Induction of type I interferon signaling determines the relative pathogenicity of Staphylococcus aureus strains.
Induction of type I interferon signaling determines the relative pathogenicity of Staphylococcus aureus strains.
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DOI：
10.1371/journal.ppat.1003951
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发表时间：
2014-02
期刊：
影响因子：
6.7
通讯作者：
Prince A
中科院分区：
文献类型：
--
作者：
Parker D;Planet PJ;Soong G;Narechania A;Prince A
金黄色葡萄球菌作为一种人类病原体之所以取得巨大成功，主要是因为它具有一系列毒力因子，使有机体能够逃避宿主免疫。也许同样重要但了解较少的是，宿主反应的强度在确定金黄色葡萄球菌感染引起的病理程度方面的重要性，特别是在肺炎的发病机制中。我们比较了由两种不同的金黄色葡萄球菌引起的感染的发病机制，这两种不同的金黄色葡萄球菌在人类中的行为已经得到很好的描述。菌株502a通过NOD2-IRF5途径诱导I型干扰素级联，是导致肺炎小鼠重症肺炎和死亡的主要因素，并与自溶和肽聚糖的释放有关。与USA300相比，502a在体外很容易从上皮表面清除。尽管如此，由于能够系统入侵并触发I型干扰素反应的微生物，502a导致组织损伤显著增加，这在Ifnar-/-小鼠中得到了改善。USA300能否成功引起侵袭性感染似乎取决于其对从上皮表面根除的抵抗力，而不是特定毒素的产生。我们的研究阐明了I型干扰素信号在物种中的重要和高度可变的作用，并表明对特定的先天免疫信号级联进行靶向免疫调节可能有助于防止金黄色葡萄球菌肺炎相关的过度发病率。金黄色葡萄球菌的毒力，特别是与流行的MRSA USA300菌株相关的毒力，主要是由其表达一组特定的毒力因子来解释的。我们推测，由特定葡萄球菌菌株激活的宿主先天免疫反应的强度在决定感染的严重程度方面也是至关重要的。通过比较两个不同的金黄色葡萄球菌菌株，USA300与侵袭性疾病相关，502A主要与表面定植相关，我们发现毒力与菌株刺激I型干扰素途径的能力直接相关。与USA300相关的发病率和死亡率可能归因于它对粘膜表面的杀伤耐受；一旦通过上皮屏障，它引起的病理比502A更少。相比之下，尽管502a更容易被上皮抗菌因子杀死，但一旦进入肺部，它在急性肺炎小鼠模型中引起的病理明显更多。这些观察表明，调节宿主对感染的反应可能有助于预防一些与金黄色葡萄球菌肺炎相关的疾病。
The tremendous success of S. aureus as a human pathogen has been explained primarily by its array of virulence factors that enable the organism to evade host immunity. Perhaps equally important, but less well understood, is the importance of the intensity of the host response in determining the extent of pathology induced by S. aureus infection, particularly in the pathogenesis of pneumonia. We compared the pathogenesis of infection caused by two phylogenetically and epidemiologically distinct strains of S. aureus whose behavior in humans has been well characterized. Induction of the type I IFN cascade by strain 502A, due to a NOD2-IRF5 pathway, was the major factor in causing severe pneumonia and death in a murine model of pneumonia and was associated with autolysis and release of peptidogylcan. In contrast to USA300, 502A was readily eliminated from epithelial surfaces in vitro. Nonetheless, 502A caused significantly increased tissue damage due to the organisms that were able to invade systemically and trigger type I IFN responses, and this was ameliorated in Ifnar -/- mice. The success of USA300 to cause invasive infection appears to depend upon its resistance to eradication from epithelial surfaces, but not production of specific toxins. Our studies illustrate the important and highly variable role of type I IFN signaling within a species and suggest that targeted immunomodulation of specific innate immune signaling cascades may be useful to prevent the excessive morbidity associated with S. aureus pneumonia. The virulence of the S. aureus, and especially that associated with the epidemic MRSA USA300 strains, has been primarily explained by its expression of a specific set of virulence factors. We postulated that that intensity of the host innate immune response activated by specific staphylococcal strains is also critical in determining the severity of infection. By comparing two divergent S. aureus strains, USA300, associated with invasive disease, and 502A, primarily associated with surface colonization, we found that virulence was directly associated with the ability of a strain to stimulate the type I interferon pathway. The morbidity and mortality associated with USA300 could be attributed to its resistance to killing at mucosal surfaces; once past the epithelial barrier it caused less pathology than 502A. In contrast, although 502A was more readily killed by epithelial antimicrobial factors, once into the lung, it caused significantly more pathology in a mouse model of acute pneumonia. These observations suggest that modulating the host response to infection may be useful in preventing some of the disease associated with S. aureus pneumonia.
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影响因子：
6.7
作者：
Pandey AK;Yang Y;Jiang Z;Fortune SM;Coulombe F;Behr MA;Fitzgerald KA;Sassetti CM;Kelliher MA
通讯作者：
Kelliher MA
影响因子：
11.8
作者：
Macia, Eric;Ehrlich, Marcelo;Kirchhausen, Tomas
通讯作者：
Kirchhausen, Tomas
影响因子：
6.4
作者：
Parker D;Martin FJ;Soong G;Harfenist BS;Aguilar JL;Ratner AJ;Fitzgerald KA;Schindler C;Prince A
通讯作者：
Prince A
影响因子：
158.5
作者：
Huang, Susan S.;Septimus, Edward;Platt, Richard
通讯作者：
Platt, Richard
DOI：
10.1165/rcmb.2011-0011rt
发表时间：
2011-08-01
影响因子：
6.4
作者：
Parker, Dane;Prince, Alice
通讯作者：
Prince, Alice