South Texas Center for Emerging Infectious Diseases and Center of Excellence in Infection Genomics, University of Texas at San Antonio, San Antonio, Texas, USA.
Infect Immun. 2012 Jun;80(6):2177-85. doi: 10.1128/IAI.00036-12. Epub 2012 Apr 9.
A licensed vaccine against Francisella tularensis is currently not available. Two Francisella tularensis subsp. novicida (herein referred to by its earlier name, Francisella novicida) attenuated strains, the ΔiglB and ΔfopC strains, have previously been evaluated as potential vaccine candidates against pneumonic tularemia in experimental animals. F. novicida ΔiglB, a Francisella pathogenicity island (FPI) mutant, is deficient in phagosomal escape and intracellular growth, whereas F. novicida ΔfopC, lacking the outer membrane lipoprotein FopC, which is required for evasion of gamma interferon (IFN-γ)-mediated signaling, is able to escape and replicate in the cytosol. To dissect the difference in protective immune mechanisms conferred by these two vaccine strains, we examined the efficacy of the F. novicida ΔiglB and ΔfopC mutants against pulmonary live-vaccine-strain (LVS) challenge and found that both strains provided comparable protection in wild-type, major histocompatibility complex class I (MHC I) knockout, and MHC II knockout mice. However, F. novicida ΔfopC-vaccinated but not F. novicida ΔiglB-vaccinated perforin-deficient mice were more susceptible and exhibited greater bacterial burdens than similarly vaccinated wild-type mice. Moreover, perforin produced by natural killer (NK) cells and release of granzyme contributed to inhibition of LVS replication within macrophages. This NK cell-mediated LVS inhibition was enhanced with anti-F. novicida ΔfopC immune serum, suggesting antibody-dependent cell-mediated cytotoxicity (ADCC) in F. novicida ΔfopC-mediated protection. Overall, this study provides additional immunological insight into the basis for protection conferred by live attenuated F. novicida strains with different phenotypes and supports further investigation of this organism as a vaccine platform for tularemia.
目前，尚无针对土拉弗朗西斯菌的许可疫苗。两种土拉弗朗西斯菌亚种 novicida（以前称为弗朗西斯菌 novicida）减毒菌株，ΔiglB 和 ΔfopC 菌株，此前已被评估为实验动物中预防肺炎性土拉弗朗西斯菌的潜在候选疫苗。F. novicida ΔiglB 是一种弗朗西斯菌致病岛（FPI）突变体，在吞噬体逃逸和细胞内生长方面存在缺陷，而 F. novicida ΔfopC 缺乏外膜脂蛋白 FopC，该蛋白对于逃避 γ干扰素（IFN-γ）介导的信号传导是必需的，能够逃避并在细胞质中复制。为了剖析这两种疫苗菌株赋予的保护性免疫机制的差异，我们检查了 F. novicida ΔiglB 和 ΔfopC 突变体对肺活疫苗株（LVS）挑战的功效，发现两种菌株在野生型、主要组织相容性复合体 I（MHC I）敲除和 MHC II 敲除小鼠中均提供了相当的保护。然而，与同样接种的野生型小鼠相比，穿孔蛋白缺陷型小鼠接种 F. novicida ΔfopC 但不接种 F. novicida ΔiglB 的小鼠更容易受到感染，并且细菌负荷更高。此外，自然杀伤（NK）细胞产生的穿孔蛋白和颗粒酶的释放有助于抑制巨噬细胞内的 LVS 复制。这种 NK 细胞介导的 LVS 抑制作用随着抗 F. novicida ΔfopC 免疫血清的增加而增强，表明在 F. novicida ΔfopC 介导的保护中存在抗体依赖性细胞介导的细胞毒性（ADCC）。总体而言，这项研究为具有不同表型的活减毒 F. novicida 菌株赋予保护的基础提供了额外的免疫学见解，并支持进一步研究该生物体作为土拉弗朗西斯菌疫苗平台。
