Bacterial virulence plays a crucial role in MRSA sepsis.
Bacterial virulence plays a crucial role in MRSA sepsis.
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细菌毒力在MRSA败血症中起着至关重要的作用。
DOI：
10.1371/journal.ppat.1009369
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发表时间：
2021-03
期刊：
影响因子：
6.7
通讯作者：
Otto M
中科院分区：
文献类型：
--
作者：
Cheung GYC;Bae JS;Liu R;Hunt RL;Zheng Y;Otto M
细菌性败血症是全球主要的死亡原因。然而，脓毒症的病理生理学仍然知之甚少。在工业化国家，金黄色葡萄球菌是导致败血症死亡的最常见病原体。由于抗生素耐药性的惊人传播，抗毒策略经常被提出治疗葡萄球菌脓毒症。然而，我们尚未完全了解细菌毒力是否以及如何导致败血症，这对于彻底评估此类策略至关重要。我们在此研究了耐甲氧西林金黄色葡萄球菌（MRSA）引起的小鼠和兔脓毒症模型中毒力和群体感应调节的作用。我们确定白细胞减少是脓毒症早期关键阶段疾病结局的预测因子。此外，器械相关感染是葡萄球菌血液感染中最常见的类型，群体感应缺陷导致死亡率显著升高。我们的研究结果为葡萄球菌脓毒症治疗的抗毒力药物开发策略提供了重要的指导。此外，通过揭示感染的关键早期阶段，细菌和白细胞之间的斗争决定了败血症的结果，它们大大增加了我们对细菌性败血症如何发展的理解。虽然败血症传统上主要归因于宿主因素，但我们的研究强调了入侵病原体及其毒力机制的关键作用。细菌感染常并发脓毒症。败血症是一种严重的血液感染，是导致死亡的主要原因之一，特别是在发达国家的医院。脓毒症被认为是由于对大多数细菌共有的结构的过度免疫反应。然而，这个模型无法解释为什么一些细菌比其他细菌更频繁和更严重地导致败血症。在我们的研究中，我们对主要的脓毒症细菌金黄色葡萄球菌进行了研究，我们表明脓毒症的结果取决于感染早期细菌和白细胞之间的战斗。细菌在这场战斗中使用的许多武器都是由群体感应调节器控制的，这意味着针对该调节器的所谓抗毒力策略可能对治疗败血症有效。然而，我们也表明，当脓毒症起源于植入导管上的生物膜时，靶向群体感应是适得其反的，而这种情况经常发生。我们的研究表明，细菌武器在败血症中起着关键作用，并为如何利用这一发现开发替代药物提供了重要建议。
Bacterial sepsis is a major global cause of death. However, the pathophysiology of sepsis has remained poorly understood. In industrialized nations, Staphylococcus aureus represents the pathogen most commonly associated with mortality due to sepsis. Because of the alarming spread of antibiotic resistance, anti-virulence strategies are often proposed to treat staphylococcal sepsis. However, we do not yet completely understand if and how bacterial virulence contributes to sepsis, which is vital for a thorough assessment of such strategies. We here examined the role of virulence and quorum-sensing regulation in mouse and rabbit models of sepsis caused by methicillin-resistant S. aureus (MRSA). We determined that leukopenia was a predictor of disease outcome during an early critical stage of sepsis. Furthermore, in device-associated infection as the most frequent type of staphylococcal blood infection, quorum-sensing deficiency resulted in significantly higher mortality. Our findings give important guidance regarding anti-virulence drug development strategies for the treatment of staphylococcal sepsis. Moreover, they considerably add to our understanding of how bacterial sepsis develops by revealing a critical early stage of infection during which the battle between bacteria and leukocytes determines sepsis outcome. While sepsis has traditionally been attributed mainly to host factors, our study highlights a key role of the invading pathogen and its virulence mechanisms. Bacterial infections often develop sepsis as a complication. Sepsis is a severe blood infection and one of the main reasons for death, especially in hospitals of the developed world. Sepsis is believed to be due to an overshooting immune reaction to structures that most bacteria share. However, this model fails to explain why some bacteria cause more frequent and severe sepsis than others. In our study, which we performed with the main sepsis-causing bacteria, Staphylococcus aureus, we show that the outcome of sepsis depends on the battle between bacteria and white blood cells that happens early during infection. Many of the weapons that bacteria use for that battle are controlled by a quorum-sensing regulator, which implies that so-called anti-virulence strategies directed at that regulator may work to treat sepsis. However, we also show that targeting quorum-sensing is counterproductive when sepsis originates from biofilms on implanted catheters, which it often does. Our study shows that bacterial weaponry plays a key role in sepsis and gives important advice on how to use this finding for alternative drug development.
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影响因子：
3.1
作者：
Altman DR;Sullivan MJ;Chacko KI;Balasubramanian D;Pak TR;Sause WE;Kumar K;Sebra R;Deikus G;Attie O;Rose H;Lewis M;Fulmer Y;Bashir A;Kasarskis A;Schadt EE;Richardson AR;Torres VJ;Shopsin B;van Bakel H
通讯作者：
van Bakel H
影响因子：
3.6
作者：
Alonzo F 3rd;Benson MA;Chen J;Novick RP;Shopsin B;Torres VJ
通讯作者：
Torres VJ
影响因子：
120.7
作者：
Boomer, Jonathan S.;To, Kathleen;Chang, Kathy C.;Takasu, Osamu;Osborne, Dale F.;Walton, Andrew H.;Bricker, Traci L.;Jarman, Stephen D., II;Kreisel, Daniel;Krupnick, Alexander S.;Srivastava, Anil;Swanson, Paul E.;Green, Jonathan M.;Hotchkiss, Richard S.
通讯作者：
Hotchkiss, Richard S.
影响因子：
6.7
作者：
Cheung GY;Kretschmer D;Duong AC;Yeh AJ;Ho TV;Chen Y;Joo HS;Kreiswirth BN;Peschel A;Otto M
通讯作者：
Otto M
影响因子：
6.4
作者：
Diep, Binh An;Stone, Gregory G.;Chambers, Henry F.
通讯作者：
Chambers, Henry F.