<i>Francisella tularensis</i>Infection-Derived Monoclonal Antibodies Provide Detection, Protection, and Therapy

Abstract

Francisella tularensis is the causative agent of tularemia and a potential agent of biowarfare. As an easily transmissible infectious agent, rapid detection and treatment are necessary to provide a positive clinical outcome. As an agent of biowarfare, there is an additional need to prevent infection. We made monoclonal antibodies to the F. tularensis subsp. holarctica live vaccine strain (F. tularensis LVS) by infecting mice with a sublethal dose of bacteria and, following recovery, by boosting the mice with sonicated organisms. The response to the initial and primary infection was restricted to immunoglobulin M antibody directed solely against lipopolysaccharide (LPS). After boosting with sonicated organisms, the specificity repertoire broadened against protein antigens, including DnaK, LpnA, FopA, bacterioferritin, the 50S ribosomal protein L7/L12, and metabolic enzymes. These monoclonal antibodies detect F. tularensis LVS by routine immunoassays, including enzyme-linked immunosorbent assay, Western blot analysis, and immunofluorescence. The ability of the antibodies to protect mice from intradermal infection, both prophylactically and therapeutically, was examined. An antibody to LPS which provides complete protection from infection with F. tularensis LVS and partial protection from infection with F. tularensis subsp. tularensis strain SchuS4 was identified. There was no bacteremia and reduced organ burden within the first 24 h when mice were protected from F. tularensis LVS infection with the anti-LPS antibody. No antibody that provided complete protection when administered therapeutically was identified; however, passive transfer of antibodies against LPS, FopA, and LpnA resulted in 40 to 50% survival of mice infected with F. tularensis LVS.