Production of an attenuated phenol-soluble modulin variant unique to the MRSA clonal complex 30 increases severity of bloodstream infection.
Production of an attenuated phenol-soluble modulin variant unique to the MRSA clonal complex 30 increases severity of bloodstream infection.
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DOI：
10.1371/journal.ppat.1004298
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发表时间：
2014-08
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 GY;Kretschmer D;Duong AC;Yeh AJ;Ho TV;Chen Y;Joo HS;Kreiswirth BN;Peschel A;Otto M
耐甲氧西林金黄色葡萄球菌（MRSA）是发病和死亡的主要原因。酚可溶性调节蛋白（PSM）是最近发现的毒素，对金黄色葡萄球菌感染的发展具有关键影响。PSM的等位基因变体及其在感染期间对病原体成功的潜在影响尚未被描述。我们发现，克隆复合物（CC）30谱系是医院相关性脓毒症和血源性并发症的主要原因，表达PSMα3肽的等位基因变体。我们发现这种变体PSMα 3N22 Y是CC30菌株的特征，具有显著降低的细胞溶解和促炎潜力。值得注意的是，与基因组改变以表达非CC30 PSMα3的菌株相比，CC30菌株对人中性粒细胞的细胞溶解和趋化潜力降低，菌血症模型中的血源性接种增加。我们的研究结果描述了一个分子机制，有助于衰减的促炎潜力在一个主要的MRSA谱系。他们认为，通过PSM减少病原体识别可以使细菌在血流感染期间逃避先天宿主防御的消除。此外，他们强调了关键S点突变的作用。金黄色葡萄球菌毒素基因在适应中作用以及PSM在确定关键S.金黄色葡萄球菌的免疫逃避和毒力机制。耐甲氧西林金黄色葡萄球菌（MRSA）是致病和致死的主要原因，也是公共卫生的一个重要问题。CC30 MRSA谱系尤其因引起血液感染并发症而臭名昭著，如播种到器官中。在我们的研究中，我们表明，这一谱系产生了一种衰减形式的关键S。具有降低的促炎特征的金黄色葡萄球菌毒素。我们的研究结果表明，这种毒素的衰减允许细菌逃避宿主防御的识别和随后的消除，从而增加血液感染期间病原体的成功。
Methicillin-resistant Staphylococcus aureus (MRSA) is a leading cause of morbidity and death. Phenol-soluble modulins (PSMs) are recently-discovered toxins with a key impact on the development of Staphylococcus aureus infections. Allelic variants of PSMs and their potential impact on pathogen success during infection have not yet been described. Here we show that the clonal complex (CC) 30 lineage, a major cause of hospital-associated sepsis and hematogenous complications, expresses an allelic variant of the PSMα3 peptide. We found that this variant, PSMα3N22Y, is characteristic of CC30 strains and has significantly reduced cytolytic and pro-inflammatory potential. Notably, CC30 strains showed reduced cytolytic and chemotactic potential toward human neutrophils, and increased hematogenous seeding in a bacteremia model, compared to strains in which the genome was altered to express non-CC30 PSMα3. Our findings describe a molecular mechanism contributing to attenuated pro-inflammatory potential in a main MRSA lineage. They suggest that reduced pathogen recognition via PSMs allows the bacteria to evade elimination by innate host defenses during bloodstream infections. Furthermore, they underscore the role of point mutations in key S. aureus toxin genes in that adaptation and the pivotal importance PSMs have in defining key S. aureus immune evasion and virulence mechanisms. Methicillin-resistant Staphylococcus aureus (MRSA) is a major cause of morbidity and mortality and a great concern for public health. The CC30 MRSA lineage is especially notorious for causing bloodstream infections with complications such as seeding into organs. In our study, we show that this lineage produces an attenuated form of a key S. aureus toxin with decreased pro-inflammatory features. Our results suggest that attenuation of this toxin allows the bacteria to evade recognition and subsequent elimination by host defenses, thereby increasing pathogen success during blood infection.
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DOI：
10.1016/j.ijmm.2013.02.007
发表时间：
2013-08
期刊：
International journal of medical microbiology : IJMM
影响因子：
--
作者：
Otto M
通讯作者：
Otto M
影响因子：
4.8
作者：
Joo, Hwang-Soo;Cheung, Gordon Y. C.;Otto, Michael
通讯作者：
Otto, Michael
影响因子：
6.4
作者：
Fowler, Vance G., Jr.;Nelson, Charlotte L.;Gill, Steven R.
通讯作者：
Gill, Steven R.
影响因子：
5.5
作者：
Holzinger, Dirk;Gieldon, Laura;Loeffler, Bettina
通讯作者：
Loeffler, Bettina
影响因子：
6.4
作者：
Kobayashi, Scott D.;Malachowa, Natalia;DeLeo, Frank R.
通讯作者：
DeLeo, Frank R.