Molecular mechanisms of pathogenesis in staphylococci

葡萄球菌发病机制的分子机制

• 批准号: 7592270
• 负责人: MICHAEL J OTTO
• 金额: $ 159.71万
• 依托单位: NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7592270
• 关键词: Anti-Bacterial Agents; Charge; Disease; Endopeptidases; Epithelial; Epithelium; Genome; Genus staphylococcus; Goals; Gram-Positive Bacteria; Host Defense; Human; Human body; Infection; Microbial Biofilms; Molecular; Pathogenesis; Peptide Hydrolases; Peptides; Phagocytes; Process; Proteins; Regulator Genes; Resistance; Role; Signal Transduction; Staphylococcus aureus; Staphylococcus epidermidis; Surface; System; Testing; Transducers; antimicrobial drug; antimicrobial peptide; bacterial resistance; beta-defensin 3; dermcidin; drug development; extracellular; microorganism; pathogen; resistance mechanism; response; sensor; sensory system; staphylococcal protease; success

In the past year, we have focussed on mechanisms that determine the interaction of staphylococci with innate host defense, specifically how S. epidermidis and S. aureus sense and respond to antibacterial peptides. To survive during colonization or infection of the human body, microorganisms must circumvent mechanisms of innate host defense. Antimicrobial peptides represent a key component of innate host defense, especially in phagocytes and on epithelial surfaces. However, it is not known how the clinically important group of Gram-positive bacteria sense antimicrobial peptides to coordinate a directed defensive response. By determining the genome-wide gene regulatory response to human beta defensin 3 in the nosocomial pathogen Staphylococcus epidermidis, we discovered an antimicrobial peptide sensor system that controls major specific resistance mechanisms of Gram-positive bacteria and is unrelated to the Gram-negative PhoP/PhoQ system. It contains a classical two-component signal transducer and an unusual third protein, all of which are indispensable for signal transduction and antimicrobial peptide resistance. Our study shows that Gram-positive bacteria have developed an efficient and unique way of controlling resistance mechanisms to antimicrobial peptides, which may provide a promising target for antimicrobial drug development. Moreover, we demonstrated that many antimicrobial peptides (including negatively charged peptides that do not activate the beforementioned sensory system) induced differential expression of global regulatory systems, leading to increased expression of proteases with the capacity to degrade antimicrobial peptides, particularly S. epidermidis SepA. A similar induction of extracellular proteolytic activity was found in S. aureus, suggesting a common regulatory mechanism in staphylococci. Notably, inactivation of dermcidin by SepA was much more effective than of the tested cationic peptides. The ability to react to the unusual, anionic dermcidin with effective countermeasures likely contributes to the extraordinary success of staphylococci as colonizers and infective agents on human epithelia. Our study indicates that staphylococci can react to human antimicrobial peptides by specific mechanisms of resistance and establishes a crucial role for staphylococcal proteases in the interaction with human innate host defense.

在过去的一年中，我们专注于确定葡萄球菌与先天宿主防御的相互作用的机制，特别是表皮链球菌和金黄色葡萄球菌如何感和对抗菌肽的反应。 为了在人体殖民或感染期间生存，微生物必须规避先天宿主防御的机制。抗菌肽是先天宿主防御的关键组成部分，尤其是在吞噬细胞和上皮表面上。但是，尚不清楚临床上重要的革兰氏阳性细菌如何感觉抗菌肽来协调定向的防御反应。通过确定全基因组调控对人β防御蛋白3的基因调节反应，在肾上腺病原体葡萄球菌表皮中，我们发现了一个抗菌肽传感器系统，该抗菌肽传感器系统控制着革兰氏阳性细菌的主要特异性耐药机制，并与Gram-Negation Phop/Phop Systems无关。它包含经典的两组分量信号传感器和不寻常的第三蛋白，所有这些蛋白对于信号转导和抗菌肽耐药性都是必不可少的。 我们的研究表明，革兰氏阳性细菌已经开发了一种有效且独特的方法来控制抗菌肽的抗性机制，这可能为抗菌药物发育提供了有希望的靶标。此外，我们证明，许多抗菌肽（包括未激活贝福德感觉系统的负电荷肽）诱导全球调节系统的差异表达，从而增加蛋白酶的表达增加，具有降解抗菌肽的能力，尤其是表皮链球菌SEPA。在金黄色葡萄球菌中发现了类似的细胞外蛋白水解活性的诱导，这表明葡萄球菌中具有常见的调节机制。值得注意的是，SEPA对Dermcidin的灭活比测试的阳离子肽的有效性要多得多。与有效对策的异常阴离子皮肤素反应的能力可能有助于葡萄球菌作为殖民者和感染剂对人上皮菌的非凡成功。我们的研究表明，葡萄球菌可以通过耐药的特定机制对人类抗菌肽反应，并在与人类先天宿主防御的相互作用中对葡萄球菌蛋白酶的相互作用确立至关重要的作用。