Plague Bacterium Research Articles

Oral Sylvatic Plague Vaccine Does Not Adequately Protect Prairie Dogs (Cynomys spp.) for Endangered Black-Footed Ferret (Mustela nigripes) Conservation.

The plague bacterium Yersinia pestis is lethal to endangered black-footed ferrets (Mustela nigripes, BFF) and the prairie dogs (Cynomys spp., PD) on which they depend for habitat and prey. We assessed the effectiveness of an oral sylvatic plague vaccine delivered in baits to black-tailed PD (Cynomys ludovicianus, BTPD) from 2013 to 2017 on the Charles M. Russell National Wildlife Refuge (CMR) in northcentral Montana. We permanently marked BTPD on four paired vaccine (N = 1,349 individuals) and placebo plots (N = 926; 7,027 total captures). We analyzed capture–recapture data under a Cormack–Jolly–Seber model to estimate annual apparent survival. Overall, survival averaged 0.05 lower on vaccine plots than on paired placebo plots. Immediately before noticeable die-offs and detecting plague on pairs CMR1 and CMR2, 89% of BTPD sampled on vaccine plots had consumed at least one bait and the immune systems of 40% were likely boosted by consuming baits over multiple years. Survival to the following year was 0.16 and 0.05 on the vaccine plots and 0.19 and 0.06 on the placebo plots for pairs CMR1 and CMR2, respectively. These rates were markedly lower than 0.63, the overall average estimate on those same plots during the previous 3 years. PD populations subjected to such large die-offs would not be expected to sustain a BFF population. An overriding limitation to achieving sufficient protection rests with vaccine delivery constraints. Late summer/fall bait distribution results in the highest bait uptake rates. However, the PD birth pulse each spring can double the size of populations in most years, greatly reducing the proportion of vaccinates in populations and diminishing potential herd immunity benefits. In addition to nonvaccinated juveniles and PD that do not consume bait, incomplete vaccine protection and time required for immunity to develop leaves a large majority of PD populations vulnerable to plague for 6–7 months or more each year.

Identification of a substrate-like cleavage-resistant thrombin inhibitor from the saliva of the flea Xenopsylla cheopis

The salivary glands of the flea Xenopsylla cheopis, a vector of the plague bacterium, Yersinia pestis, express proteins and peptides thought to target the hemostatic and inflammatory systems of its mammalian hosts. Past transcriptomic analyses of salivary gland tissue revealed the presence of two similar peptides (XC-42 and XC-43) having no extensive similarities to any other deposited sequences. Here we show that these peptides specifically inhibit coagulation of plasma and the amidolytic activity of α-thrombin. XC-43, the smaller of the two peptides, is a fast, tight-binding inhibitor of thrombin with a dissociation constant of less than 10 pM. XC-42 exhibits similar selectivity as well as kinetic and binding properties. The crystal structure of XC-43 in complex with thrombin shows that despite its substrate-like binding mode, XC-43 is not detectably cleaved by thrombin and that it interacts with the thrombin surface from the enzyme catalytic site through the fibrinogen-binding exosite I. The low rate of hydrolysis was verified in solution experiments with XC-43, which show the substrate to be largely intact after 2 h of incubation with thrombin at 37 °C. The low rate of XC-43 cleavage by thrombin may be attributable to specific changes in the catalytic triad observable in the crystal structure of the complex or to extensive interactions in the prime sites that may stabilize the binding of cleavage products. Based on the increased arterial occlusion time, tail bleeding time, and blood coagulation parameters in rat models of thrombosis XC-43 could be valuable as an anticoagulant.

(IN1330) common name: oriental rat flea; scientific name: Xenopsylla cheopis (Rothschild, 1903) (Insecta: Siphonaptera: Pulicidae)

This is an FC submission; below I have pasted the Introduction.
 The oriental rat flea, Xenopsylla cheopis (Rothschild, 1903), is a member of the family Pulicidae in the order Siphonaptera. Fleas are highly specialized insects that are demonstrably successful as ectoparasites of birds and mammals (Marquardt, et al. 2000). Of the nearly 2,500 species of fleas known from around the world (Triplehorn & Johnson 2005), few are as infamous as the oriental rat flea. This species is best known as the carrier of the plague bacterium (Yersinia pestis) that was responsible for decimating large populations of people, including nearly a third of the human population of Europe, and influenced the trajectory of human history (Fasulo 2004). In addition to its role as a vector of the plague bacterium, this species can vector other pathogens and at least two tapeworm parasites of humans (Marquardt, et al. 2000; Gage 2005).

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.

Plague vaccines: new developments in an ongoing search.

As the reality of pandemic threats challenges humanity, exemplified during the ongoing SARS-CoV-2 infections, the development of vaccines targeting these etiological agents of disease has become increasingly critical. Of paramount concern are novel and reemerging pathogens that could trigger such events, including the plague bacterium Yersinia pestis. Y. pestis is responsible for more human deaths than any other known pathogen and exists globally in endemic regions of the world, including the four corners region and Northern California in the USA. Recent cases have been scattered throughout the world, including China and the USA, with serious outbreaks in Madagascar during 2008, 2013–2014, and, most recently, 2017–2018. This review will focus on recent advances in plague vaccine development, a seemingly necessary endeavor, as there is no Food and Drug Administration–licensed vaccine available for human distribution in western nations, and that antibiotic-resistant strains are recovered clinically or intentionally developed. Progress and recent development involving subunit, live-attenuated, and nucleic acid–based plague vaccine candidates will be discussed in this review.Key points• Plague vaccine development remains elusive yet critical.• DNA, animal, and live-attenuated vaccine candidates gain traction.

Genomogenesis of the Plague Bacteria Yersinia pestis as a Process of Mosaic Evolution

The guiding methodological principle of the modern molecular genetic (MG) approach to the problem of speciation of the plague bacteria Yersinia pestis is the saltationist paradigm of horizontal gene transfer. The main speciation events include the insertion of two virulence plasmids specific to Y. pestis, pFra and pPst, into the genome of ancestral psychrophilic saprozoonotic pseudotuberculosis bacteria Y. pseudotuberculosis O:1b, as well as inactivation/deletion of genes that have lost their functions. An alternative ecological approach suggests the “Darwinian” mechanism of the plague bacterium genome formation in the temperature-continuous (5–37°C) environment, i.e., the Tarbagan marmot–marmot flea (Marmota sibirica–Oropsylla silantiewi) parasitic system, which demonstrates intermediate properties between the habitats of progenitor and derivative species. In accordance with the ecological scenario of the plague origin, the evolutionary fate of 18 well-studied plague bacterium genes and gene structures was interpreted. It was demonstrated that gradual transformation of the genome of the pseudotuberculosis bacterium into the genome of plague causative agent proceeded according to the principle of mosaic evolution and corresponded to three types of adaptation, i.e., inadaptation, pre-adaptation and neo-adaptation. The prospects for further development of the theory of plague origin are thought to be in the synthesis of MG and ecological approaches.

Epizootic Plague in Prairie Dogs: Correlates and Control with Deltamethrin.

The plague bacterium, Yersinia pestis, is a generalist pathogen of flea (Siphonaptera) vectors and mammalian hosts. In colonies of prairie dogs (PDs, Cynomys spp.), Y. pestis causes occasional epizootics, killing ≥90% of PDs within weeks to several months. We evaluated the effectiveness of deltamethrin, a pyrethroid insecticide, as a tool for preventing plague epizootics among three PD species. Specifically, we studied PD population growth on paired plots treated with deltamethrin for flea control or left untreated as baselines. We also evaluated PD population growth relative to flea abundance and PD density. All epizootics occurred on nontreated plots. Epizootics occurred on plots with very low PD densities as well as high densities. Mean population change, assessed by comparing visual counts of PDs in years before and during epizootics, was +88% for treated plots and -97% for nontreated plots. For comparison, an experimental oral vaccine against plague had an average change in population index or estimate during epizootics of -69% on vaccine plots compared with -83% for associated nontreated (placebo) plots. In our study and on plots not treated with deltamethrin, PD population growth was negatively correlated with flea abundance in the year before the epizootic, lending support to the hypothesis that flea abundance plays a critical role in plague transmission under natural conditions. Generally speaking, deltamethrin is a highly effective tool for plague management on PD colonies. That said, continued study is needed to refine deltamethrin treatments and to develop a more integrated strategy for plague management.

АНТРОПОЛОГИЧЕСКИЙ ВЗГЛЯД НА ЭПИДЕМИИ ЧУМЫ В ИСТОРИЧЕСКОМ ПРОШЛОМ

At many times in their history, humans have faced major epidemics. The “Black Death”, which broke out in the middle of the 14th century, is believed to be the deadliest one. The total number of the deceased population and the scale in many ways had a dramatic impact on the course of subsequent historical events. Until recently, the myths dating back to the Middle Ages have prevailed in scientific circles. They have remained unrevised despite the latest achievements in the research on the plague bacterium Yersinia pestis, the history of climate and medicine, and the extensive published data, making it of an interest to both reconsider certain established dogmas and reconstruct the algorithm of the course of major plague epidemics from the historical past using the results of the available paleogenetic, epidemiological, and climatological studies. This triggered our discussion on the nonlinear nature of the course of plague pandemics. The analysis of the historical sources showed that the scale and speed of the spread of plague epidemics in new territories directly depended on the degree of inclusion of cities and regions of the Afro-Eurasian space in the economic system of the Great Silk Road, the proximity to various epidemic centers of plague. The decisive influence of the anthropogenic factor on the duration and main directions of the spread of plague epidemics was revealed. The multivariate onset and course of pandemic plague waves were recognized. Therefore, it is difficult to pinpoint the exact place where the spread of the plague epidemics ended or to identify their consequences.

Yersinia pestis escapes entrapment in thrombi by targeting platelet function

BackgroundPlatelets are classically recognized for their role in hemostasis and thrombosis. Recent work has demonstrated that platelets can also execute a variety of immune functions. The dual prothrombotic and immunological roles of platelets suggest that they may pose a barrier to the replication or dissemination of extracellular bacteria. However, some bloodborne pathogens, such as the plague bacterium Yersinia pestis, routinely achieve high vascular titers that are necessary for pathogen transmission. ObjectivesIt is not currently known how or if pathogens circumvent platelet barriers to bacterial dissemination and replication. We sought to determine whether extracellular bloodborne bacterial pathogens actively interfere with platelet function, using Y pestis as a model system. MethodsThe interactions and morphological changes of human platelets with various genetically modified Y pestis strains were examined using aggregation assays, immunofluorescence, and scanning electron microscopy. ResultsYersinia pestis directly destabilized platelet thrombi, preventing bacterial entrapment in fibrin/platelet clots. This activity was dependent on two well‐characterized bacterial virulence factors: the Y pestis plasminogen activator Pla, which stimulates host‐mediated fibrinolysis, and the bacterial type III secretion system (T3SS), which delivers bacterial proteins into the cytoplasm of targeted host cells to reduce or prevent effective immunological responses. Platelets intoxicated by the Y pestis T3SS were unable to respond to prothrombotic stimuli, and T3SS expression decreased the formation of neutrophil extracellular traps in platelet thrombi. ConclusionsThese findings are the first demonstration of a bacterial pathogen using its T3SS and an endogenous protease to manipulate platelet function and to escape entrapment in platelet thrombi.

Development of Immunodiagnostic Preparations for Detection of the Plague Pathogen (Capsular and Capsule-Free Forms)

Introduction: Plague is endemic in a number of states around the world. Despite all public health measures taken to eradicate plague, the disease persists and even reappears in some countries. Today, traditional serological methods searching for the capsular antigen of the plague microbe are widely used to monitor the presence of Y. pestis in the environment. Yet, for the causative agent of the plague, the possibility of eliminating plasmids and maintaining of the ability to cause an infectious process by atypical strains is not excluded, which reduces the diagnostic value of preparations based on the detection of species-specific antigens of the plague microbe. Our objective was to develop biotechnology for the production of immunodiagnostic drugs for detection of the plague bacteria (capsular and capsule-free forms). Materials and methods: When performing the work, 27 strains of microorganisms of pathogenicity groups I–IV of different genera and species were used. Results: The development of immunodiagnostic preparations for the detection of Y. pestis in environmental samples is described. The presented experimental preparations allow detection of typical and antigenically modified plague microbe strains with a positive and/or negative expression of fraction 1. To evaluate the effectiveness of the designed diagnosticums, both laboratory and field testing was performed demonstrating positive results in the study of both artificially and naturally contaminated samples. The possibility of using the plague immunomagnetic sorbent providing selective concentration of material with a low pathogen content and purification of samples from possible contamination with extraneous microflora during epizootological examination was also confirmed. Conclusions: We constructed promising diagnostic preparations that help identify Y. pestis strains in the studied objects regardless of the cultivation temperature and plasmid profile.

Presence of the Oriental Rat Flea (Siphonaptera: Pulicidae) Infesting an Endemic Mammal and Confirmed Plague Circulation in a Forest Area of Madagascar.

The Oriental rat flea, Xenopsylla cheopis (Rothschild 1903), is a cosmopolitan flea usually found infesting domestic rats. This flea is a well-known major human plague vector in Madagascar. As part of field sampling, fleas and small mammals were collected in the village of South Andranofeno and the natural reserve of Sohisika, two sites of the district of Ankazobe, located in the Central Highlands of Madagascar. Rats inside houses and forest small mammals were trapped using Besancon Technical Services and pitfall traps, respectively. Their fleas were collected and preserved for laboratory works. Collected fleas from the village and forest belonged to five species, which were X. cheopis, Synopsyllus fonquerniei (Wagner and Roubaud 1932) (Siphonaptera: Pulicidae), Echidnophaga gallinacea (Westwood 1875) (Siphonaptera: Pulicidae), Ctenocephalides felisstrongylus (Jordan 1925) (Siphonaptera: Pulicidae), Pulex irritans (Linnaeus 1758) (Siphonaptera: Pulicidae). After sampling in the forest zone, one specimen of X. cheopis was unexpectedly collected while infesting an endemic tenrec Setifer setosus (Schreber 1777) (Afrosoricida: Tenrecidae). Polymerase chain reaction (PCR) diagnosis on all collected fleas allowed detecting plague bacterium Yersinia pestis (Lehmann and Neumann 1896) (Enterobacterales: Yersiniaceae) on nine specimens of the endemic flea S. fonquerniei collected inside forest. The presence of the oriental rat flea in forest highlights the connection between human and wild environments due to animal movements and the fact that the rat flea can infest various hosts. As only one specimen of X. cheopis was collected on S. setosus, we hypothesize that flea was carried from the village to forest. Yersinia pestis infection of forest fleas outlines plague circulation in this sylvatic area.

The Genome of the Great Gerbil Reveals Species-Specific Duplication of an MHCII Gene.

The great gerbil (Rhombomys opimus) is a social rodent living in permanent, complex burrow systems distributed throughout Central Asia, where it serves as the main host of several important vector-borne infectious pathogens including the well-known plague bacterium (Yersinia pestis). Here, we present a continuous annotated genome assembly of the great gerbil, covering over 96% of the estimated 2.47-Gb genome. Taking advantage of the recent genome assemblies of the sand rat (Psammomys obesus) and the Mongolian gerbil (Meriones unguiculatus), comparative immunogenomic analyses reveal shared gene losses within TLR gene families (i.e., TLR8, TLR10, and the entire TLR11-subfamily) for Gerbillinae, accompanied with signs of diversifying selection of TLR7 and TLR9. Most notably, we find a great gerbil-specific duplication of the MHCII DRB locus. In silico analyses suggest that the duplicated gene provides high peptide binding affinity for Yersiniae epitopes as well as Leishmania and Leptospira epitopes, putatively leading to increased capability to withstand infections by these pathogens. Our study demonstrates the power of whole-genome sequencing combined with comparative genomic analyses to gain deeper insight into the immunogenomic landscape of the great gerbil and its close relatives.

Oh, what a tangled web we weave

Oh, what a tangled web we weave

FPR1 is the plague receptor on host immune cells.

The plague agent, Yersinia pestis, employs a type III secretion system (T3SS) to selectively destroy human immune cells, thereby enabling its replication in the bloodstream and transmission to new hosts via fleabite. The host factors responsible for the selective destruction of immune cells by plague bacteria were not known. Here we show that LcrV, the needle cap protein of the Y. pestis T3SS, binds N-formylpeptide receptor (FPR1) on human immune cells to promote the translocation of bacterial effectors. Plague infection in mice is characterized by high mortality, however N-formylpeptide receptor deficient animals exhibit increased survival and plague-protective antibody responses. We identified FPR1 p.R190W as a candidate human resistance allele that protects neutrophils from Y. pestis T3SS. These findings reveal the plague receptor on immune cells and show that FPR1 mutations provide for plague survival, which appears to have shaped human immune responses towards other infectious diseases and malignant neoplasms.

Epidemiology of Plague: Problems with the Use of Mathematical Epidemiological Models in Plague Research and the Question of Transmission by Human Fleas and Lice.

This article addresses the recent use of mathematical epidemiological SIR or SEIR models in plague research. This use of S(E)IR models is highly problematic, but the problems are not presented and considered. Serious problems show in that such models are used to “prove” that historical plague was a (1) Filoviridae disease and (2) a bacterial disease caused by Yersinia pestis which was transmitted by human fleas and lice. (3) They also support early-phase transmission (by fleas). They purportedly consistently disprove (4) the conventional view that plague is/was a rat-and-rat-flea-borne disease. For these reasons, the focus is on methodological problems and on empirical testing by modern medical, entomological, and historical epidemiological data. An important or predominant vectorial role in plague epidemics for human fleas and lice requires that several necessary conditions are satisfied, which are generally not considered by advocates of the human ectoparasite hypothesis of plague transmission: (1) the prevalence and levels of human plague bacteraemia (human plague cases as sources of infection of feeding human ectoparasites); (2) the general size of blood meals ingested by human fleas and lice; (3) the consequent number of ingested plague bacteria; (4) the lethal dose of bacteria for 50% of a normal sample of infected human beings, LD50; and (5) efficient mechanism of transmission by lice and by fleas. The factual answers to these crucial questions can be ascertained and shown to invalidate the human ectoparasite hypothesis. The view of the standard works on plague has been corroborated, that bubonic plague, historical and modern, is/was a rat-and-rat-flea-borne disease caused by Yersinia pestis. These conclusions are concordant with and corroborate recent studies which, by laboratory experiments, invalidated the early-transmission hypothesis as a mechanism of transmission of LDs to humans in plague epidemics and removed this solution to the problem of transmission by human fleas.

Field assessment of insecticide dusting and bait station treatment impact against rodent flea and house flea species in the Madagascar plague context.

Bubonic is the most prevalent plague form in Madagascar. Indoor ground application of insecticide dust is the conventional method used to control potentially infected rodent fleas that transmit the plague bacterium from rodents to humans. The use of bait stations is an alternative approach for vector control during plague epidemics, as well as a preventive control method during non-epidemic seasons. Bait stations have many advantages, principally by reducing the amount of insecticide used, lowering the cost of the treatment and minimizing insecticide exposure in the environment. A previous study reported promising results on controlling simultaneously the reservoir and vectors, when slow-acting rodenticide was incorporated in bait stations called “Boîtes de Kartman”. However, little evidence of an effective control of the fleas prior to the elimination of rodents was found. In this study, we evaluated bait stations containing insecticide powder and non-toxic attractive rodent bait for their potential to control rat fleas. Its efficacy was compared to the standard method. The impact of both methods on indoor and outdoor rodent fleas, as well as the human household flea Pulex irritans were analyzed at different time points after treatments. Bait stations did not cause any significant immediate or delayed reduction of rat fleas and increasing the number of operational bait stations per household did not significantly improve their efficacy. Insecticide ground dusting appeared to be the most efficient method to control indoor rat fleas. Both methods appeared to have little impact on the density of outdoor rat fleas and human fleas. These results demonstrate limited effectiveness for bait stations and encourage the maintenance of insecticide dusting as a first-line control strategy in case of epidemic emergence of plague, when immediate effect on rodent fleas is needed. Recommendations are given to improve the efficacy of the bait station method.

Marmots and Yersinia pestis Strains in Two Plague Endemic Areas of Tien Shan Mountains.

The main purpose of this study was to clarify the role of gray marmots (Marmota baibacina) in the long-term maintenance of highly virulent strains of Yersinia pestis in two plague endemic foci of the Tien Shan Mountains in Kyrgyzstan. We present data from regular observations of populations of M. baibacina and small rodents cohabiting with marmots in the mountainous grasslands of the Sari-Dzhas (east of Issyk-Kul Lake) and the Upper-Naryn (south of Issyk-Kul Lake) natural foci. During 2012–2017, an abundance of marmots and their ectoparasites (fleas and ticks) was significantly higher in Upper-Naryn comparing to Sari-Dzhas, although there were no differences in a number and diversity of small rodents cohabiting with marmots. The plague bacterium was detected either in marmots or in their ectoparasites collected during 4 of 6 years of observation in Sari-Dzhas and during 2 of 4 years of observation in Upper-Naryn. Plague was found in three sectors situated closely to each other in Sari-Dzhas and in 1 of 8 repeatedly surveyed sectors in Upper-Naryn. During 6 years, we isolated 9 strains of Y. pestis from marmots, two from their fleas Oropsylla silantiewi, one from an unidentified tick, and one from the gray hamster (Cricetulus migratorius). All plague strains isolated from the rodents and their ectoparasites in this study were similar to Antiqua biovar specific for marmots. The results indicate that plague can circulate continuously in the Tien Shan Mountains in populations of gray marmots and their ectoparasites with a facultative involvement of other rodent species after significant changes in rodent communities that happened in Kyrgyzstan during the previous two decades. The simultaneous field survey of two natural foci of plague, Sari-Dzhas, and Upper-Naryn, would be important for further analysis of circulation of Y. pestis strains belonging to Antiqua biovar in the Tien Shan Mountains.

Disruption of the NlpD lipoprotein of the plague pathogen Yersinia pestis affects iron acquisition and the activity of the twin-arginine translocation system.

We have previously shown that the cell morphogenesis NlpD lipoprotein is essential for virulence of the plague bacteria, Yersinia pestis. To elucidate the role of NlpD in Y. pestis pathogenicity, we conducted a whole-genome comparative transcriptome analysis of the wild-type Y. pestis strain and an nlpD mutant under conditions mimicking early stages of infection. The analysis suggested that NlpD is involved in three phenomena: (i) Envelope stability/integrity evidenced by compensatory up-regulation of the Cpx and Psp membrane stress-response systems in the mutant; (ii) iron acquisition, supported by modulation of iron metabolism genes and by limited growth in iron-deprived medium; (iii) activity of the twin-arginine (Tat) system, which translocates folded proteins across the cytoplasmic membrane. Virulence studies of Y. pestis strains mutated in individual Tat components clearly indicated that the Tat system is central in Y. pestis pathogenicity and substantiated the assumption that NlpD essentiality in iron utilization involves the activity of the Tat system. This study reveals a new role for NlpD in Tat system activity and iron assimilation suggesting a modality by which this lipoprotein is involved in Y. pestis pathogenesis.

Use of bioengineered human commensal gut bacteria-derived microvesicles for mucosal plague vaccine delivery and immunization.

SummaryPlague caused by the Gram‐negative bacterium, Yersinia pestis, is still endemic in parts of the world today. Protection against pneumonic plague is essential to prevent the development and spread of epidemics. Despite this, there are currently no licensed plague vaccines in the western world. Here we describe the means of delivering biologically active plague vaccine antigens directly to mucosal sites of plague infection using highly stable microvesicles (outer membrane vesicles; OMVs) that are naturally produced by the abundant and harmless human commensal gut bacterium Bacteroides thetaiotaomicron (Bt). Bt was engineered to express major plague protective antigens in its OMVs, specifically Fraction 1 (F1) in the outer membrane and LcrV (V antigen) in the lumen, for targeted delivery to the gastrointestinal (GI) and respiratory tracts in a non‐human primate (NHP) host. Our key findings were that Bt OMVs stably expresses F1 and V plague antigens, particularly the V antigen, in the correct, immunogenic form. When delivered intranasally V‐OMVs elicited substantive and specific immune and antibody responses, both in the serum [immunoglobulin (Ig)G] and in the upper and lower respiratory tract (IgA); this included the generation of serum antibodies able to kill plague bacteria. Our results also showed that Bt OMV‐based vaccines had many desirable characteristics, including: biosafety and an absence of any adverse effects, pathology or gross alteration of resident microbial communities (microbiotas); high stability and thermo‐tolerance; needle‐free delivery; intrinsic adjuvanticity; the ability to stimulate both humoral and cell‐mediated immune responses; and targeting of primary sites of plague infection.

Prairie Dogs, Persistent Plague, Flocking Fleas, and Pernicious Positive Feedback.

Plague (caused by the bacterium Yersinia pestis) is a deadly flea-borne disease that remains a threat to public health nearly worldwide and is particularly disruptive ecologically where it has been introduced. We review hypotheses regarding maintenance and transmission of Y. pestis, emphasizing recent data from North America supporting maintenance by persistent transmission that results in sustained non-epizootic (but variable) rates of mortality in hosts. This maintenance mechanism may facilitate periodic epizootic eruptions “in place” because the need for repeated reinvasion from disjunct sources is eliminated. Resulting explosive outbreaks that spread rapidly in time and space are likely enhanced by synergistic positive feedback (PFB) cycles involving flea vectors, hosts, and the plague bacterium itself. Although PFB has been implied in plague literature for at least 50 years, we propose this mechanism, particularly with regard to flea responses, as central to epizootic plague rather than a phenomenon worthy of just peripheral mention. We also present new data on increases in flea:host ratios resulting from recreational shooting and poisoning as possible triggers for the transition from enzootic maintenance to PFB cycles and epizootic explosions. Although plague outbreaks have received much historic attention, PFB cycles that result in decimation of host populations lead to speculation that epizootic eruptions might not be part of the adaptive evolutionary strategy of Y. pestis but might instead be a tolerated intermittent cost of its modus operandi. We also speculate that there may be mammal communities where epizootics, as we define them, are rare or absent. Absence of plague epizootics might translate into reduced public health risk but does not necessarily equate to inconsequential ecologic impact.