Vaccination of Fischer 344 rats against pulmonary infections by Francisella tularensis type A strains

Abstract

Pneumonic tularemia caused by inhalation of the type A strains of Francisella tularensis is associated with high morbidity and mortality in humans. The only vaccine known to protect humans against this disease is the attenuated live vaccine strain (LVS), but it is not currently registered for human use. To develop a new generation of vaccines, multiple animal models are needed that reproduce the human response to F. tularensis infection and vaccination. We examined the potential use of Fischer 344 rat as such a model. Fischer 344 rats were very sensitive to intratracheal infection with the virulent type A strain SCHU S4 and generally succumbed less than 2 weeks after infection. Similar to humans and non-human primates, Fischer 344 rats vaccinated with LVS by subcutaneous or intradermal routes were protected against a greater range of respiratory SCHU S4 challenge doses than has been reported for LVS-vaccinated mice. Intratracheal LVS vaccination also induced effective immunity, but it was less protective when the challenge dose exceeded 105 SCHU S4. LVS vaccination did not prevent SCHU S4 infection but rather controlled bacterial growth and pathology, leading to the eventual clearance of the bacteria. Our results suggest that the Fischer 344 rat may be a good model for studying pneumonic tularemia and evaluating potential vaccine candidates.

The Natural History of Pneumonic Tularemia in Female Fischer 344 Rats after Inhalational Exposure to Aerosolized Francisella tularensis Subspecies tularensis Strain SCHU S4

“…However, on the basis of previous studies in rats, the clinical progression, LD 50 , and terminal histopathology and bacterial burdens in the lungs, liver, and spleen appear to be similar whether F. tularensis is delivered via the intratracheal route or via small particle aerosol. 23 However, one notable difference observed is that the aerosol inhalation method produces a more uniform distribution of lesions within the deep lung than intratracheal instillation. In addition, deposition of F. tularensis after aerosol exposoure was not only in the lungs but also in the nasopharyngeal region and the gastrointestinal tract, similar to what would be expected after its use as a bioweapon.…”

“…2,19e22 Previously published data demonstrate that Fischer 344 (F344) rats show a similar susceptibility to F. tularensis strains as has been reported for humans. 23,24 F344 rats were sensitive to an intratracheal inoculation of the highly virulent SCHU S4 strain of F. tularensis [lethal dose 50% (LD 50 ) < 200], but were resistant to infection with subspecies holarctica (strain OR96-0246, LD 50 Z 10 5 ) and subspecies novicida (strain U112, LD 50 Z 5 Â 10 6 ). Preliminary studies also suggested that SCHU S4 infection causes similar physiological responses in F344 rats and humans, including elevated temperature, respiratory rate, and blood pressure.…”

“…In addition, F344 rats have been shown to have similar responses to immunization with LVS as humans. 2,23,25 The objective of the current natural history studies described in this report was to characterize the pathogenesis of primary pneumonic tularemia in female F344 rats exposed to aerosolized F. tularensis, SCHU S4. A secondary goal was to identify an early, reliable indicator of infection that could be used as a treatment trigger point in future efficacy studies to evaluate novel potential therapeutics against F. tularensis.…”

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

“…To further characterize the mechanism of antibody-medi-ated protection, we utilized the recently characterized Fischer 344 (F344) rat model (45). Since F344 rats developed much stronger resistance to respiratory SCHU S4 challenge after LVS vaccination than previously observed in mice, we speculated that antibodies may provide better protection in this model and allow us to define their protective mechanism more thoroughly.…”

Medical Countermeasures for Biothreat Agents: Need for Inhalation Challenge Models

“…Notably, the most common human form of anthrax is cutaneous anthrax with a mortality rate of nearly 20% if untreated; gastrointestinal anthrax generally leading to fatal systemic disease if untreated [5]. Similarly, pneumonic tularemia caused by inhalation of the type A strains of Francisella tularensis is associated with high morbidity and mortality in humans and attenuated live vaccine strain (LVS) which were tested for inhalation challenge in Fischer 344 rat which was proposed as a model for studying pneumonic tularemia and evaluating potential vaccine candidates [6]. Brucella melitensis is a highly infectious pathogen that can infect animals and humans and is an etiologic agent for brucellosis.…”