Brucella abortus Induces a Warburg Shift in Host Metabolism That Is Linked to Enhanced Intracellular Survival of the Pathogen
Brucella abortus Induces a Warburg Shift in Host Metabolism That Is Linked to Enhanced Intracellular Survival of the Pathogen
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DOI：
10.1128/jb.00227-17
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发表时间：
2017-08-01
影响因子：
3.2
通讯作者：
Crosson, Sean
中科院分区：
文献类型：
--
作者：
Czyz, Daniel M.;Willett, Jonathan W.;Crosson, Sean
胞内细菌病原体利用宿主细胞资源在宿主内复制和生存。靶向这些宿主系统是开发新型抗微生物药物治疗细胞内感染的一种有希望的方法。我们发现，感染了流产布鲁氏菌的人巨噬细胞样细胞发生代谢转变，其特征是三羧酸循环代谢减弱，氨基酸消耗减少，线粒体定位改变，乳酸生成增加。这种向有氧糖酵解状态的转变类似于Warburg效应，这是一种在癌细胞中很好地描述的能量产生的变化，也发生在活化的炎症细胞中。B. abortus有效地将乳酸作为其唯一的碳和能量来源，并需要代谢乳酸的能力才能在人类巨噬细胞样细胞中正常生存。我们证明了寄主糖酵解和乳酸生成的化学抑制剂不影响试管试管中B. abortus的体外生长，但会降低其在细胞内生态位中的存活率。我们的数据支持感染将宿主代谢转变为warburg样状态的模型，而B. abortus利用这种代谢变化来促进细胞内存活。对宿主细胞代谢的这些特征进行药理学扰动可能是抑制细胞内病原体感染的有效策略。布鲁氏菌属是细胞内致病菌，可引起包括家畜在内的多种哺乳动物的疾病。从牲畜到人类的传播很常见，并可导致慢性人类疾病。感染流产布鲁氏菌的人巨噬细胞样细胞经历warburg样代谢转变为有氧糖酵解状态，宿主细胞产生乳酸并减少氨基酸分解代谢。我们提供的证据表明，病原体可以利用宿主代谢的这种变化来支持细胞内生态位的生长和生存。在体外感染模型中，抑制宿主细胞代谢转变的药物抑制胞内复制并降低流产芽孢杆菌的存活；这些药物可能广泛用于治疗细胞内感染。
Intracellular bacterial pathogens exploit host cell resources to replicate and survive inside the host. Targeting these host systems is one promising approach to developing novel antimicrobials to treat intracellular infections. We show that human macrophage-like cells infected with Brucella abortus undergo a metabolic shift characterized by attenuated tricarboxylic acid cycle metabolism, reduced amino acid consumption, altered mitochondrial localization, and increased lactate production. This shift to an aerobic glycolytic state resembles the Warburg effect, a change in energy production that is well described in cancer cells and also occurs in activated inflammatory cells. B. abortus efficiently uses lactic acid as its sole carbon and energy source and requires the ability to metabolize lactate for normal survival in human macrophage-like cells. We demonstrate that chemical inhibitors of host glycolysis and lactate production do not affect in vitro growth of B. abortus in axenic culture but decrease its survival in the intracellular niche. Our data support a model in which infection shifts host metabolism to a Warburg-like state, and B. abortus uses this change in metabolism to promote intracellular survival. Pharmacological perturbation of these features of host cell metabolism may be a useful strategy to inhibit infection by intracellular pathogens.IMPORTANCE Brucella spp. are intracellular bacterial pathogens that cause disease in a range of mammals, including livestock. Transmission from livestock to humans is common and can lead to chronic human disease. Human macrophage-like cells infected with Brucella abortus undergo a Warburg-like metabolic shift to an aerobic glycolytic state where the host cells produce lactic acid and have reduced amino acid catabolism. We provide evidence that the pathogen can exploit this change in host metabolism to support growth and survival in the intracellular niche. Drugs that inhibit this shift in host cell metabolism inhibit intracellular replication and decrease the survival of B. abortus in an in vitro infection model; these drugs may be broadly useful therapeutics for intracellular infections.