Growth and Stress Tolerance Comprise Independent Metabolic Strategies Critical for Staphylococcus aureus Infection.
Growth and Stress Tolerance Comprise Independent Metabolic Strategies Critical for Staphylococcus aureus Infection.
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DOI：
10.1128/mbio.00814-21
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发表时间：
2021-06-29
期刊：
影响因子：
6.4
通讯作者：
Parker D
中科院分区：
文献类型：
--
作者：
Kim GL;Hooven TA;Norambuena J;Li B;Boyd JM;Yang JH;Parker D
金黄色葡萄球菌是导致高发病率和死亡率的重要病原体。虽然金黄色葡萄球菌产生许多致病的重要因子，但很少有被证实在金黄色葡萄球菌肺炎的发病机制中起作用。为了更好地了解金黄色葡萄球菌在气道中的发病机制所需的遗传元件，我们在急性小鼠肺炎模型中进行了无偏倚的全基因组转座子测序（Tn-seq）筛选。我们确定了136个基因在感染期间对细菌存活很重要，其中很大一部分涉及代谢过程。通过不同的体外和体内实验对80个缺失突变体进行表型分析，表明代谢与几个过程有关，包括生物膜的形成、生长和对宿主应激源的抗性。我们进一步验证了23个突变在肺炎中的重要性。多变量和主成分分析确定了两个关键的代谢机制，使气道感染，生长（例如，复制和形成生物膜的能力）和对宿主应激的抵抗力。为了进一步验证这些假设，我们研究了丙酮酸羧化酶的作用，丙酮酸羧化酶在多种感染模型中都很重要，并证实了生长与抵抗宿主细胞杀伤之间的联系。发病机制通常被理解为宿主-病原体的相互作用，使病原体能够中和宿主的免疫反应。我们用重要的细菌病原体金黄色葡萄球菌证明，微生物代谢影响体内感染的重要关键特征，独立于宿主免疫调节。
Staphylococcus aureus is an important pathogen that leads to high morbidity and mortality. Although S. aureus produces many factors important for pathogenesis, few have been validated as playing a role in the pathogenesis of S. aureus pneumonia. To gain a better understanding of the genetic elements required for S. aureus pathogenesis in the airway, we performed an unbiased genome-wide transposon sequencing (Tn-seq) screen in a model of acute murine pneumonia. We identified 136 genes important for bacterial survival during infection, with a high proportion involved in metabolic processes. Phenotyping 80 individual deletion mutants through diverse in vitro and in vivo assays demonstrated that metabolism is linked to several processes, which include biofilm formation, growth, and resistance to host stressors. We further validated the importance of 23 mutations in pneumonia. Multivariate and principal-component analyses identified two key metabolic mechanisms enabling infection in the airway, growth (e.g., the ability to replicate and form biofilms) and resistance to host stresses. As deep validation of these hypotheses, we investigated the role of pyruvate carboxylase, which was important across multiple infection models and confirmed a connection between growth and resistance to host cell killing. Pathogenesis is conventionally understood in terms of the host-pathogen interactions that enable a pathogen to neutralize a host’s immune response. We demonstrate with the important bacterial pathogen S. aureus that microbial metabolism influences key traits important for in vivo infection, independent from host immunomodulation.