Post-exposure immunization against Francisella tularensis membrane proteins augments protective efficacy of gentamicin in a mouse model of pneumonic tularemia.
Successful treatment of pneumonic infection with Francisella tularensis, the causative agent of tularemia, requires rapid initiation of antibiotic therapy, yet even then treatment failures may occur. Consequently, new treatments are needed to enhance the effectiveness of antimicrobial therapy for acute pneumonic tularemia. In a prior study, immunization with F. tularensis membrane protein fraction (MPF) antigens 3 days prior to challenge was reported to induce significant protection from inhalational challenge. We therefore hypothesized that MPF immunization might also be effective in enhancing infection control if combined with antibiotic therapy and administered after infection as post-exposure immunotherapy. To address this question, a 24h post-exposure treatment model of acute pulmonary Schu S4 strain of F. tularensis infection in BALB/c mice was used. Following exposure, mice were immunized with MPF and treated with low-dose gentamicin, alone or in combination and the effects on survival, bacterial burden and dissemination were assessed. We found that immunization with MPF significantly increased the effectiveness of subtherapeutic gentamicin for post-exposure treatment of pneumonic tularemia, with 100% of combination-treated mice surviving long-term. Bacterial burdens in the liver and spleen were significantly reduced in combination MPF-gentamicin treated mice at 7 days after challenge. Passively transferred antibodies against MPF antigens also increased the effectiveness of gentamicin therapy. Thus, we concluded that post-exposure immunization with MPF antigens was an effective means of enhancing conventional antimicrobial therapy for pneumonic tularemia.
Department of Microbiology, Immunology and Pathology, Rocky Mountain Regional Center of Excellence for Biodefense and Emerging Infectious Diseases Research, Colorado State University, Fort Collins, CO 80523, USA.
Marjorie D
MD
Sutherland
Andrew W
AW
Goodyear
Ryan M
RM
Troyer
Jeffrey C
JC
Chandler
Steven W
SW
Dow
John T
JT
Belisle
D000818:Animals; D000900:Anti-Bacterial Agents / Q000008:administration & dosage*; D019072:Antibiotic Prophylaxis / Q000379:methods*; D058491:Bacterial Load; D001428:Bacterial Vaccines / Q000008:administration & dosage* / Q000276:immunology; D004195:Disease Models, Animal; D005260:Female; D005604:Francisella tularensis / Q000276:immunology; D005839:Gentamicins / Q000008:administration & dosage*; D008099:Liver / Q000382:microbiology; D008565:Membrane Proteins / Q000008:administration & dosage / Q000276:immunology; D000090204:Mesothelin; D051379:Mice; D008807:Mice, Inbred BALB C; D056990:Post-Exposure Prophylaxis / Q000379:methods*; D013154:Spleen / Q000382:microbiology; D016019:Survival Analysis; D016896:Treatment Outcome; D014406:Tularemia / Q000517:prevention & control*; D014611:Vaccination / Q000379:methods*
D000900:Anti-Bacterial Agents; D001428:Bacterial Vaccines; D005839:Gentamicins; D008565:Membrane Proteins; C000715528:Msln protein, mouse; D000090204:Mesothelin