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Infect. Immun. doi:10.1128/IAI.01834-06
Copyright (c) 2007, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

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 and Microbiology Research Division, Bureau of Microbial Hazards, Health Products and Food Branch, Health Canada, Tunney's Pasture, Ottawa, ON, K1A 0L2, Canada

^* To whom correspondence should be addressed. Email: wangxue.chen{at}nrc.gc.ca.

	Abstract

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 an LD₅₀ of 10⁶ organisms, which was 100,000-fold higher than the LD₁₀₀ for intradermal or respiratory routes of infection. Mice deficient in interferon-gamma 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. Following oral inoculation, F. tularensis appeared first in the mesenteric lymph nodes (MLN) and then rapidly spread to the liver and spleen where they 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 dpi 2 and in the liver and spleen at dpi 3. Serum levels of IFN-, IL-1, IL-6, TNF-, MIP-1, KC, IP-10 and MCP-1 were elevated from day 2 post-inoculation onwards. Moreover, mice intradermally immunized with the live vaccine strain (LVS) of F. tularensis showed little survival advantage over naïve mice following 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.

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