Department of Immunology & Microbial Disease, Albany Medical College, Albany, NY, United States of America.
PLoS One. 2018 Dec 11;13(12):e0207587. doi: 10.1371/journal.pone.0207587. eCollection 2018.
Francisella tularensis (Ft) is a biothreat agent for which there is no FDA-approved human vaccine. Currently, there are substantial efforts underway to develop both vaccines and the tools to assess these vaccines. Tularemia laboratory research has historically relied primarily upon a small number of inbred mouse strains, but the utility of such findings to outbred animals may be limited. Specifically, C57BL/6 mice are more susceptible than BALB/c mice to Ft infection and less easily protected against challenge with highly virulent type A Ft. Thus, depending on the inbred mouse strain used, one could be misled as to which immunogen(s)/vaccine will ultimately be effective in an outbred human population. Accordingly, we evaluated an outbred Swiss Webster (SW) mouse model in direct comparison to a well-established, inbred C57BL/6 mouse model. Mucosal vaccination with the live, attenuated Ft LVS superoxide dismutase (sodB) mutant demonstrated significantly higher protection in outbred SW mice compared to inbred C57BL/6 mice against Ft SchuS4 respiratory challenge. The protection observed in vaccinated outbred mice correlated with lower bacterial density, reduced tissue inflammation, and reduced levels of pro-inflammatory cytokine production. This protection was CD4+ and CD8+ T cell-dependent and characterized by lower titers of serum antibody (Ab) that qualitatively differed from vaccinated inbred mice. Enhanced protection of vaccinated outbred mice correlated with early and robust production of IFN-γ and IL-17A. Neutralizing Ab administered at the time of challenge revealed that IFN-γ was central to this protection, while IL-17A neutralization did not alter bacterial burden or survival. The present study demonstrates the utility of the outbred mouse as an alternative vaccination model for testing tularemia vaccines. Given the limited MHC repertoire in inbred mice, this outbred model is more analogous to the human in terms of immunological diversity.
弗朗西斯菌（Ft）是一种生物威胁剂，目前还没有获得 FDA 批准的人类疫苗。目前，人们正在大力开发疫苗和评估这些疫苗的工具。 历史上， 兔热病实验室研究主要依赖于少数近交系小鼠品系，但这些发现对于杂种动物的应用可能有限。具体来说，C57BL/6 小鼠比 BALB/c 小鼠更容易感染 Ft，并且更难用高毒力的 A 型 Ft 进行挑战保护。因此，根据使用的近交系小鼠品系，人们可能会对哪种免疫原/疫苗最终在杂种人群中有效产生误解。因此，我们评估了一种近交系瑞士 Webster (SW) 小鼠模型与一种成熟的近交系 C57BL/6 小鼠模型的直接比较。用活的、减毒的 Ft LVS 超氧化物歧化酶（sodB）突变体进行粘膜接种，与近交系 C57BL/6 小鼠相比，在 Ft SchuS4 呼吸道挑战中，对 SW 杂合小鼠的保护作用显著提高。在接种疫苗的杂合小鼠中观察到的保护作用与较低的细菌密度、减少的组织炎症和减少的促炎细胞因子产生相关。这种保护作用依赖于 CD4+和 CD8+T 细胞，并表现为血清抗体（Ab）滴度较低，与接种的近交系小鼠不同。接种疫苗的杂合小鼠的保护作用增强与 IFN-γ和 IL-17A 的早期和强烈产生相关。在挑战时给予中和 Ab 表明 IFN-γ是这种保护的关键，而 IL-17A 中和不改变细菌负荷或存活。本研究证明了近交系作为测试兔热病疫苗的替代疫苗模型的效用。鉴于近交系小鼠 MHC 谱有限，这种近交系模型在免疫学多样性方面更类似于人类。
