Interleukin-17 Protects against the Francisella tularensis Live Vaccine Strain but Not against a Virulent F. tularensis Type A Strain

Skyberg, Jerod A.; Rollins, MaryClare F.; Samuel, Joshua W.; Sutherland, Marjorie D.; Belisle, John T.; Pascual, David W.

doi:10.1128/iai.00203-13

Cited by 26 publications

(28 citation statements)

References 39 publications

(61 reference statements)

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“…Interestingly, higher levels of IL-17 were also found at day 3 postinfection in i Ft -MHB immunized mice compared to that of i Ft -BHI immunized (Figure 5B). IL-17 has been found to be protective against mucosal infections with bacteria including Ft (18, 19). Thus, higher IL-17 levels at early stages of infection correlate with superior protection afforded by i Ft -MHB compared to i Ft -BHI.…”

Section: Resultsmentioning

confidence: 99%

Differential Cultivation of Francisella tularensis Induces Changes in the Immune Response to and Protective Efficacy of Whole Cell-Based Inactivated Vaccines

et al. 2017

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Francisella tularensis (Ft) is a category A biothreat agent for which there is no Food and Drug Administration-approved vaccine. Ft can survive in a variety of habitats with a remarkable ability to adapt to changing environmental conditions. Furthermore, Ft expresses distinct sets of antigens (Ags) when inside of macrophages (its in vivo host) as compared to those grown in vitro with Mueller Hinton Broth (MHB). However, in contrast to MHB-grown Ft, Ft grown in Brain-Heart Infusion (BHI) more closely mimics the antigenic profile of macrophage-grown Ft. Thus, we anticipated that when used as a vaccine, BHI-grown Ft would provide better protection compared to MHB-grown Ft, primarily due to its greater antigenic similarity to Ft circulating inside the host (macrophages) during natural infection. Our investigation, however, revealed that inactivated Ft (iFt) grown in MHB (iFt-MHB) exhibited superior protective activity when used as a vaccine, as compared to iFt grown in BHI (iFt-BHI). The superior protection afforded by iFt-MHB compared to that of iFt-BHI was associated with significantly lower bacterial burden and inflammation in the lungs and spleens of vaccinated mice. Moreover, iFt-MHB also induced increased levels of Ft-specific IgG. Further evaluation of early immunological cues also revealed that iFt-MHB exhibits increased engagement of Ag-presenting cells including increased iFt binding to dendritic cells, increased expression of costimulatory markers, and increased secretion of pro-inflammatory cytokines. Importantly, these studies directly demonstrate that Ft growth conditions strongly impact Ft vaccine efficacy and that the growth medium used to produce whole cell vaccines to Ft must be a key consideration in the development of a tularemia vaccine.

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Section: Resultsmentioning

confidence: 99%

Differential Cultivation of Francisella tularensis Induces Changes in the Immune Response to and Protective Efficacy of Whole Cell-Based Inactivated Vaccines

et al. 2017

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“…ϩ T cell population not found in intradermally inoculated mice (2,8,9). We conclude that T cell effector function is influenced by the inoculation route.…”

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confidence: 81%

Identification of Early Interactions between Francisella and the Host

et al. 2014

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The adaptive immune response to Francisella tularensis is dependent on the route of inoculation. Intradermal inoculation with the F. tularensis live vaccine strain (LVS) results in a robust Th1 response in the lungs, whereas intranasal inoculation produces fewer Th1 cells and instead many Th17 cells. Interestingly, bacterial loads in the lungs are similar early after inoculation by these two routes. We hypothesize that the adaptive immune response is influenced by local events in the lungs, such as the type of cells that are first infected with Francisella. Using fluorescence-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.

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“…Treatment with recombinant IFN-γ decreases bacterial burdens further confirming the importance of IFN-γ for bacterial control (9). IL-17A is also important for bacterial control following intranasal inoculation as IL17a −/− and IL-17Ra −/− mice have increased LVS burden in the lung compared to wild-type B6 mice (10, 11). Furthermore, treatment with anti-IL-17A increases lung bacterial burdens compared to isotype control antibody treated mice and decreases the mean time to death (10, 12).…”

Section: Introductionmentioning

confidence: 99%

IFN-?, but not IL-17A, is required for survival during secondary pulmonary Francisella tularensis Live Vaccine Stain infection

Roberts

Davies

Sempowski³

et al. 2014

Vaccine

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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.

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Interleukin-17 Protects against the Francisella tularensis Live Vaccine Strain but Not against a Virulent F. tularensis Type A Strain

Cited by 26 publications

References 39 publications

Differential Cultivation of Francisella tularensis Induces Changes in the Immune Response to and Protective Efficacy of Whole Cell-Based Inactivated Vaccines

Differential Cultivation of Francisella tularensis Induces Changes in the Immune Response to and Protective Efficacy of Whole Cell-Based Inactivated Vaccines

Identification of Early Interactions between Francisella and the Host

IFN-?, but not IL-17A, is required for survival during secondary pulmonary Francisella tularensis Live Vaccine Stain infection

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