitarias futuras. (AU)

Literature about disease –particularly about epidemics- involves numerous resources that allow us to deepen our knowledge of the noxa not only from a nosological point of view, but also from a sociological one. This paper analyzes these and other relevant aspects that can be extracted from the reading of "A Journal of the Plague Year", as opposed to the situation derived from the Sars-Cov-2 pandemic. Significant similarities have been found between both processes, especially regarding to the public measures adopted and the social response, as well as substantial differences that may be based on the scientific-technological development that has culminated in obtaining vaccines against Covid 19 in the shortest time. Although each epidemic is unique, its comparative study can provide us with a global vision that coud helps us learn and guide us when facing possible future health crises. (AU)

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.

Host traits, identity, and ecological conditions predict consistent flea abundance and prevalence on free-living California ground squirrels.

Understanding why some individuals are more prone to carry parasites and spread diseases than others is a key question in biology. Although epidemiologists and disease ecologists increasingly recognize that individuals of the same species can vary tremendously in their relative contributions to the emergence of diseases, very few empirical studies systematically assess consistent individual differences in parasite loads within populations over time. Two species of fleas (Oropsylla montana and Hoplopsyllus anomalous) and their hosts, California ground squirrels (Otospermophilus beecheyi), form a major complex for amplifying epizootic plague in the western United States. Understanding its biology is primarily of major ecological importance and is also relevant to public health. Here, we capitalize on a long-term data set to explain flea incidence on California ground squirrels at Briones Regional Park in Contra Costa County, USA. In a 7 year study, we detected 42,358 fleas from 2,759 live trapping events involving 803 unique squirrels from two free-living populations that differed in the amount of human disturbance in those areas. In general, fleas were most abundant and prevalent on adult males, on heavy squirrels, and at the pristine site, but flea distributions varied among years, with seasonal conditions (e.g., temperature, rainfall, humidity), temporally within summers, and between flea species. Although on-host abundances of the two flea species were positively correlated, each flea species occupied a distinctive ecological niche. The common flea (O. montana) occurred primarily on adults in cool, moist conditions in early summer whereas the rare flea (H. anomalous) was mainly on juveniles in hot, dry conditions in late summer. Beyond this, we uncovered significantly repeatable and persistent effects of host individual identity on flea loads, finding consistent individual differences among hosts in all parasite measures. Taken together, we reveal multiple determinants of parasites on free-living mammals, including the underappreciated potential for host heterogeneity - within populations - to structure the emergence of zoonotic diseases such as bubonic plague.

Peptidoglycan-Free Bacterial Ghosts Confer Enhanced Protection against Yersinia pestis Infection.

To develop a modern plague vaccine, we used hypo-endotoxic Yersinia pestis bacterial ghosts (BGs) with combinations of genes encoding the bacteriophage ɸX174 lysis-mediating protein E and/or holin-endolysin systems from λ or L-413C phages. Expression of the protein E gene resulted in the BGs that retained the shape of the original bacterium. Co-expression of this gene with genes coding for holin-endolysin system of the phage L-413C caused formation of structures resembling collapsed sacs. Such structures, which have lost their rigidity, were also formed as a result of the expression of only the L-413C holin-endolysin genes. A similar holin-endolysin system from phage λ containing mutated holin gene S and intact genes R-Rz coding for the endolysins caused generation of mixtures of BGs that had (i) practically preserved and (ii) completely lost their original rigidity. The addition of protein E to the work of this system shifted the equilibrium in the mixture towards the collapsed sacs. The collapse of the structure of BGs can be explained by endolysis of peptidoglycan sacculi. Immunizations of laboratory animals with the variants of BGs followed by infection with a wild-type Y. pestis strain showed that bacterial envelopes protected only cavies. BGs with maximally hydrolyzed peptidoglycan had a greater protectivity compared to BGs with a preserved peptidoglycan skeleton.

History of the Plague: An Ancient Pandemic for the Age of COVID-19.

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.

Bartolomé Coronel: Rescate del olvido con la memoria - Uno de los primeros médicos de niños de la Medicina Paraguaya / Bartolomé Coronel: Rescue from oblivion with memory - One of the first children's doctors of Paraguayan Medicine

La sistematización de una historia de vida requiere una rigurosa selección de la información proveniente de diversas fuentes. Este breve estudio cualitativo utiliza el método biográfico y su objetivo es describir la figura de Bartolomé Coronel, considerado uno de los primeros médicos de niños y su aporte a la sociedad asuncena de principios del siglo XX, fallecido en plena pandemia de la peste Bubónica, en 1911. Se toman diversas fuentes desde la semblanza realizada por la insigne educadora Celsa Speratti de Garcete, cartas familiares, datos de su biografía aportados por un familiar cercano, discursos alusivos al sujeto de estudio y otros textos que permiten elaborar una mirada colectiva hacia el mismo. En conclusión, el contexto actual de Covid19 y el de la peste Bubónica presenta el mismo riesgo y escasas medidas de bioseguridad a pesar del avance de la ciencia y la medicina en nuestros días. La figura del Dr. Bartolomé Coronel presenta una riqueza de matices y merece ser rescatado con la memoria del olvido.

Life story systematization requires a rigorous selection of information from various sources. This brief qualitative study uses the biographical method and its objective is to describe the figure of Bartolomé Coronel. Considered one of the first children doctors and his contribution to Asuncion society at the beginning of the 20th century, who died in the Bubonic plague pandemic, in 1911. Various sources are taken: from the profile made by the distinguished educator Celsa Speratti de Garcete, family letters, details of her biography provided by a familiar, speeches allusive to the subject of study and other texts that allow a collective view of him. In conclusion, the current context of Covid19 and the Bubonic plague in the past present the same risk and scarce biosecurity measures taked despite the advancement of science and medicine in our days. The figure of Dr. Bartolomé Coronel presents a wealth of nuances and deserves to be rescued with the memory of oblivion.

An open-label, randomized, non-inferiority trial of the efficacy and safety of ciprofloxacin versus streptomycin + ciprofloxacin in the treatment of bubonic plague (IMASOY): study protocol for a randomized control trial.

BACKGROUND: Bubonic plague is the primary manifestation of infection with Yersinia pestis, accounting for 90% of all plague cases and with 75% of global cases reported in Madagascar. All drugs in use for treating plague are registered based on experimental data and anecdotal evidence, and no regimen currently recommended is supported by a randomized clinical trial. The IMASOY trial intends to fill this knowledge gap by comparing two 10-day regimens included in the national guidelines in Madagascar. The primary objective of the trial is to test the hypothesis that ciprofloxacin monotherapy is non-inferior to streptomycin followed by ciprofloxacin for the treatment of bubonic plague, thus avoiding the need for injectable, potentially toxic, aminoglycosides. METHODS: A two-arm parallel-group randomized control trial will be conducted across peripheral health centres in Madagascar in five districts. Males and non-pregnant females of all ages with suspected bubonic or pneumonic plague will be recruited over the course of three plague 'seasons'. The primary endpoint of the trial is to assess the proportion of patients with bubonic plague who have a therapeutic response to treatment (defined as alive, resolution of fever, 25% reduction in the size of measurable buboes, has not received an alternative treatment and no clinical decision to continue antibiotics) as assessed on day 11. DISCUSSION: If successful, the trial has the potential to inform the standard of care guidelines not just in Madagascar but in other countries afflicted by plague. The trial is currently ongoing and expected to complete recruitment in 2022. TRIAL REGISTRATION: ClinicalTrials.gov NCT04110340 . Registered on 1 October 2019.

Treatment of Human Plague: A Systematic Review of Published Aggregate Data on Antimicrobial Efficacy, 1939-2019.

BACKGROUND: Plague, caused by the bacterium Yersinia pestis, has killed millions in historic pandemics and continues to cause sporadic outbreaks. Numerous antimicrobials are considered effective for treating plague; however, well-defined information on the relative efficacy of various treatments is lacking. We conducted a systematic review of published data on antimicrobial treatment of plague reported in aggregate. METHODS: We searched databases including Embase, Medline, CINAHL, Cochrane Library, and others for publications with terms related to plague and antimicrobials. Articles were included if they contained 1) a group of patients treated for plague, with outcomes reported by antimicrobial regimen, and 2) laboratory evidence of Y. pestis infection or an epidemiologic link to patients with laboratory evidence of Y. pestis. Case fatality rate by antimicrobial regimen was calculated. RESULTS: In total, 5837 articles were identified; among these, 26 articles published between 1939 and 2008 met inclusion criteria. A total of 2631 cases of human plague reported within these articles were included. Among cases classified by primary clinical form of plague, 93.6% were bubonic, 5.9% pneumonic, and 0.5% septicemic with associated case fatalities of 14.2%, 31.1%, and 20.0%, respectively. Case fatality rate among patients who received monotherapy with tetracyclines, chloramphenicol, aminoglycosides, or sulfonamides was 1.3%, 1.4%, 7.5%, and 20.2%, respectively. Fluoroquinolones were only given as part of combination therapy. Penicillin was associated with a case fatality rate of 75%. CONCLUSIONS: Tetracyclines, chloramphenicol, and aminoglycosides were associated with the lowest case fatality rates of all antimicrobials used for treatment of plague. Additional research is needed to determine the efficacy of fluoroquinolones as monotherapy.

Subcutaneous vaccination with a live attenuated Yersinia pseudotuberculosis plague vaccine.

A single oral inoculation to mice of the live attenuated Yersinia pseudotuberculosis VTnF1 strain producing an F1 pseudocapsule protects against bubonic and pneumonic plague. However oral vaccination can fail in humans exposed to frequent intestinal infections. We evaluated in mice the efficacy of subcutaneous vaccine injection as an alternative way to induce protective immunity, while reducing the dose and avoiding strain release in nature. A single subcutaneous dose of up to 108 CFU induced dose-dependent antibody production. At the dose of 107 CFU, i.e. 10 times less than via the oral route, it caused a modest skin reaction and protected 100% against bubonic and 80% against pneumonic plague, caused by high doses of Yersinia pestis. Bacteria migrating to lymph nodes and spleen, but not feces, were rapidly eliminated. Thus, subcutaneous injection of VTnF1 would represent a good alternative when dissemination in nature and human intestinal responsiveness are limitations.

Principales pandemias en la historia de la humanidad / Major pandemics in the history of mankind

Introducción: Se describen las principales pandemias en la historia de la humanidad desde a.n.e. hasta la más reciente causada por el coronavirus SARS-CoV-2. Objetivo: Examinar las principales pandemias en la historia de la humanidad y su repercusión en la salud pública, ámbito social y perspectivas de la actual pandemia de la COVID-19 en el desarrollo de la sociedad. Métodos: Se revisaron las publicaciones sobre el tema en español e inglés en bases de datos de PubMed, Google Scholar, SciELO y Latindex desde el 2000 hasta al 25 de mayo 2020. Resultados: Se describen los aspectos más sobresalientes de las epidemias causadas por viruela, peste bubónica, cólera, VIH/sida. gripes y la actual producida por el coronavirus SARS-CoV-2, atendiendo a su aparición, duración en años, fallecidos, localización mundial, países más afectados e impacto en la sociedad y ámbito sanitario. Se exponen las perspectivas sociales determinadas por la pandemia de la COVID-19. Conclusiones: Se examinan los rasgos sobresalientes, en especial las pérdidas de vidas humanas en las principales pandemias que han azotado a la humanidad, desde a.n.e. hasta la más reciente causada por el coronavirus SARS-CoV-2. La sociedad en su momento actual se enfrenta a incertidumbres y retos sociales, económicos, culturales, éticos, sanitarios y existenciales, provenientes de las implicaciones que está teniendo la pandemia de la COVID-19, lo que determinará consecuencias para la salud y la vida humana. Esta pandemia es mucho más que una crisis sanitaria(AU)

Introduction: This work describes the major pandemics in the history of mankind from B.C. until the most recent caused by the coronavirus SARS-CoV-2. Objective: To examine the major pandemics in the history of mankind and their impact on public health, social scopes and prospects of the current pandemic of COVID-19 in the development of mankind. Methods: There were reviewed publications on the subject in Spanish and English in databases of PubMed, Google Scholar, SciELO and Latindex from 2000 to 25 May, 2020. Results: There is a description of the most important aspects of epidemics caused by smallpox, bubonic plague, cholera, HIV/AIDS, influenzas and the current one produced by the coronavirus SARS-CoV-2, on the basis of their onsets, duration in years, amount of deceased, world location, most affected countries and impact on society and the health field. The social perspectives determined by the pandemic of COVID-19 are presented. Conclusions: There was an study on the outstanding features, especially the loss of human lives in the major pandemics that have plagued mankind, from B.C. until the most recent caused by the coronavirus SARS-CoV-2. The global society at present time is facing uncertainties and challenges of social, economic, cultural, ethical, health and existential kind coming from the implications caused by the COVID-19 pandemic, which will determine consequences for human health and life. This pandemic is much more than a health crisis(AU)

Peste septicémica rápidamente fatal secundaria a peste bubónica primaria inicialmente no diagnosticada: reporte de caso / Rapidly fatal septicemic plague secondary to undiagnosed primary bubonic plague: case report

RESUMEN La peste es una enfermedad reemergente causada por Yersinia pestis. Los humanos generalmente adquieren la enfermedad por picaduras de pulgas. La peste es una enfermedad sistémica fulminante, siendo la peste neumónica la forma más letal. El diagnóstico tardío es una de las principales causas de mortalidad y diseminación de la enfermedad, dado que limita la efectividad de las medidas de control. Presentamos el caso de un varón de 42 años, que previamente había viajado a una zona endémica de peste, y luego presentó hiperpirexia, hipotensión, y adenopatía inguinal inflamatoria. A pesar del cuadro clínico muy característico, nadie (antes del ingreso a nuestro hospital) sospechó peste. Se inició una combinación antibiótica efectiva y tratamiento intensivo recién al quinto día de enfermedad. El paciente evolucionó con shock séptico, falla respiratoria, y muerte. Se confirmó peste por reacción en cadena de polimerasa (PCR). Este caso enfatiza la importancia de tener un alto índice de sospecha para peste.

ABSTRACT Plague is a re-emerging disease caused by the bacteria Yersinia pestis. Humans usually get the disease through the bite of an infected flea. Plague is a fulminant systemic disease, with pneumonic plague being the most lethal form. Late diagnosis is one of the main causes of mortality and spread of the disease, as it limits the effectiveness of control measures. We present the case of a 42-year-old male, who had previously traveled to an endemic plague area and then presented hyperpyrexia, hypotension, and inflammatory inguinal adenopathy. Despite the very characteristic clinical picture, nobody (before admission to our hospital) suspected plague. An effective combination of antibiotics and intensive treatment was initiated only on the fifth day of illness. The patient went into septic shock, respiratory failure, and death. Plague was confirmed by polymerase chain reaction (PCR). This case emphasizes the importance of having a high suspicion rate for plague.

An Intradermal Model for Yersinia pestis Inoculation.

The dermis and the subcutaneous space vary in many fundamental characteristics, which include composition of lymphatic vessels, density of blood vasculature, and cells of the immune response. Traditional approaches employ the subcutaneous space as the preferred layer of the skin to inoculate Yersinia pestis for bubonic plague studies. Because fleas transmit Y. pestis in nature, and because these insects target the dermal layer of the skin, an intradermal model of infection is more biologically relevant than a subcutaneous model. Among many features, the use of an intradermal model results in robust and reproducible colonization of lymph nodes, blood, and deeper tissues. Remarkably, intradermal inoculation in the murine ear pinna also allows for the study of cutaneous infection without severely disrupting the architecture and physiology of the skin.

Drosophila as a Model for Understanding the Insect Host of Yersinia pestis.

With the limited availability of genomic sequence information and no established methods for genetic knockdowns or the creation of transgenic fleas and flea cell lines, we have adopted Drosophila melanogaster as a model for the study of the insect life cycle of Yersinia pestis. Infection of Drosophila larvae can be used to model early colonization of fleas, while the established embryonic cell lines can be used to model insect-pathogen interactions that underlie the unique capacity of Y. pestis to colonize the gut of its flea host. In this chapter, we present the methods we developed for infection of Drosophila in vivo and in vitro.

Contagious Horror: Infectious Themes in Fiction and Film.

Infectious diseases have been a preeminent part of literature since the earliest human writings. In particular, they have contributed greatly to the genre of horror-written or visual art intended to startle or scare. Horror fiction has emphasized infectious themes from the earliest Babylonian and Hebrew texts. In medieval times, stories of vampires and werewolves often had a contagious component, and pivotal works of Victorian horror centered around fear of infection and contamination. As film became prominent in the 20th Century, a strong emphasis on themes of plague and apocalypse developed. An analysis of the use of infection in horror fiction and film shows that it often represents a metaphor for societal concerns, and it is extremely useful in framing challenging issues for a wide audience.