Cutaneous resistance against Francisella tularensis

Francisella tularensis, the causative agent of tularemia, is a potent pathogen in humans and other mammals. The ulceroglandular form of the disease is the most common expression in humans with a clinical picture characterized by a skin ulcer, enlarged regional lymph nodes and fever. Despite being a preferred route of infection, the skin also affords an effective defense barrier against F. tularensis. Doses required to induce infection by intradermal inoculation are several logs higher than those needed for infection by other routes. In the present thesis, the requirements for the local and systemic host defense to intradermal infection with F. tularensis was studied in experimental mouse models. Naïve mice and mice immunized by previous infection were challenged, mostly with the live vaccine strain F. tularensis LVS but also with a clinical isolate of F. tularensis.In naïve mice, intradermal inoculation of F. tularensis LVS resulted in a rapid increase of bacterial numbers during the first few days in the skin, lymph nodes, spleen and liver, followed by a decrease and eradication of the bacteria within two weeks of inoculation. Immune mice controlled the infection at the site of infection and very few bacteria spread to internal organs. When immunohistochemical staining of skin specimens was performed during the first 3 days, naïve mice showed a weak or barely discernible local expression of TNF-α, IL-12 and IFN-γ. In immune mice, the expression of all three cytokines was strongly enhanced, TNF-α and IL-12 within 24 h and IFN-γ within 72 h of inoculation.To investigate the role of T cells in the defense against intradermal infection with F. tularensis LVS, naïve and immune T-cell knockout mice (e.g., αβ TCR-/-, γδ TCR-/-, αβγδ TCR-/-) were used. Naïve mice lacking the αβ TCR had persistently high bacterial numbers in all organs and died at 4 weeks. Mice lacking the γδ TCR, on the other hand, controlled the infection as effectively as did wild-type mice. To enable αβ TCR-/- and αβγδ TCR-/- mice to survive, antibiotic treatment was given from day 10 to 20 of infection. When intradermally challenged 2 weeks later, these animals were found to control a secondary infection, resulting in decreasing viable counts in skin and lymph nodes and prevention of spread to liver and spleen…


Francisella tularensis and Tularemia
The pathogen
Vaccination and the live vaccin strain, F. tularensis LVS
Natural route of infection and clinical presentation
Antibiotic treatment
F. tularensis as an intracellular pathogen
An early T-cell independent host resistance to F. tularensis
T-cell mediated immunity
Humoral immunity
Skin-associated immunity
Arguments and rationale for using a mouse model in studies on the host response to F. tularensis
In vivo infection in mice
Paper I. F. tularensis-immunized mice respond to a secondary intradermal challenge by
enhanced local expression of TNF-α, IFN-γ, and IL-12 and by rapid control of infection
Paper II. F. tularensis LVS induces a partial host protection locally in the skin of mice lacking αβ T cells
Paper III. F. tularensis-specific antibodies afford protection against intradermal challenge
of mice with F. tularensis LVS as well as a wild-type isolate of F. tularensis subsp. holarctica
Paper IV. F. tularensis-specific antibodies induce a local expression of TNF-α and IL-12
and recruitment of neutrophils early upon intradermal infection with F. tularensis LVS

Author: Stenmark, Stephan

Source: Umea University

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