Pan Genome Systems, Madison, WI 53719, USA; Department of Pathobiological Sciences, University of Wisconsin-Madison, Madison, WI 53706, USA.
Pan Genome Systems, Madison, WI 53719, USA.
Vaccine. 2014 Apr 11;32(18):2062-9. doi: 10.1016/j.vaccine.2014.02.010. Epub 2014 Feb 22.
Mycobacterium avium subspecies paratuberculosis (M. paratuberculosis) is the causative agent of Johne's disease in ruminants. Johne's disease has a severe economic impact on the dairy industry in the USA and worldwide. In an effort to combat this disease, we screened several transposon mutants that were attenuated in the murine model of paratuberculosis for the potential use as live attenuated vaccines. Using the murine model, two vaccine candidates (pgs1360, pgs3965 with mutations of fabG2_2 and umaA1, respectively) were at or below the limit of detection for tissue colonization suggesting their low level persistence and hence safety. Prior to challenge, both candidates induced a M. paratuberculosis-specific IFN-γ, an indication of eliciting cell-mediated immunity. Following challenge with a virulent strain of M. paratuberculosis, the two vaccine candidates significantly reduced bacterial colonization in organs with reduced histological scores compared to control animals. In addition, one of the vaccine candidates (pgs3965) also induced IL-17a, a cytokine associated with protective immunity in mycobacterial infection. Our analysis suggested that the pgs3965 vaccine candidate is a potential live-attenuated vaccine that could be tested further in ruminant models of paratuberculosis. The analysis also validated our screening strategy to identify effective vaccine candidates against intracellular pathogens.
分支杆菌亚种副结核分枝杆菌（M. paratuberculosis）是反刍动物中约翰氏病的病原体。约翰氏病对美国和全球的乳制品行业造成了严重的经济影响。为了对抗这种疾病，我们筛选了几种在副结核病的鼠模型中减毒的转座子突变体，以作为潜在的活减毒疫苗使用。使用鼠模型，两种候选疫苗（pgs1360 和 pgs3965，分别带有 fabG2_2 和 umaA1 的突变）在组织定植方面的检测水平以下，这表明它们的低水平持续存在，因此是安全的。在挑战之前，两种候选疫苗都诱导了 M. paratuberculosis 特异性 IFN-γ，这表明它们引发了细胞介导的免疫。用强毒的 M. paratuberculosis 菌株进行攻毒后，与对照组动物相比，两种候选疫苗均显著降低了器官中的细菌定植，且组织学评分降低。此外，其中一种候选疫苗（pgs3965）还诱导了 IL-17a，这是一种与分枝杆菌感染中的保护性免疫相关的细胞因子。我们的分析表明，pgs3965 候选疫苗是一种潜在的活减毒疫苗，可以在副结核病的反刍动物模型中进一步测试。该分析还验证了我们筛选有效针对细胞内病原体的疫苗候选物的策略。
