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Mouse Model of Oral Infection with Virulent Type A Francisella tularensis

Institute for Biological Sciences, National Research Council Canada, 100 Sussex Drive, Ottawa, Ontario K1A 0R6, Canada,¹ Microbiology Research Division, Bureau of Microbial Hazards, Health Products and Food Branch, Health Canada, Tunney's Pasture, Ottawa, Ontario K1A 0L2, Canada²

Received 20 November 2006/ Returned for modification 21 December 2006/ Accepted 10 January 2007

Francisella tularensis is a gram-negative facultative intracellular pathogen and the causative agent of tularemia. Little is known about the immunopathogenesis of oral infection with this pathogen. Here, for the first time, we examined the susceptibility of mice to intragastric inoculation with virulent type A F. tularensis and characterized the course of infection and the associated host responses. Both immunocompetent and immunodeficient mice were relatively susceptible to intragastric inoculation of type A F. tularensis with a 50% lethal dose (LD₅₀) of 10⁶ organisms, which was 100,000-fold higher than the LD₁₀₀ for intradermal or respiratory routes of infection. Mice deficient in gamma interferon or tumor necrosis factor receptors 1 and 2 were more susceptible than wild-type controls to oral infection with a high dose of the pathogen. After oral inoculation, F. tularensis appeared first in the mesenteric lymph nodes (MLN) and then rapidly spread to the livers and spleens, where the organism multiplied to high numbers and induced marked neutrophilic infiltration and severe tissue necrosis. Infected mice showed rapid increases in tissue cytokine mRNA expression, which peaked in the MLN at 2 days postinfection (dpi) and in the liver and spleen at 3 dpi. The levels of gamma interferon, interleukin-1ß (IL-1ß), IL-6, tumor necrosis factor alpha, macrophage inflammatory protein 1, KC, interferon-inducible protein 10, and monocyte chemotactic protein 1 were elevated from day 2 postinoculation onward. Moreover, mice intradermally immunized with the live vaccine strain of F. tularensis showed little survival advantage over naive mice after oral challenge with type A F. tularensis. These results suggest that type A F. tularensis is an effective oral pathogen that can cause fatal systemic infection and could pose a public health concern, particularly to immunocompromised individuals, if ingested in contaminated water and food.

Published ahead of print on 22 January 2007.

Editor: R. P. Morrison

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