Protective efficacy of an attenuated Mtb ΔLprG vaccine in mice.
Protective efficacy of an attenuated Mtb ΔLprG vaccine in mice.
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DOI：
10.1371/journal.ppat.1009096
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发表时间：
2020-12
期刊：
影响因子：
6.7
通讯作者：
Barouch DH
中科院分区：
文献类型：
--
作者：
Martinot AJ;Blass E;Yu J;Aid M;Mahrokhian SH;Cohen SB;Plumlee CR;Larocca RA;Siddiqi N;Wakabayashi S;Gardner M;Audette R;Devorak A;Urdahl KB;Rubin EJ;Barouch DH
卡介苗（BCG）是一种基于牛分枝杆菌的减毒全细胞疫苗，是唯一获得许可的针对结核分枝杆菌（Mtb）的疫苗，但其疗效不佳，无法预防肺结核。我们先前报道了缺乏毒力基因lprG和rv1410c（Δ LprG）的Mtb在免疫缺陷小鼠中高度减毒。在这项研究中，我们表明减毒的Δ LprG Mtb保护C57 BL/6J、Balb/cJ和C3 HeB/FeJ小鼠免受Mtb攻击，并且在SCID小鼠中与BCG一样减毒。在C3HeB/FeJ小鼠中，Δ LprG疫苗接种导致先天性外周细胞因子产生，并诱导外周血中高水平的多克隆PPD特异性分泌精氨酸的CD4 + T淋巴细胞。Δ LprG疫苗在H37Rv和Erdman雾化Mtb攻击后在C3H/FeJ小鼠的肺中提供保护效力。疫苗效力与抗原特异性PD-1阴性CD4 + T淋巴细胞以及疫苗接种后血清IL-17水平相关。我们假设肺中Th17细胞的诱导对于疫苗保护是至关重要的，并且我们显示在疫苗接种后不久IL-17的血清细胞因子生物标志物可以预测保护效力。许多成功的疫苗是基于减毒的人类病原体。唯一获得许可的结核病疫苗BCG是基于活的全细胞牛分枝杆菌（Mycobacterium bovis）的减毒版本，牛结核病（TB）的病原体。使用减毒病原体作为疫苗的优点包括广泛的抗原组成，包括蛋白质、脂质、碳水化合物和其他分子，其可以诱导持久的免疫应答，有时持续数十年。在这里，我们测试了减毒结核分枝杆菌（Mtb），人类结核病的病原体，缺乏一个关键的毒力因子作为替代的全细胞疫苗在小鼠中。缺乏关键毒力蛋白LprG的减毒Mtb具有免疫原性并保护小鼠免受Mtb攻击。LprG全细胞疫苗在小鼠中具有保护性，所述小鼠发展出与人TB中描述的肺病理学更相似的肺病理学，并且LprG疫苗在接种后早期在外周血中诱导关键细胞因子IL-17，其被认为对疫苗保护重要。这些数据共同支持减毒结核病作为一种潜在的候选疫苗的继续发展。此外，我们的数据表明，血清IL-17应被探索作为一个潜在的生物标志物的疫苗疗效在临床前动物模型。
Bacille Calmette-Guerin (BCG), an attenuated whole cell vaccine based on Mycobacterium bovis, is the only licensed vaccine against Mycobacterium tuberculosis (Mtb), but its efficacy is suboptimal and it fails to protect against pulmonary tuberculosis. We previously reported that Mtb lacking the virulence genes lprG and rv1410c (ΔLprG) was highly attenuated in immune deficient mice. In this study, we show that attenuated ΔLprG Mtb protects C57BL/6J, Balb/cJ, and C3HeB/FeJ mice against Mtb challenge and is as attenuated as BCG in SCID mice. In C3HeB/FeJ mice, ΔLprG vaccination resulted in innate peripheral cytokine production and induced high polyclonal PPD-specific cytokine-secreting CD4+ T lymphocytes in peripheral blood. The ΔLprG vaccine afforded protective efficacy in the lungs of C3H/FeJ mice following both H37Rv and Erdman aerosolized Mtb challenges. Vaccine efficacy correlated with antigen-specific PD-1-negative CD4+ T lymphocytes as well as with serum IL-17 levels after vaccination. We hypothesize that induction of Th17 cells in lung is critical for vaccine protection, and we show a serum cytokine biomarker for IL-17 shortly after vaccination may predict protective efficacy. Many successful vaccines are based on attenuated human pathogens. The only licensed tuberculosis vaccine, BCG, is based on an attenuated version of live whole cell Mycobacterium bovis, the causative agent of tuberculosis (TB) in cattle. Advantages to using attenuated pathogens as vaccines include a broad antigen composition including proteins, lipids, carbohydrates and other molecules that can induce durable immune responses sometimes lasting decades. Here we test an attenuated Mycobacterium tuberculosis (Mtb), the causative agent of human TB, that lacks a key virulence factor as an alternative whole cell vaccine in mice. Attenuated Mtb lacking a key virulence protein, LprG, is immunogenic and protects mice against Mtb challenge. The LprG whole cell vaccine is protective in mice that develop lung pathology more similar to what is described in human TB and the LprG vaccine induces a key cytokine, IL-17, thought to be important for vaccine protection, in the peripheral blood early after vaccination. Together these data support the continued development of attenuated TB as a potential vaccine candidate. Furthermore our data suggests that serum IL-17 should be explored as a potential biomarker for vaccine efficacy in preclinical animal models.
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影响因子：
16.8
作者：
通讯作者：
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结核分枝杆菌对抗原呈递的调节：Toll 样受体的作用。
DOI：
10.1038/nrmicro2321
发表时间：
2010-04
期刊：
Nature reviews. Microbiology
影响因子：
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