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.

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High-Throughput Identification of New Protective Antigens from a Yersinia pestis Live Vaccine by Enzyme-Linked Immunospot Assay

Infection and Immunity ◽

10.1128/iai.00242-09 ◽

2009 ◽

Vol 77 (10) ◽

pp. 4356-4361 ◽

Cited By ~ 22

Author(s):

Bei Li ◽

Lei Zhou ◽

JingYu Guo ◽

Xiaoyi Wang ◽

Bin Ni ◽

...

Keyword(s):

T Cell ◽

Yersinia Pestis ◽

Cellular Immunity ◽

Vaccine Development ◽

Lethal Dose ◽

Live Vaccine ◽

Intracellular Bacteria ◽

Partial Protection ◽

Cell Responses ◽

Protective Antigens

ABSTRACT Yersinia pestis, the plague pathogen, is a facultative intracellular bacterium. Cellular immunity plays important roles in defense against infections. The identification of T-cell targets is critical for the development of effective vaccines against intracellular bacteria; however, the function of cellular immunity in protection from plague was not clearly understood. In this study, 261 genes from Y. pestis were selected on the basis of bioinformatics analysis and previous research results for expression in Escherichia coli BL21(DE3). After purification, 101 proteins were qualified for examination of their abilities to induce the production of gamma interferon in mice immunized with live vaccine EV76 by enzyme-linked immunospot assay. Thirty-four proteins were found to stimulate strong T-cell responses. The protective efficiencies for 24 of them were preliminarily evaluated using a mouse plague model. In addition to LcrV, nine proteins (YPO0606, YPO1914, YPO0612, YPO3119, YPO3047, YPO1377, YPCD1.05c, YPO0420, and YPO3720) may provide partial protection against challenge with a low dose (20 times the 50% lethal dose [20× LD50]) of Y. pestis, but only YPO0606 could partially protect mice from infection with Y. pestis at a higher challenge dosage (200× LD50). These proteins would be the potential components for Y. pestis vaccine development.

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Aggravation of Human Diseases and Climate Change Nexus

International Journal of Environmental Research and Public Health ◽

10.3390/ijerph16152799 ◽

2019 ◽

Vol 16 (15) ◽

pp. 2799 ◽

Cited By ~ 7

Author(s):

Mohd Danish Khan ◽

Hong Ha Thi Vu ◽

Quang Tuan Lai ◽

Ji Whan Ahn

Keyword(s):

Climate Change ◽

Infectious Diseases ◽

Strong Relationship ◽

Epidemiological Data ◽

Extreme Weather ◽

Control Measures ◽

Extreme Weather Events ◽

Human Beings ◽

Impact Of Climate Change ◽

The Impact

For decades, researchers have debated whether climate change has an adverse impact on diseases, especially infectious diseases. They have identified a strong relationship between climate variables and vector’s growth, mortality rate, reproduction, and spatiotemporal distribution. Epidemiological data further indicates the emergence and re-emergence of infectious diseases post every single extreme weather event. Based on studies conducted mostly between 1990-2018, three aspects that resemble the impact of climate change impact on diseases are: (a) emergence and re-emergence of vector-borne diseases, (b) impact of extreme weather events, and (c) social upliftment with education and adaptation. This review mainly examines and discusses the impact of climate change based on scientific evidences in published literature. Humans are highly vulnerable to diseases and other post-catastrophic effects of extreme events, as evidenced in literature. It is high time that human beings understand the adverse impacts of climate change and take proper and sustainable control measures. There is also the important requirement for allocation of effective technologies, maintenance of healthy lifestyles, and public education.

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Induction of Protective Antiplague Immune Responses by Self-Adjuvanting Bionanoparticles Derived from Engineered Yersinia pestis

Infection and Immunity ◽

10.1128/iai.00081-20 ◽

2020 ◽

Vol 88 (5) ◽

Cited By ~ 2

Author(s):

Xiuran Wang ◽

Amit K. Singh ◽

Xiangmin Zhang ◽

Wei Sun

Keyword(s):

Immune Responses ◽

Yersinia Pestis ◽

Rational Design ◽

Lipid A ◽

Vaccine Development ◽

Lethal Dose ◽

Outer Membrane Vesicles ◽

Vector System ◽

Content Type ◽

Monophosphoryl Lipid A

ABSTRACT A Yersinia pestis mutant synthesizing an adjuvant form of lipid A (monophosphoryl lipid A, MPLA) displayed increased biogenesis of bacterial outer membrane vesicles (OMVs). To enhance the immunogenicity of the OMVs, we constructed an Asd-based balanced-lethal host-vector system that oversynthesized the LcrV antigen of Y. pestis, raised the amounts of LcrV enclosed in OMVs by the type II secretion system, and eliminated harmful factors like plasminogen activator (Pla) and murine toxin from the OMVs. Vaccination with OMVs containing MPLA and increased amounts of LcrV with diminished toxicity afforded complete protection in mice against subcutaneous challenge with 8 × 105 CFU (80,000 50% lethal dose [LD50]) and intranasal challenge with 5 × 103 CFU (50 LD50) of virulent Y. pestis. This protection was significantly superior to that resulting from vaccination with LcrV/alhydrogel or rF1-V/alhydrogel. At week 4 postimmunization, the OMV-immunized mice showed more robust titers of antibodies against LcrV, Y. pestis whole-cell lysate (YPL), and F1 antigen and more balanced IgG1:IgG2a/IgG2b-derived Th1 and Th2 responses than LcrV-immunized mice. Moreover, potent adaptive and innate immune responses were stimulated in the OMV-immunized mice. Our findings demonstrate that self-adjuvanting Y. pestis OMVs provide a novel plague vaccine candidate and that the rational design of OMVs could serve as a robust approach for vaccine development.

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Early-Phase Transmission of Yersinia pestis by Unblocked Xenopsylla cheopis (Siphonaptera: Pulicidae) Is as Efficient as Transmission by Blocked Fleas

Journal of Medical Entomology ◽

10.1603/0022-2585(2007)44[678:etoypb]2.0.co;2 ◽

2007 ◽

Vol 44 (4) ◽

pp. 678-682 ◽

Cited By ~ 21

Author(s):

Rebecca J. Eisen ◽

Aryn P. Wilder ◽

Scott W. Bearden ◽

John A. Montenieri ◽

Kenneth L. Gage

Keyword(s):

Yersinia Pestis ◽

Early Phase ◽

Xenopsylla Cheopis ◽

Phase Transmission

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Serpulina pilosicoli, waterbirds and water: potential sources of infection for humans and other animals

Epidemiology and Infection ◽

10.1017/s0950268898008863 ◽

1998 ◽

Vol 121 (1) ◽

pp. 219-225 ◽

Cited By ~ 56

Author(s):

S. L. OXBERRY ◽

D. J. TROTT ◽

D. J. HAMPSON

Keyword(s):

Water Potential ◽

Lake Water ◽

Tap Water ◽

Abdominal Discomfort ◽

Enzyme Electrophoresis ◽

Human Beings ◽

Healthy Human ◽

Multilocus Enzyme Electrophoresis ◽

Potential Sources ◽

Sources Of Infection

Serpulina pilosicoli was isolated from 8 of 43 (19%) faecal specimens obtained from feral waterbirds sampled around a small lake at Perth Zoological Gardens, Western Australia, and from 3 of 7 (43%) samples of the lake water. The organism was only isolated from 1 of 204 (0·5%) samples from captive birds and animals in the zoological collection. Multilocus enzyme electrophoresis analysis of the isolates showed that they were genetically diverse, and none had identical electrophoretic profiles as those previously obtained from human beings, dogs, pigs and other avian species. To determine the survival time of S. pilosicoli in water, cells of strain 1648 were seeded into lake and tap water, and incubated at 4, 25 and 37°C. The organism could be recultured from lake water for up to 66 days at 4°C, and for 4 days at 25°C. A healthy human volunteer who drank water seeded with S. pilosicoli strain Wes B became colonized, and developed abdominal discomfort and headaches. Contamination of water by faeces may represent a source of S. pilosicoli infection for both humans and animals.

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Early-phase Transmission of Yersinia pestis by Cat Fleas (Ctenocephalides felis) and Their Potential Role as Vectors in a Plague-endemic Region of Uganda

American Journal of Tropical Medicine and Hygiene ◽

10.4269/ajtmh.2008.78.949 ◽

2008 ◽

Vol 78 (6) ◽

pp. 949-956 ◽

Cited By ~ 64

Author(s):

Rebecca J. Eisen ◽

Sara M. Vetter ◽

Kenneth L. Gage ◽

Jeff N. Borchert ◽

Russell E. Enscore ◽

...

Keyword(s):

Yersinia Pestis ◽

Early Phase ◽

Potential Role ◽

Ctenocephalides Felis ◽

Endemic Region ◽

Cat Fleas ◽

Phase Transmission

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The Cyclic AMP Receptor Protein, CRP, Is Required for Both Virulence and Expression of the Minimal CRP Regulon in Yersinia pestis Biovar microtus

Infection and Immunity ◽

10.1128/iai.00370-08 ◽

2008 ◽

Vol 76 (11) ◽

pp. 5028-5037 ◽

Cited By ~ 60

Author(s):

Lingjun Zhan ◽

Yanping Han ◽

Lei Yang ◽

Jing Geng ◽

Yingli Li ◽

...

Keyword(s):

Cyclic Amp ◽

Yersinia Pestis ◽

Core Promoter ◽

Lethal Dose ◽

Receptor Protein ◽

Cyclic Amp Receptor Protein ◽

Subcutaneous Infection ◽

Growth Phenotype ◽

In Vivo Growth

ABSTRACT The cyclic AMP receptor protein (CRP) is a bacterial regulator that controls more than 100 promoters, including those involved in catabolite repression. In the present study, a null deletion of the crp gene was constructed for Yersinia pestis bv. microtus strain 201. Microarray expression analysis disclosed that at least 6% of Y. pestis genes were affected by this mutation. Further reverse transcription-PCR and electrophoretic mobility shift assay analyses disclosed a set of 37 genes or putative operons to be the direct targets of CRP, and thus they constitute the minimal CRP regulon in Y. pestis. Subsequent primer extension and DNase I footprinting assays mapped transcriptional start sites, core promoter elements, and CRP binding sites within the DNA regions upstream of pla and pst, revealing positive and direct control of these two laterally acquired plasmid genes by CRP. The crp disruption affected both in vitro and in vivo growth of the mutant and led to a >15,000-fold loss of virulence after subcutaneous infection but a <40-fold increase in the 50% lethal dose by intravenous inoculation. Therefore, CRP is required for the virulence of Y. pestis and, particularly, is more important for infection by subcutaneous inoculation. It can further be concluded that the reduced in vivo growth phenotype of the crp mutant should contribute, at least partially, to its attenuation of virulence by both routes of infection. Consistent with a previous study of Y. pestis bv. medievalis, lacZ reporter fusion analysis indicated that the crp deletion resulted in the almost absolute loss of pla promoter activity. The plasminogen activator encoded by pla was previously shown to specifically promote Y. pestis dissemination from peripheral infection routes (subcutaneous infection [flea bite] or inhalation). The above evidence supports the notion that in addition to the reduced in vivo growth phenotype, the defect of pla expression in the crp mutant will greatly contribute to the huge loss of virulence of this mutant strain in subcutaneous infection.

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Gr1+ Cells Control Growth of YopM-Negative Yersinia pestis during Systemic Plague

Infection and Immunity ◽

10.1128/iai.00284-09 ◽

2009 ◽

Vol 77 (9) ◽

pp. 3791-3806 ◽

Cited By ~ 42

Author(s):

Zhan Ye ◽

Edward J. Kerschen ◽

Donald A. Cohen ◽

Alan M. Kaplan ◽

Nico van Rooijen ◽

...

Keyword(s):

Nk Cells ◽

Yersinia Pestis ◽

Nk Cell ◽

Early Stage ◽

Lethal Dose ◽

Cell Types ◽

Growth Defect ◽

Protein Toxin ◽

Inflammatory Monocytes ◽

Control Growth

ABSTRACT YopM, a protein toxin of Yersinia pestis, is necessary for virulence in a mouse model of systemic plague. We previously reported YopM-dependent natural killer (NK) cell depletion from blood and spleen samples of infected mice. However, in this study we found that infection with Y. pestis KIM5 (YopM+) caused depletion of NK cells in the spleen, but not in the liver, and antibody-mediated ablation of NK cells had no effect on bacterial growth. There was no YopM-associated effect on the percentage of dendritic cells (DCs) or polymorphonuclear leukocytes (PMNs) in the early stage of infection; however, there was a YopM-associated effect on PMN integrity and on the influx of monocytes into the spleen. Ablation of Gr1+ cells caused loss of the growth defect of YopM− Y. pestis in both the liver and spleen. In contrast, ablation of macrophages/DCs inhibited growth of both parent and mutant bacteria, accompanied by significantly fewer lesion sites in the liver. These results point toward PMNs and inflammatory monocytes as major cell types that control growth of YopM− Y. pestis. Infection with fully virulent Y. pestis CO92 and a YopM− derivative by intradermal and intranasal routes showed that the absence of YopM significantly increased the 50% lethal dose only in the intradermal model, suggesting a role for YopM in bubonic plague, in which acute inflammation occurs soon after infection.

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