IL-17 Protects Against the Francisella tularensis Live Vaccine Strain, but not Against Virulent Type A F. tularensis.

Department of Immunology and Infectious Diseases, Montana State University, Bozeman, Montana, 59717.
Infection and immunity (Impact Factor: 3.73). 06/2013; 81(9). DOI: 10.1128/IAI.00203-13
Source: PubMed

ABSTRACT Francisella tularensis is a highly infectious intracellular bacterium that causes the zoonotic infection, tularemia. While much literature exists on the host response to F. tularensis infection, the vast majority of work has been conducted using attenuated strains of Francisella that do not cause disease in humans. However, emerging data indicate the protective immune response against attenuated versus type A F. tularensis differs. Several groups have recently reported that IL-17 confers protection against the Live Vaccine Strain (LVS) of Francisella. While we, too, have found that IL-17Rα(-/-) mice are more susceptible to F. tularensis LVS infection, our studies, using a virulent type A strain of F. tularensis (SchuS4), indicate IL-17Rα(-/-) mice display similar organ burdens and pulmonary IFN-γ responses as do wild-type mice following infection. In addition, oral LVS vaccination conferred equivalent protection against pulmonary challenge with SchuS4 in both IL-17Rα(-/-) and wild-type mice. While IFN-γ was found to be critically important for survival in a convalescent model of SchuS4 infection, IL-17 neutralization from either wild-type or IFN-γ(-/-) mice had no effect on morbidity or mortality in this model. IL-17 protein levels were also higher in the lungs of mice infected with LVS rather than type A Francisella, while IL-23p19 mRNA expression was found to be caspase-1 dependent in macrophages infected with LVS, but not SchuS4. Collectively, these results demonstrate IL-17 is dispensable for host immunity to type A F. tularensis infection and that induced and protective immunity differs between attenuated and virulent strains of F. tularensis.

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    ABSTRACT: Francisella tularensis is a gram-negative bacterium that causes the zoonotic disease tularemia. Francisella is highly infectious via the respiratory route (~10 CFUs) and pulmonary infections due to type A strains of F. tularensis are highly lethal in untreated patients (> 30%). In addition, no vaccines are licensed to prevent tularemia in humans. Due to the high infectivity and mortality of pulmonary tularemia, F. tularensis has been weaponized, including via the introduction of antibiotic resistance, by several countries. Because of the lack of efficacious vaccines, and concerns about F. tularensis acquiring resistance to antibiotics via natural or illicit means, augmentation of host immunity, and humoral immunotherapy have been investigated as countermeasures against tularemia. This manuscript will review advances made and challenges in the field of immunotherapy against tularemia.
    Virulence 06/2013; 4(7). DOI:10.4161/viru.25454 · 4.22 Impact Factor
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    ABSTRACT: The adaptive immune response to Francisella tularensis is dependent on the route of inoculation. Intradermal inoculation with F. tularensis live vaccine strain (LVS) results in a robust Th1 response in the lung whereas intranasal inoculation produces fewer Th1 cells and instead many Th17 cells. Interestingly, bacterial loads in the lung are similar early after inoculation regardless of the inoculation route. We hypothesize that the adaptive immune response is influenced by local events in the lung, such as the type of cells that are first infected with Francisella. Using fluorescent activated cell sorting, we identified alveolar macrophages as the first cell type infected in the lungs of mice intranasally inoculated with F. novicida U112, LVS, or F. tularensis Schu S4. Following bacterial dissemination from the skin to the lung, interstitial macrophages or neutrophils are infected. Overall, we identified the early interactions between Francisella and the host following two different routes of inoculation.
    Infection and immunity 03/2014; 82(6). DOI:10.1128/IAI.01654-13 · 3.73 Impact Factor
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    ABSTRACT: IL-17 and IFN-γ production by Th17 and Th1 cells, respectively, is critical for survival during primary respiratory infection with the pathogenic bacterium, Francisella tularensis Live Vaccine Strain (LVS). The importance, however, of these T cell subsets and their soluble mediators is not well understood during a secondary or memory response. We measured the number of CD4(+) T cells producing IFN-γ or IL-17 in the spleen and lungs of vaccinated mice on day four of the secondary response using intracellular cytokine staining in order to identify protective T cell subsets participating in the memory response. Few bacteria were present in spleens of vaccinated mice on day four and a T cell response was not observed. In the lung, where more bacteria were present, there was a robust Th1 response in vaccinated mice but Th17 cells were not present at higher numbers in vaccinated mice compared to unvaccinated mice. These data show that the lung is the dominant site of the secondary immune response and suggest that Th17 cells are not required for survival during secondary challenge. To further investigate the importance of IFN-γ and IL-17 during the secondary response to F. tularensis, we neutralized either IFN-γ or IL-17 in vivo using monoclonal antibody treatment. Vaccinated mice treated with anti-IFN-γ lost more weight and had higher bacterial burdens compared to vaccinated mice treated with isotype control antibody. In contrast, treatment with anti-IL-17A antibody did not alter weight loss profiles or bacterial burdens compared to mice treated with isotype control antibody. Together, these results suggested that IFN-γ is required during both primary and secondary respiratory F. tularensis infection. IL-17, on the other hand, is only critical during the primary response to respiratory F. tularensis but dispensable during the secondary response.
    Vaccine 05/2014; 32(29). DOI:10.1016/j.vaccine.2014.05.013 · 3.62 Impact Factor
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