The Fischer 344 rat reflects human susceptibility to Francisella pulmonary challenge and provides a new platform for virulence and protection studies

Background. The pathogenesis of Francisella tularensis the causative agent of tularemia has been primarily characterized in mice. However, the sensitivity of mice to bacterial challenge especially with the human virulent strains of F. tularensis limits this animal model for screening of defined attenuated vaccine candidates for protection studies.

Methods. We analyzed the sensitivity of the Fischer 344 rat to pulmonary (intratracheal) challenge with the four major subspecies (subsp.) of F. tularensis and characterized the bacterial replication profile in rat bone marrow-derived macrophages (BMDM).

Results. In contrast to the mouse, Fischer 344 rats exhibit a broader range of sensitivity to pulmonary challenge with the human infectious F. tularensis strains, subsp. tularensis and holarctica. Unlike mice, Fischer rats exhibited high degree of resistance to pulmonary challenge with LVS (a derivative of subsp. holarctica) and subsp. novicida. Moreover, while subsp. tularensis and LVS minimally replicated within BMDMs, there was marginal replication with subsp. novicida and robust bacterial division with subsp. holartica. The intramacrophage replication of the subsp. tularensis and novicida strains was found to be correlated with the induction of nitric oxide production respectively. Importantly, Fischer 344 rats which were resistant to primary subsp. novicida challenge were markedly protected against subsequent pulmonary challenge with subsp. tularensis.

Conclusions. The Fischer 344 rat may exhibit similar sensitivities to F. tularensis as reflected in humans and better serve as a robust animal model for assessing the efficacy of vaccine candidates, including the use of subsp. novicida as a vaccine platform.