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Superior protection elicited by live-attenuated vaccines in the murine model of paratuberculosis

机译：减毒活疫苗在副结核病小鼠模型中产生的卓越保护

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Mycobacterium avium subspecies paratuberculosis (M. paratuberculosis) causes Johne's disease, a chronic enteric infection in ruminants with severe economic impact on the dairy industry in the USA and worldwide. Currently, available vaccines have limited protective efficacy against disease progression and does not prevent spread of the infection among animals. Because of their ability to elicit wide-spectrum immune responses, we adopted a live-attenuated vaccine approach based on a sigH knock-out strain of M. paratuberculosis (Delta sigH). Earlier analysis of the Delta sigH mutant in mice indicated their inadequate ability to colonize host tissues, unlike the isogenic wild-type strain, validating the role of this sigma factor in M. paratuberculosis virulence. In the present study, we evaluated the performance of the Delta sigH mutant compared to inactivated vaccine constructs in a vaccine/challenge model of murine paratuberculosis. The presented analysis indicated that Delta sigH mutant with or without QuilA adjuvant is capable of eliciting strong immune responses (such as interferon gamma-gamma, IFN-gamma) suggesting their immunogenicity and ability to potentially initiate effective vaccine-induced immunity. Following a challenge with virulent strains of M. paratuberculosis, Delta sigH conferred protective immunity as indicated by the reduced bacterial burden accompanied with reduced lesions in main body organs (liver, spleen and intestine) usually infected with M. paratuberculosis. More importantly, our data indicated better ability of the Delta sigH vaccine to confer protection compared to the inactivated vaccine constructs even with the presence of oil-adjuvant. Overall, our approach provides a rational basis for using live-attenuated mutant strains to develop improved vaccines that elicit robust immunity against this chronic infection. (C) 2015 Elsevier Ltd. All rights reserved.
机译：鸟分枝杆菌副结核分枝杆菌（M. paratuberculosis）引起约翰内氏病，这是反刍动物中的一种慢性肠感染，对美国和全世界的乳品业产生了严重的经济影响。当前，可用的疫苗对疾病进展的保护作用有限，并且不能防止感染在动物之间传播。由于它们具有引起广谱免疫反应的能力，我们采用了一种基于副结核分枝杆菌的sigH敲除菌株（Delta sigH）的减毒活疫苗方法。小鼠Delta sigH突变体的早期分析表明，它们与定基因野生型菌株不同，它们无法定植宿主组织，这证实了该sigma因子在副结核分枝杆菌毒力中的作用。在本研究中，我们评估了鼠副结核病疫苗/攻击模型中与灭活疫苗构建体相比的Delta sigH突变体的性能。提出的分析表明，具有或不具有QuilA佐剂的Delta sigH突变体都能引起强烈的免疫反应（例如干扰素γ-γ，IFN-γ），表明它们的免疫原性和潜在地启动有效的疫苗诱导的免疫力的能力。在用副结核分枝杆菌的强毒株攻击后，Delta sigH赋予了保护性免疫，如细菌负荷减少以及通常感染副结核分枝杆菌的主要器官（肝脏，脾脏和肠道）病变减少所表明的。更重要的是，我们的数据表明，即使存在油佐剂，与灭活的疫苗构建物相比，Delta sigH疫苗具有更好的保护能力。总体而言，我们的方法为使用减毒活突变株开发改良的疫苗提供了合理的基础，这些疫苗可引发针对这种慢性感染的强大免疫力。 （C）2015 Elsevier Ltd.保留所有权利。

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