The glycerol-3-phosphate dehydrogenases GpsA and GlpD constitute the oxidoreductive metabolic linchpin for Lyme disease spirochete host infectivity and persistence in the tick.
The glycerol-3-phosphate dehydrogenases GpsA and GlpD constitute the oxidoreductive metabolic linchpin for Lyme disease spirochete host infectivity and persistence in the tick.
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DOI：
10.1371/journal.ppat.1010385
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发表时间：
2022-03
期刊：
影响因子：
6.7
通讯作者：
Samuels DS
中科院分区：
文献类型：
--
作者：
Drecktrah D;Hall LS;Crouse B;Schwarz B;Richards C;Bohrnsen E;Wulf M;Long B;Bailey J;Gherardini F;Bosio CM;Lybecker MC;Samuels DS
我们已经确定了GpsA，一种预测的甘油-3-磷酸脱氢酶，作为莱姆病螺旋体伯氏疏螺旋体的毒力因子：GpsA是小鼠感染所必需的，对蜱虫中螺旋体的持久性至关重要。B。伯氏螺旋体具有有限的生物合成和代谢能力;连接中心碳水化合物和脂质代谢的关键是由GpsA和另一种甘油-3-磷酸脱氢酶GlpD催化的甘油-3-磷酸和二羟丙酮磷酸的相互转化。使用广泛的代谢组学方法，我们发现，GpsA作为一个主要的调节剂的NADH和甘油-3-磷酸水平在体外，代谢中间体，反映了细胞的氧化还原电位，并作为前体的脂质和脂蛋白的生物合成，分别。此外，GpsA是营养胁迫下生存所必需的，调节整体还原酶活性并控制B。离体Burgdorferi形态学。此外，在体外营养胁迫期间，甘油和N-乙酰氨基葡萄糖对B都具有杀菌作用。Burgdorferi以GlpD依赖的方式。这项研究也是第一次在B中鉴定出抑制突变。burgdorferi：glpD缺失使野生型表型恢复为多效性gpsA突变体，包括通过高剂量针接种的鼠感染性、营养应激下的存活、形态学变化以及NADH和甘油-3-磷酸的代谢失衡。这些结果说明了体外生长所必需的基本代谢功能如何对B的体内感染性至关重要。并且可以作为有吸引力的治疗靶点。莱姆病（疏螺旋体病）是北方最常见的蜱传疾病，其患病率正在上升。莱姆病的病原体伯氏疏螺旋体（Borrelia burgdorferi）是在蜱媒介和脊椎动物宿主之间交替的地方病病原体。人类被认为是B传播后的偶然宿主。被受感染的蜱虫叮咬后出现伯氏症。B.伯氏螺旋体在硬蜱中持续存在，传播到脊椎动物宿主并建立感染尚不清楚。因此，确定毒力因子和揭示螺旋体的致病策略仍然是重要的，以解决莱姆病的公共卫生问题。在这项研究中，我们确定了一种参与三碳代谢的酶，GpsA，作为一种新的毒力因子，对蜱的持久性有影响。GpsA和GlpD（另一种酶）构成连接脂质生物合成和糖酵解的双向代谢节点，其充当调节B的碳利用的关键。burgdorferi在其整个地方病周期。这个节点的破坏会导致致命的代谢失衡，揭示了莱姆病治疗的潜在治疗靶点。
We have identified GpsA, a predicted glycerol-3-phosphate dehydrogenase, as a virulence factor in the Lyme disease spirochete Borrelia (Borreliella) burgdorferi: GpsA is essential for murine infection and crucial for persistence of the spirochete in the tick. B. burgdorferi has a limited biosynthetic and metabolic capacity; the linchpin connecting central carbohydrate and lipid metabolism is at the interconversion of glycerol-3-phosphate and dihydroxyacetone phosphate, catalyzed by GpsA and another glycerol-3-phosphate dehydrogenase, GlpD. Using a broad metabolomics approach, we found that GpsA serves as a dominant regulator of NADH and glycerol-3-phosphate levels in vitro, metabolic intermediates that reflect the cellular redox potential and serve as a precursor for lipid and lipoprotein biosynthesis, respectively. Additionally, GpsA was required for survival under nutrient stress, regulated overall reductase activity and controlled B. burgdorferi morphology in vitro. Furthermore, during in vitro nutrient stress, both glycerol and N-acetylglucosamine were bactericidal to B. burgdorferi in a GlpD-dependent manner. This study is also the first to identify a suppressor mutation in B. burgdorferi: a glpD deletion restored the wild-type phenotype to the pleiotropic gpsA mutant, including murine infectivity by needle inoculation at high doses, survival under nutrient stress, morphological changes and the metabolic imbalance of NADH and glycerol-3-phosphate. These results illustrate how basic metabolic functions that are dispensable for in vitro growth can be essential for in vivo infectivity of B. burgdorferi and may serve as attractive therapeutic targets. Lyme disease (borreliosis) is the most common tick-borne disease in the Northern hemisphere and its prevalence is increasing. Borrelia burgdorferi, the etiological agent of Lyme disease, is an enzootic pathogen that alternates between a tick vector and vertebrate host. Humans are considered an incidental host after transmission of B. burgdorferi following the bite of an infected tick. The mechanisms by which B. burgdorferi persists in the Ixodid tick, transmits to a vertebrate host and establishes infection are not well understood. Therefore, identifying virulence factors and uncovering the pathogenic strategies in the spirochete remain important to address the public health concerns of Lyme disease. In this study, we identify an enzyme involved in three-carbon metabolism, GpsA, as a new virulence factor with an effect on persistence in ticks. GpsA and GlpD, another enzyme, constitute a bidirectional metabolic node connecting lipid biosynthesis and glycolysis, which serves as the linchpin for regulating carbon utilization for B. burgdorferi throughout its enzootic cycle. Disruption of this node causes a lethal metabolic imbalance revealing a potential therapeutic target for the treatment of Lyme disease.
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