Live attenuated Francisella novicida vaccine protects against Francisella tularensis pulmonary challenge in rats and non-human primates.
Live attenuated Francisella novicida vaccine protects against Francisella tularensis pulmonary challenge in rats and non-human primates.
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DOI：
10.1371/journal.ppat.1004439
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发表时间：
2014-10
期刊：
影响因子：
6.7
通讯作者：
Klose KE
中科院分区：
文献类型：
--
作者：
Chu P;Cunningham AL;Yu JJ;Nguyen JQ;Barker JR;Lyons CR;Wilder J;Valderas M;Sherwood RL;Arulanandam BP;Klose KE
土拉热弗朗西丝菌引起土拉菌病。人体肺部暴露于最致命的形式，F。土拉热亚种土拉热菌（Ftt）导致高发病率和死亡率，导致这种细菌被归类为潜在的生物威胁剂。然而，一个密切相关的物种，F。novicida在健康人体内是无毒的。目前还没有兔热病疫苗被批准用于人类。我们证明，单剂量活减毒F。使用两种不同的动物模型，Fischer 344大鼠和食蟹猴（NHP），novicida菌株（Fn iglD）保护免受随后的Ftt肺攻击。Fn iglD疫苗在大鼠中显示出保护性功效，如Ftt iglD疫苗一样，表明利用低人毒性弗朗西斯菌属物种诱导保护性免疫没有缺点。通过蛋白质组阵列比较接种疫苗的大鼠和NHP血清中的特异性抗体谱，在接种疫苗的动物中鉴定了一组核心免疫显性抗原。这是第一份关于确定的减毒活疫苗的报告，该疫苗证实了对NHP中肺兔热病的有效性，并表明低人类毒力F。novicida作为有效的兔热病疫苗平台发挥作用。 土拉热弗朗西丝菌是一种引起土拉菌病的细菌。F.土拉热已被开发为一种生物威胁剂，因为它通过气溶胶传播时造成高发病率和死亡率。目前还没有批准用于人类的疫苗，使人类容易受到非法使用这种生物体的影响。F.土拉热菌在弗朗西斯菌致病性岛（FPI）中含有宿主巨噬细胞内复制和毒力所需的基因簇。在目前的研究中，我们通过灭活FPI基因iglD，在一个不引起人类疾病的密切相关的物种，F。novicida（Fn iglD）。我们证明了接种Fn iglD可防止暴露于空气中的F。土拉热。Fn iglD疫苗接种诱导抗体和细胞免疫应答，并保护两种不同的动物（大鼠和非人灵长类动物）免受致死性肺兔热病攻击。这两种动物模型反映了人类对F.土拉热。我们的研究结果表明，从低毒力F。novicida将保护人类免受这种危险病原体的气溶胶暴露。
Francisella tularensis causes the disease tularemia. Human pulmonary exposure to the most virulent form, F. tularensis subsp. tularensis (Ftt), leads to high morbidity and mortality, resulting in this bacterium being classified as a potential biothreat agent. However, a closely-related species, F. novicida, is avirulent in healthy humans. No tularemia vaccine is currently approved for human use. We demonstrate that a single dose vaccine of a live attenuated F. novicida strain (Fn iglD) protects against subsequent pulmonary challenge with Ftt using two different animal models, Fischer 344 rats and cynomolgus macaques (NHP). The Fn iglD vaccine showed protective efficacy in rats, as did a Ftt iglD vaccine, suggesting no disadvantage to utilizing the low human virulent Francisella species to induce protective immunity. Comparison of specific antibody profiles in vaccinated rat and NHP sera by proteome array identified a core set of immunodominant antigens in vaccinated animals. This is the first report of a defined live attenuated vaccine that demonstrates efficacy against pulmonary tularemia in a NHP, and indicates that the low human virulence F. novicida functions as an effective tularemia vaccine platform. Francisella tularensis is a bacterium that causes the infectious disease tularemia. F. tularensis has been developed as a biothreat agent, because it causes high morbidity and mortality when spread by aerosol. There is currently no approved vaccine for human use, making mankind vulnerable to the illicit use of this organism. F. tularensis contains a cluster of genes in the Francisella Pathogenicity Island (FPI) that are required for replication inside host macrophages and virulence. In the current study we created a live vaccine strain by inactivating an FPI gene, iglD, in a closely-related species that does not cause disease in humans, F. novicida (Fn iglD). We demonstrate that vaccination with Fn iglD protects against exposure to airborne F. tularensis. Fn iglD vaccination induces antibody and cellular immune responses and protects two different animals, rats and non-human primates, against lethal pulmonary tularemia challenges. These two animal models reflect human sensitivity to F. tularensis. Our results suggest that a vaccine made from the low virulence F. novicida will protect humans against aerosol exposure to this dangerous pathogen.
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影响因子：
3.2
作者：
Nano, FE;Zhang, N;Elkins, KL
通讯作者：
Elkins, KL
影响因子：
3.1
作者：
Golovliov, I;Baranov, V;Sjöstedt, A
通讯作者：
Sjöstedt, A
影响因子：
4.4
作者：
Rodriguez, Stephen A.;Yu, Jieh-Juen;Klose, Karl E.
通讯作者：
Klose, Karl E.
影响因子：
3.1
作者：
Salomonsson, Emelie;Kuoppa, Kerstin;Forsberg, Ake
通讯作者：
Forsberg, Ake
影响因子：
3.1
作者：
SCHRICKER, RL;HALL, WC;EIGELSBACH, HT
通讯作者：
EIGELSBACH, HT