Different Pathologies but Equal Levels of Responsiveness to the Recombinant F1 and V Antigen Vaccine and Ciprofloxacin in a Murine Model of Plague Caused by Small- and Large-Particle Aerosols

Abstract

Presently there is a significant effort to develop and evaluate vaccines and antibiotics against the potential bioterrorism agent Yersinia pestis. The animal models used to test these countermeasures involve the deposition of small particles within the lung. However, deliberate aerosol release of Y. pestis will generate both small and large inhalable particles. We report in this study that the pathogenesis patterns of plague infections caused by the deposition of 1-and 12-m-particle aerosols of Y. pestis in the lower and upper respiratory tracts (URTs) of mice are different. The median lethal dose for 12-m particles was 4.9-fold greater than that for 1-m particles. The 12-m-particle infection resulted in the degradation of the nasal mucosa and nasal-associated lymphoid tissue (NALT) plus cervical lymphadenopathy prior to bacteremic dissemination. Lung involvement was limited to secondary pneumonia. In contrast, the 1-m-particle infection resulted in primary pneumonia; in 40% of mice, the involvement of NALT and cervical lymphadenopathy were observed, indicating entry via both URT lymphoid tissues and lungs. Despite bacterial deposition in the gastrointestinal tract, the involvement of Peyer's patches was not observed in either infection. Although there were major differences in pathogenesis, the recombinant F1 and V antigen vaccine and ciprofloxacin protected against plague infections caused by small-and large-particle aerosols.In humans, Yersinia pestis infections present clinically as bubonic, septicemic, and pneumonic plague. The introduction of Y. pestis into the bloodstream by flea bites results in the characteristic lymphadenopathy of bubonic plague. Lymphatic and circulatory dissemination causes hematogenous seeding of the lungs, producing secondary pneumonia. Primary pneumonic plague arises from the inhalation of aerosols containing Y. pestis. Both bubonic and primary pneumonic plague can progress to septicemia, resulting in endotoxic shock during the terminal stages of infection (26,29). There is currently a high level of interest in biodefense models of airborne diseases for the identification of virulence mechanisms and the testing of medical countermeasures. The focus is on the pneumonic forms of these diseases caused by the inhalation of smallparticle aerosols.Over the past decade, and in the context of the possible use of Y. pestis in bioterrorism, there has been significant interest in devising therapeutics for pneumonic plague. Antibiotics including tetracyclines, streptomycin, and chloramphenicol are used to treat pneumonic plague (5, 44). Recently, the broadspectrum fluoroquinolone antibiotic ciprofloxacin has been proposed for postexposure prophylaxis for mass-casualty-setting plague (26). Ciprofloxacin possesses excellent pharmacokinetic properties, with high lung concentrations providing efficacy against murine pneumonic plague (11, 41, 42). Significant progress in the development of plague vaccines has been made. Vaccines containing F1 capsular polypeptide and LcrV (V) antigens protect agai...

Inhaled Liposomal Ciprofloxacin Protects against a Lethal Infection in a Murine Model of Pneumonic Plague

“…Each mouse received a retained dose of approximately 1 × 10 4 CFU in the treatment study or 3 × 10 4 CFU in the prophylaxis study (determined though enumeration of the bacterial concentration in the aerosol with a calculation (Harper and Morton, 1953) using Guyton’s formula (Guyton, 1947)). The aerosol exposure system has previously been validated for Y. pestis (Thomas et al, 2009). Exposing animals to an aerosol of 1.52 × 10 9 CFU of Y. pestis , resulted in a lung dose of 1.76 × 10 4 ± 0.085 × 10 4 CFU (experimentally determined) compared to an estimated retained dose of 1.9 × 10 4 CFU (Thomas et al, 2009).…”

“…The aerosol exposure system has previously been validated for Y. pestis (Thomas et al, 2009). Exposing animals to an aerosol of 1.52 × 10 9 CFU of Y. pestis , resulted in a lung dose of 1.76 × 10 4 ± 0.085 × 10 4 CFU (experimentally determined) compared to an estimated retained dose of 1.9 × 10 4 CFU (Thomas et al, 2009). …”

Plague Gives Surprises in the First Decade of the 21st Century in the United States and Worldwide

“…The fluoroquinolone ciprofloxacin was effective in protecting mice against lung infection after exposure by inhalation to aerosols of Y. pestis. 39,40 It is recommended for prophylaxis after exposure to suspected cases and as an alternative drug for infected patients. 15,16,20 However, fluoroquinolones have not been adequately evaluated in human treatment trials and should not be chosen as a first-line drug.…”

Development of Yersinia pestis F1 antigen-loaded microspheres vaccine against plague

“…[2][3][4] Protecting against the pneumonic form of the disease has been possible only with live attenuated strains of Y. pestis. 5 Subunit antigens of Y. pestis were identified as long ago as the mid-twentieth century, [3][4][5][6][7][8][9] but it was only with the advent of recombinant DNA technology that these could be fully exploited with consistent production of pure, stable recombinant proteins. 6,7,[10][11][12] The field of nanotechnology has growing applicability to medical biotechnology, including drug and vaccine delivery.…”

“…5 Subunit antigens of Y. pestis were identified as long ago as the mid-twentieth century, [3][4][5][6][7][8][9] but it was only with the advent of recombinant DNA technology that these could be fully exploited with consistent production of pure, stable recombinant proteins. 6,7,[10][11][12] The field of nanotechnology has growing applicability to medical biotechnology, including drug and vaccine delivery. 9,[13][14][15][16][17] Polymeric particles made from inert materials or biodegradable polymers such as poly-l-lactide (PLA) 18,19 or poly-l-lactide-co-glycolides (PLGAs) [20][21][22][23] allow drug encapsulation within a hydrophobic core or absorption to the hydrophilic shell.…”