A LigA three-domain region protects hamsters from lethal infection by Leptospira interrogans.
A LigA three-domain region protects hamsters from lethal infection by Leptospira interrogans.
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DOI：
10.1371/journal.pntd.0001422
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发表时间：
2011-12
影响因子：
3.8
通讯作者：
Haake DA
中科院分区：
文献类型：
--
作者：
Coutinho ML;Choy HA;Kelley MM;Matsunaga J;Babbitt JT;Lewis MS;Aleixo JA;Haake DA
钩端螺旋体LigA蛋白由13个细菌免疫球蛋白样（Big）结构域组成，是唯一纯化的重组亚单位疫苗，已被证明可以在钩端螺旋体仓鼠模型中抵抗临床分离的疑问钩端螺旋体的致命攻击。我们确定了免疫保护所需的LigA结构域的最小数量和位置。发现需要免疫11和12域，但不足以提供保护。在用审问钩端螺旋体哥本哈根菌株Fiocruz L1-130腹腔内攻击后，需要包含第三结构域10或13，以达到100%的存活率。与之前的研究一样，幸存者有肾脏定植；在这里，我们通过qPCR定量钩端螺旋体负荷为1.2×103至8×105每微克肾DNA的钩端螺旋体DNA拷贝数。尽管幸存者的肾脏组织病理学显示小管间质改变表明对感染的炎症反应，但血液化学分析表明肾功能正常。这些研究确定了LigA的大结构域，说明了其疫苗效力，并强调需要其他策略来实现绝育免疫，以保护哺乳动物宿主免受钩端螺旋体感染及其后果。钩端螺旋体病是最广泛的细菌感染，通过宿主动物的肾脏携带细菌传播给人类。由钩端螺旋体这种细菌引起的人类感染，经常导致以黄疸和肾衰竭为特征的危及生命的疾病。迫切需要疫苗来预防高危人群的钩端螺旋体病。钩端螺旋体蛋白LigA是一种很有希望的候选疫苗，因为它是第一个被证明可以保护动物免受致命钩端螺旋体病的纯化蛋白。这项研究的目的是确定LigA的13个结构域中哪一个是保护作用所必需的。研究发现，需要免疫11和12域，但不足以提供保护。第三个域，10或13，是100%存活所必需的。与以前的研究一样，从幸存者的肾脏中培养残余细菌。然而，与以前的研究相反，我们确定了肾脏中细菌DNA的数量作为疫苗效力的衡量标准。我们还在显微镜下检查肾脏损伤的迹象，并测量血液化学来评估肾功能。这些都是朝着开发防止肾脏损伤和感染的疫苗迈出的重要一步。
The leptospiral LigA protein consists of 13 bacterial immunoglobulin-like (Big) domains and is the only purified recombinant subunit vaccine that has been demonstrated to protect against lethal challenge by a clinical isolate of Leptospira interrogans in the hamster model of leptospirosis. We determined the minimum number and location of LigA domains required for immunoprotection. Immunization with domains 11 and 12 was found to be required but insufficient for protection. Inclusion of a third domain, either 10 or 13, was required for 100% survival after intraperitoneal challenge with Leptospira interrogans serovar Copenhageni strain Fiocruz L1-130. As in previous studies, survivors had renal colonization; here, we quantitated the leptospiral burden by qPCR to be 1.2×103 to 8×105 copies of leptospiral DNA per microgram of kidney DNA. Although renal histopathology in survivors revealed tubulointerstitial changes indicating an inflammatory response to the infection, blood chemistry analysis indicated that renal function was normal. These studies define the Big domains of LigA that account for its vaccine efficacy and highlight the need for additional strategies to achieve sterilizing immunity to protect the mammalian host from leptospiral infection and its consequences. Leptospirosis is the most widespread bacterial infection transmitted to humans from host animals that harbor the bacteria in their kidneys. Human infections caused by the bacterium, Leptospira interrogans, frequently result in a life-threatening illness characterized by jaundice and kidney failure. Vaccines are urgently needed to prevent leptospirosis in populations at risk. The leptospiral protein, LigA, is a promising vaccine candidate because it is the first purified protein to be shown to protect animals from fatal leptospirosis. The goal of this study was to determine which of LigA's 13 domains are required for the protective effect. Immunization with domains 11 and 12 was found to be required, but was insufficient, for protection. A third domain, either 10 or 13, was required for 100% survival. As in previous studies, residual bacteria were cultured from the kidneys of survivors. However, in contrast to previous studies, we determined the amount of bacterial DNA in the kidneys as a measure of vaccine efficacy. We also examined the kidneys microscopically for signs of damage and measured blood chemistries to assess kidney function. These are important steps towards developing vaccines that provide protection from kidney damage and infection.
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