Levofloxacin rescues mice from lethal intra-nasal infections with virulent Francisella tularensis and induces immunity and production of protective antibody

Abstract

The ability to protect mice against respiratory infections with virulent Francisella tularensis has been problematic and the role of antibody-versus-cell-mediated immunity controversial. In this study, we tested the hypothesis that protective immunity can develop in mice that were given antibiotic therapy following infection via the respiratory tract with Francisella tularensis SCHU S4. We show that mice infected with a lethal dose of SCHU S4, via an intra-nasal challenge, could be protected with levofloxacin treatment. This protection was evident even when levofloxacin treatment was delayed 72 hours post-infection. At early time points after levofloxacin treatment, significant numbers of bacteria could be recovered from the lungs and spleens of mice, which was followed by a dramatic disappearance of bacteria from these tissues. Mice successfully treated with levofloxacin were later shown to be almost completely resistant to rechallenge with SCHU S4 by the intra-nasal route. Serum antibody appeared to play an important role in this immunity. Normal mice, when given sera from animals protected by levofloxacin treatment, were solidly protected from a lethal intra-nasal challenge with SCHU S4. The protective antiserum contained high titers of SCHU S4 specific IgG2a, indicating that a strong Th1 response was induced following levofloxacin treatment. Thus, this study describes a potentially valuable animal model for furthering our understanding of respiratory tularemia and provides suggestive evidence that antibody can protect against respiratory infections with virulent F. tularensis.

Toll-Like Receptor 3 Agonist Protection against ExperimentalFrancisella tularensisRespiratory Tract Infection

“…4B). This is in dramatic contrast to our previous findings that showed LEVO therapy initiated at 5 days postchallenge did not resolve lethal F. tularensis infection (21). Importantly, these increased survival times also allowed for successful initiation of LEVO treatment even 5 days after Schu 4 challenge (Fig.…”

“…To determine whether poly(I:C) could extend the time before effective LEVO therapy initiation, mice were treated with poly(I:C) 1 h post-Schu 4 challenge and then, 5 days later, they were i.p. injected with 40 mg of LEVO/kg (21). This study also repeated groups of animals treated with poly(I:C), followed by Schu 4 infection, to confirm the previous results.…”

“…The longer the delay in the start of standard intervention against F. tularensis, the less effective "front line" antibiotics are against an infection (21). Further, agents to protect at risk populations from F. tularensis should be employable when forewarning is available or just after exposure.…”

“…poly(I:C) could engender an innate immune response against F. tularensis, providing an extended period of resistance before an antibiotic, such as levofloxacin (LEVO), can be administered. LEVO belongs to the group of antibiotics known as fluoroquinolones and has been used to treat respiratory infections such as tularemia (1,21,25).…”

Antibodies Contribute to Effective Vaccination against Respiratory Infection by Type A Francisella tularensis Strains

“…Klimpel et al also reported a similar finding using immune serum from mice cured of a lethal intranasal (i.n.) SCHU S4 infection with levofloxacin in a passive immunization model (27). Thus, the protective effects of antibodies appear not to be restricted only to low-virulence strains but may also contribute to the protection against highly virulent type A strains.…”