scholarly journals Protection Elicited by Attenuated Live Yersinia pestis Vaccine Strains against Lethal Infection with Virulent Y. pestis

Vaccines ◽  
2021 ◽  
Vol 9 (2) ◽  
pp. 161
Author(s):  
Christopher K. Cote ◽  
Sergei S. Biryukov ◽  
Christopher P. Klimko ◽  
Jennifer L. Shoe ◽  
Melissa Hunter ◽  
...  
Keyword(s):  
Yersinia Pestis ◽  
Etiologic Agent ◽  
Partial Protection ◽  
Pneumonic Plague ◽  
Virulent Strains ◽  
Lethal Infection ◽  
Outbred Mice ◽  
Antibody Levels ◽  
Globally Distributed ◽  
Selection Of

The etiologic agent of plague, Yersinia pestis, is a globally distributed pathogen which poses both a natural and adversarial threat. Due largely to the rapid course and high mortality of pneumonic plague, vaccines are greatly needed. Two-component protein vaccines have been unreliable and potentially vulnerable to vaccine resistance. We evaluated the safety and efficacy of eight live Y. pestis strains derived from virulent strains CO92 or KIM6+ and mutated in one or more virulence-associated gene(s) or cured of plasmid pPst. Stringent, single-dose vaccination allowed down-selection of the two safest and most protective vaccine candidates, CO92 mutants pgm- pPst- and ΔyscN. Both completely protected BALB/c mice against subcutaneous and aerosol challenge with Y. pestis. Strain CD-1 outbred mice were more resistant to bubonic (but not pneumonic) plague than BALB/c mice, but the vaccines elicited partial protection of CD-1 mice against aerosol challenge, while providing full protection against subcutaneous challenge. A ΔyscN mutant of the nonencapsulated C12 strain was expected to display antigens previously concealed by the capsule. C12 ΔyscN elicited negligible titers to F1 but comparable antibody levels to whole killed bacteria, as did CO92 ΔyscN. Although one dose of C12 ΔyscN was not protective, vaccination with two doses of either CO92 ΔyscN, or a combination of the ΔyscN mutants of C12 and CO92, protected optimally against lethal bubonic or pneumonic plague. Protection against encapsulated Y. pestis required inclusion of F1 in the vaccine and was associated with high anti-F1 titers.

scholarly journals Novel RNA Extraction Method for Dual RNA-seq Analysis of Pathogen and Host in the Early Stages of Yersinia pestis Pulmonary Infection

2021 ◽  
Vol 9 (10) ◽  
pp. 2166
Author(s):  
Ofir Israeli ◽  
Inbar Cohen-Gihon ◽  
Moshe Aftalion ◽  
David Gur ◽  
Yaron Vagima ◽  
...  
Keyword(s):  
Yersinia Pestis ◽  
Post Infection ◽  
Rna Extraction ◽  
Early Time ◽  
Transcriptomic Analysis ◽  
Rna Seq ◽  
Sequencing Technology ◽  
Pneumonic Plague ◽  
Bacterial Rna ◽  
Lethal Infection

Pneumonic plague, caused by Yersinia pestis, is a rapidly progressing lethal infection. The various phases of pneumonic plague are yet to be fully understood. A well-established way to address the pathology of infectious diseases in general, and pneumonic plague in particular, is to conduct concomitant transcriptomic analysis of the bacteria and the host. The analysis of dual RNA by RNA sequencing technology is challenging, due the difficulties of extracting bacterial RNA, which is overwhelmingly outnumbered by the host RNA, especially at the critical early time points post-infection (prior to 48 h). Here, we describe a novel technique that employed the infusion of an RNA preserving reagent (RNAlater) into the lungs of the animals, through the trachea, under deep anesthesia. This method enabled the isolation of stable dual mRNA from the lungs of mice infected with Y. pestis, as early as 24 h post-infection. The RNA was used for transcriptomic analysis, which provided a comprehensive gene expression profile of both the host and the pathogen.

scholarly journals Perspectives for improvement of Mycoplasma hyopneumoniae vaccines in pigs

2021 ◽  
Vol 52 (1) ◽  
Author(s):  
Dominiek Maes ◽  
Filip Boyen ◽  
Bert Devriendt ◽  
Peter Kuhnert ◽  
Artur Summerfield ◽  
...  
Keyword(s):  
Immune Responses ◽  
Respiratory Infections ◽  
Mycoplasma Hyopneumoniae ◽  
Administration Route ◽  
Limited Effect ◽  
Partial Protection ◽  
Carrier Molecule ◽  
Humoral Responses ◽  
Porcine Respiratory ◽  
Selection Of

AbstractMycoplasma hyopneumoniae (M. hyopneumoniae) is one of the primary agents involved in the porcine respiratory disease complex, economically one of the most important diseases in pigs worldwide. The pathogen adheres to the ciliated epithelium of the trachea, bronchi, and bronchioles, causes damage to the mucosal clearance system, modulates the immune system and renders the animal more susceptible to other respiratory infections. The pathogenesis is very complex and not yet fully understood. Cell-mediated and likely also mucosal humoral responses are considered important for protection, although infected animals are not able to rapidly clear the pathogen from the respiratory tract. Vaccination is frequently practiced worldwide to control M. hyopneumoniae infections and the associated performance losses, animal welfare issues, and treatment costs. Commercial vaccines are mostly bacterins that are administered intramuscularly. However, the commercial vaccines provide only partial protection, they do not prevent infection and have a limited effect on transmission. Therefore, there is a need for novel vaccines that confer a better protection. The present paper gives a short overview of the pathogenesis and immune responses following M. hyopneumoniae infection, outlines the major limitations of the commercial vaccines and reviews the different experimental M. hyopneumoniae vaccines that have been developed and tested in mice and pigs. Most experimental subunit, DNA and vector vaccines are based on the P97 adhesin or other factors that are important for pathogen survival and pathogenesis. Other studies focused on bacterins combined with novel adjuvants. Very few efforts have been directed towards the development of attenuated vaccines, although such vaccines may have great potential. As cell-mediated and likely also humoral mucosal responses are important for protection, new vaccines should aim to target these arms of the immune response. The selection of proper antigens, administration route and type of adjuvant and carrier molecule is essential for success. Also practical aspects, such as cost of the vaccine, ease of production, transport and administration, and possible combination with vaccines against other porcine pathogens, are important. Possible avenues for further research to develop better vaccines and to achieve a more sustainable control of M. hyopneumoniae infections are discussed.

scholarly journals Streptozotocin and Alloxan-based Selection Improves Toxin Resistance of Insulin-Producing RINm Cells

2000 ◽  
Vol 1 (3) ◽  
pp. 211-219 ◽  
Author(s):  
Konstantin O. Bloch ◽  
Romy Zemel ◽  
Olga V. Bloch ◽  
Hagar Grief ◽  
Pnina Vardi
Keyword(s):  
Thymidine Incorporation ◽  
Colorimetric Method ◽  
Hormone Production ◽  
Partial Protection ◽  
Toxin Resistance ◽  
Cell Defense ◽  
Thymidine Incorporation Assay ◽  
Incorporation Assay ◽  
Al Treatment ◽  
Selection Of

The aim of our study was to develop a method for selection of subpopulations of insulin producing RINm cells with higher resistance to beta cell toxins. Cells, resistant to streptozotocin (RINmS) and alloxan (RINmA), were obtained by repeated exposure of parental RINm cells to these two toxins, while the defense capacity, was estimated by the MTT colorimetric method, and[H3]-thymidine incorporation assay. We found that RINmS and RINmA displayed higher resistance to both streptozotocin (STZ) and alloxan (AL) when compared to the parental RINm cells. In contrast, no differences in sensitivity to hydrogen peroxide were found between toxin selected and parental cells. Partial protection from the toxic effect of STZ and AL was obtained only in the parental RINm cells after preincubation of cells with the unmetabolizable 3- O-methyl-glucose. The possibility that GLUT-2 is involved in cell sensitivity to toxins was confirmed by Western blot analysis, which showed higher expression of GLUT-2 in parental RINm compared to RINmS and RINmA cells. In addition to the higher cell defense property evidenced in the selected cells, we also found higher insulin content and insulin secretion in both RINmS and RINmA cells when compared to the parental RINm cells. In conclusion, STZ and AL treatment can be used for selection of cell sub-populations with higher cell defense properties and hormone production. The different GLUT-2 expression in parental and re sistant cells suggest involvement of GLUT-2 in mechanisms of cell response to different toxins.

scholarly journals The Importance of the Small RNA Chaperone Hfq for Growth of Epidemic Yersinia pestis, but Not Yersinia pseudotuberculosis, with Implications for Plague Biology

2010 ◽  
Vol 192 (16) ◽  
pp. 4239-4245 ◽  
Author(s):  
Guangchun Bai ◽  
Andrey Golubov ◽  
Eric A. Smith ◽  
Kathleen A. McDonough
Keyword(s):  
Yersinia Pestis ◽  
Small Rna ◽  
Small Rnas ◽  
Yersinia Pseudotuberculosis ◽  
Etiologic Agent ◽  
Growth Restriction ◽  
Rna Chaperone ◽  
Unique Biology ◽  
Severe Growth

ABSTRACT Yersinia pestis, the etiologic agent of plague, has only recently evolved from Yersinia pseudotuberculosis. hfq deletion caused severe growth restriction at 37°C in Y. pestis but not in Y. pseudotuberculosis. Strains from all epidemic plague biovars were similarly affected, implicating Hfq, and likely small RNAs (sRNAs), in the unique biology of the plague bacillus.

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

2009 ◽  
Vol 77 (10) ◽  
pp. 4356-4361 ◽  
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.

scholarly journals EFFECT OF EXTRACHROMOSOMAL ELEMENTS OF HEREDITY ON TOXIC PROPERTIES OF YERSINIA PESTIS

2017 ◽  
pp. 28-33 ◽  
Author(s):  
G. V. Demidova ◽  
E. P. Sokolova ◽  
V. P. Zyuzina ◽  
V. A. Rykova ◽  
I. V. Morozova ◽  
...  
Keyword(s):  
Yersinia Pestis ◽  
Active Form ◽  
Infectious Agent ◽  
Toxic Shock ◽  
Toxic Activity ◽  
Virulent Strains ◽  
Extrachromosomal Elements ◽  
Live Bacteria ◽  
First Time

Aim. Elucidation of the role of extrachromosomal elements of heredity in manifestations of toxic properties of Yersinia pestis. Materials and methods. The study was carried out in vaccine strain Y. pestis EV76 (pMTl, pCDl, pPCPl) and non-plasmid variants of vaccine EV76 (pMTl\ pCDl', pPCPl') and virulent 231 (рМТГ, pCDl’, pPCPl') strains of Y. pestis. Presence of functionally active form of lipopolysaccharide (LPS) in the incubation medium of the bacteria was evaluated via toxicity of supernatant of Y. pestis for intact animals (infection-toxic shock) and mice sensitized by D-GalN. Results. 37°C cultures of Y. pestis EV76 containing a full amount of plasmids were established to release LPS into the environment. Non-plasmid variants of both vaccine and virulent strains of Y. pestis pMTl', pCD Г, рРСР 1 do not have this ability. Separation of LPS from cell wall was detected in live bacteria of plague infectious agent. This process is assumed to be coupled with translocation of proteins coded by pMTl, pCDl, pPCPl plasmids from the cell into the environment. Conclusion. Functional interconnection between extrachromosomal elements of heredity and toxic activity of Y. pestis LPS is established for the first time.

scholarly journals Cariogenic Streptococcus mutans produces strain-specific antibiotics that impair commensal colonization

2019 ◽  
Author(s):  
Xiaoyu Tang ◽  
Yuta Kudo ◽  
Jonathon Baker ◽  
Sandra LaBonte ◽  
Peter A. Jordan ◽  
...  
Keyword(s):  
Small Molecules ◽  
Streptococcus Mutans ◽  
Dental Plaque ◽  
Biosynthetic Pathway ◽  
Etiologic Agent ◽  
Commensal Bacteria ◽  
Tooth Decay ◽  
Tetramic Acid ◽  
Globally Distributed ◽  
Caries Tooth

Streptococcus mutans is a common constituent of dental plaque and an etiologic agent of dental caries (tooth decay). Here we elucidate a biosynthetic pathway, encoded by globally distributed strains of S. mutans, which produces a series of bioactive small molecules including reutericyclin and two N-acyl tetramic acid analogues active against oral commensal bacteria. This pathway may provide S. mutans with a competitive advantage, promoting dysbiosis and caries pathogenesis.

scholarly journals Yersinia pestis--etiologic agent of plague.

1997 ◽  
Vol 10 (1) ◽  
pp. 35-66 ◽  
Author(s):  
R D Perry ◽  
J D Fetherston
Keyword(s):  
Yersinia Pestis ◽  
Etiologic Agent ◽  
Clinical Aspects ◽  
Virulence Determinants ◽  
Health Issues ◽  
Regulatory Systems ◽  
Wide Range ◽  
Parasite Relationship ◽  
Obligate Pathogen ◽  
Host Parasite

Plague is a widespread zoonotic disease that is caused by Yersinia pestis and has had devastating effects on the human population throughout history. Disappearance of the disease is unlikely due to the wide range of mammalian hosts and their attendant fleas. The flea/rodent life cycle of Y. pestis, a gram-negative obligate pathogen, exposes it to very different environmental conditions and has resulted in some novel traits facilitating transmission and infection. Studies characterizing virulence determinants of Y. pestis have identified novel mechanisms for overcoming host defenses. Regulatory systems controlling the expression of some of these virulence factors have proven quite complex. These areas of research have provide new insights into the host-parasite relationship. This review will update our present understanding of the history, etiology, epidemiology, clinical aspects, and public health issues of plague.

scholarly journals Inhibition of LpxC Protects Mice from Resistant Acinetobacter baumannii by Modulating Inflammation and Enhancing Phagocytosis

mBio ◽  
2012 ◽  
Vol 3 (5) ◽  
Author(s):  
Lin Lin ◽  
Brandon Tan ◽  
Paul Pantapalangkoor ◽  
Tiffany Ho ◽  
Beverlie Baquir ◽  
...  
Keyword(s):  
Acinetobacter Baumannii ◽  
Gram Negative ◽  
Content Type ◽  
Novel Treatments ◽  
New Class ◽  
Virulent Strains ◽  
Lethal Infection ◽  
Tlr4 Activation ◽  
Opsonophagocytic Killing

ABSTRACT New treatments are needed for extensively drug-resistant (XDR) Gram-negative bacilli (GNB), such as Acinetobacter baumannii. Toll-like receptor 4 (TLR4) was previously reported to enhance bacterial clearance of GNB, including A. baumannii. However, here we have shown that 100% of wild-type mice versus 0% of TLR4-deficient mice died of septic shock due to A. baumannii infection, despite having similar tissue bacterial burdens. The strain lipopolysaccharide (LPS) content and TLR4 activation by extracted LPS did not correlate with in vivo virulence, nor did colistin resistance due to LPS phosphoethanolamine modification. However, more-virulent strains shed more LPS during growth than less-virulent strains, resulting in enhanced TLR4 activation. Due to the role of LPS in A. baumannii virulence, an LpxC inhibitor (which affects lipid A biosynthesis) antibiotic was tested. The LpxC inhibitor did not inhibit growth of the bacterium (MIC > 512 µg/ml) but suppressed A. baumannii LPS-mediated activation of TLR4. Treatment of infected mice with the LpxC inhibitor enhanced clearance of the bacteria by enhancing opsonophagocytic killing, reduced serum LPS concentrations and inflammation, and completely protected the mice from lethal infection. These results identify a previously unappreciated potential for the new class of LpxC inhibitor antibiotics to treat XDR A. baumannii infections. Furthermore, they have far-reaching implications for pathogenesis and treatment of infections caused by GNB and for the discovery of novel antibiotics not detected by standard in vitro screens. IMPORTANCE Novel treatments are needed for infections caused by Acinetobacter baumannii, a Gram-negative bacterium that is extremely antibiotic resistant. The current study was undertaken to understand the immunopathogenesis of these infections, as a basis for defining novel treatments. The primary strain characteristic that differentiated virulent from less-virulent strains was shedding of Gram-negative lipopolysaccharide (LPS) during growth. A novel class of antibiotics, called LpxC inhibitors, block LPS synthesis, but these drugs do not demonstrate the ability to kill A. baumannii in vitro. We found that an LpxC inhibitor blocked the ability of bacteria to activate the sepsis cascade, enhanced opsonophagocytic killing of the bacteria, and protected mice from lethal infection. Thus, an entire new class of antibiotics which is already in development has heretofore-unrecognized potential to treat A. baumannii infections. Furthermore, standard antibiotic screens based on in vitro killing failed to detect this treatment potential of LpxC inhibitors for A. baumannii infections.

Sign in / Sign up

Export Citation Format

Share Document