Host Iron Nutritional Immunity Induced by a Live Yersinia pestis Vaccine Strain Is Associated with Immediate Protection against Plague

Zauberman, Ayelet; Vagima, Yaron; Tidhar, Avital; Aftalion, Moshe; Gur, David; Rotem, Shahar; Chitlaru, Theodor; Levy, Yinon; Mamroud, Emanuelle

doi:10.3389/fcimb.2017.00277

Cited by 22 publications

(21 citation statements)

References 40 publications

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“…We recently showed the rapid induction of anti-plague protective mechanisms evoked by the live vaccine strain Y. pestis EV76. 37 In addition, the F1-expressing live attenuated Y. pseudotuberculosis vaccine strain with the ability to induce anti-F1 titers shortly after oral immunization was recently reported. 38 We have demonstrated that vaccination with the purified recombinant F1 capsular protein of Y. pestis can induce anti-plague immunity very rapidly, even when administered several hours after a lethal challenge.…”

Section: Discussionmentioning

confidence: 99%

Targeting of the Yersinia pestis F1 capsular antigen by innate-like B1b cells mediates a rapid protective response against bubonic plague

et al. 2018

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The generation of adaptive immunity by vaccination is usually a prolonged process that requires multiple dosing over several months. Hence, vaccines are administered for disease prevention a relatively long time prior to possible infection as opposed to post-exposure prophylaxis, which typically requires rapid intervention such as antibiotic therapy. The emergence of pathogens resistant to common antibiotic treatments has prompted the search for alternative therapeutic strategies. We previously demonstrated that vaccination of mice with the F1 capsular antigen of Yersinia pestis elicits specific and effective yet, unexpectedly, rapid anti-plague immunity. Here, we show by applying genetic and immunological approaches that the F1 antigen is targeted by peritoneal innate-like B1b cells that generate a prompt T-independent (TI) anti-F1 humoral response. The rapid F1-mediated defense response was diminished in Xid (Btkm) mice in which B1 cell numbers and activity are limited. Binding of fluorophore-labeled F1 to peritoneal B1b cells was detected as soon as 6 h post vaccination, emphasizing the high speed of this process. By assessing the ability to achieve rapid immunity with monomerized F1, we show that the natural polymeric structure of F1 is essential for (i) rapid association with peritoneal B1b cells, (ii) early induction of anti-F1 titers and (iii) rapid TI immunity in the mouse model of bubonic plague. These observations shed new light on the potential of novel as well as well-known protective antigens in generating rapid immunity and could be implemented in the rational design of future vaccines.

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Section: Discussionmentioning

confidence: 99%

Targeting of the Yersinia pestis F1 capsular antigen by innate-like B1b cells mediates a rapid protective response against bubonic plague

et al. 2018

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“…The Y. pestis strains used in this study included Kimberley53 (Kim53), a fully virulent strain (biovar orientalis) and the bioluminescent Kim53-lux derivative (Vagima et al, 2015 ; Zauberman et al, 2017 ). To construct the bioluminescent Y. pestis derivative, the plasmid pGEN-luxCDABE (a generous gift from Professor H. Mobley; Lane et al, 2007 ) was introduced into the Y. pestis Kim53 strain by electroporation.…”

Section: Methodsmentioning

confidence: 99%

Inhalational Gentamicin Treatment Is Effective Against Pneumonic Plague in a Mouse Model

et al. 2018

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Pneumonic plague is an infectious disease characterized by rapid and fulminant development of acute pneumonia and septicemia that results in death within days of exposure. The causative agent of pneumonic plague, Yersinia pestis (Y. pestis), is a Tier-1 bio-threat agent. Parenteral antibiotic treatment is effective when given within a narrow therapeutic window after symptom onset. However, the non-specific “flu-like” symptoms often lead to delayed diagnosis and therapy. In this study, we evaluated inhalational gentamicin therapy in an infected mouse model as a means to improve antibiotic treatment efficacy. Inhalation is an attractive route for treating lung infections. The advantages include directly dosing the main infection site, the relative accessibility for administration and the lack of extensive enzymatic drug degradation machinery. In this study, we show that inhalational gentamicin treatment administered 24 h post-infection, prior to the appearance of symptoms, protected against lethal intranasal challenge with the fully virulent Y. pestis Kimberley53 strain (Kim53). Similarly, a high survival rate was demonstrated in mice treated by inhalation with another aminoglycoside, tobramycin, for which an FDA-approved inhaled formulation is clinically available for cystic fibrosis patients. Inhalational treatment with gentamicin 48 h post-infection (to symptomatic mice) was also successful against a Y. pestis challenge dose of 10 i.n.LD50. Whole-body imaging using IVIS technology demonstrated that adding inhalational gentamicin to parenteral therapy accelerated the clearance of Y. pestis from the lungs of infected animals. This may reduce disease severity and the risk of secondary infections. In conclusion, our data suggest that inhalational therapy with aerosolized gentamicin may be an effective prophylactic treatment against pneumonic plague. We also demonstrate the benefit of combining this treatment with a conventional parenteral treatment against this rapidly progressing infectious disease. We suggest the inhalational administration route as a clinically relevant treatment modality against pneumonic plague and other respiratory bacterial pathogens.

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“…Bacterial strains used in this work are the Y. pestis vaccine strain EV76 [ 33 ], the plasmid-cured non-virulent Y. pestis Kimberley53∆pPCP1∆pCD1 (Kim53Δ10Δ70) strain [ 34 ] and its reduced ciprofloxacin sensitive and non-sensitive sub species Kim53Δ10Δ70–42 and Kim53Δ10Δ70–66-6 respectively [ 2 , 3 , 17 ]. Doxycycline reduced sensitivity and resistant sub species are Kim53Δ10Δ70–36 and Kim53Δ10Δ70–36-4 respectively.…”

Section: Methodsmentioning

confidence: 99%

“…Inhalation of this agent results in rapidly progressing pneumonic plague that can be transmitted from person to person. High mortality rates are observed if treatment does not start within 18–24 h after the onset of symptoms [ 1 – 3 ]. Unfortunately, the current standard AST method for Y. pestis (CLSI) [ 4 ] requires 24–48 h, not including the time required for bacterial culture isolation.…”

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Rapid Antibiotic Susceptibility Determination for Yersinia pestis Using Flow Cytometry Spectral Intensity Ratio (SIR) Fluorescence Analysis

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Rapid antimicrobial susceptibility tests (ASTs) are essential tool for proper treatment of patients infected by Yersinia pestis (Y. pestis), the causative agent of plague, or for post-exposure prophylaxis of a population exposed to a naturally acquired or deliberately prepared resistant variant. The standard AST of Y. pestis is based on bacterial growth and requires 24–48 h of incubation in addition to the time required for prior isolation of a bacterial culture from the clinical or environmental sample, which may take an additional 24–48 h. In this study, we present a new and rapid AST method based on a fluorescence determination of the minimum inhibitory concentration (MIC). Our method includes the incubation of bacteria with an antibiotic, followed by staining of the bacteria with oxonol dye (SynaptoGreen C4/FM1–43), which enables the rapid detection of an antibiotic’s effect on bacterial viability. We show that stained, non-viable bacteria exhibit a spectral redshift and an increase in fluorescence intensity compared to intact control bacteria. Based on these criteria, we developed a rapid flow cytometer measurement procedure and a unique spectral intensity ratio (SIR) analysis that enables determination of antibiotic susceptibility for Y. pestis within 6 h instead of the 24 to 48 h required for the standard AST. This new rapid determination of antibiotic susceptibility could be crucial for reducing mortality and preventing the spread of disease.

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Host Iron Nutritional Immunity Induced by a Live Yersinia pestis Vaccine Strain Is Associated with Immediate Protection against Plague

Cited by 22 publications

References 40 publications

Targeting of the Yersinia pestis F1 capsular antigen by innate-like B1b cells mediates a rapid protective response against bubonic plague

Targeting of the Yersinia pestis F1 capsular antigen by innate-like B1b cells mediates a rapid protective response against bubonic plague

Inhalational Gentamicin Treatment Is Effective Against Pneumonic Plague in a Mouse Model

Rapid Antibiotic Susceptibility Determination for Yersinia pestis Using Flow Cytometry Spectral Intensity Ratio (SIR) Fluorescence Analysis

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