Department of Pediatrics, University of California San Diego, La Jolla, CA, USA.
Biomedical Sciences Graduate Program, University of California San Diego, La Jolla, CA, USA.
J Mol Med (Berl). 2017 Oct;95(10):1127-1136. doi: 10.1007/s00109-017-1579-4. Epub 2017 Aug 26.
Pseudomonas aeruginosa is an important opportunistic pathogen that has become a serious problem due to increased rates of antibiotic resistance. Due to this along with a dearth in novel antibiotic development, especially against Gram-negative pathogens, new therapeutic strategies are needed to prevent a post-antibiotic era. Here, we describe the importance of the vacJ/Mla pathway in resisting bactericidal actions of the host innate immune response. P. aeruginosa tn5 transposon mutants in genes from the VacJ/Mla pathway showed increased susceptibility to killing by the host cathelicidin antimicrobial peptide, LL-37, when compared to the wild-type parent strain. The P. aeruginosa vacJ mutant demonstrated increased membrane permeability upon damage as well as sensitivity to killing in the presence of the detergent sodium dodecyl sulfate and the divalent cation chelator EDTA. When exposed to human whole blood and serum complement, the vacJ mutant was killed more rapidly when compared to the wild-type parent strain and complemented mutant. Finally, in an in vivo mouse lung infection model, infection with the vacJ mutant resulted in reduced mortality, lower bacterial burden, and reduced lung damage when compared to the wild-type strain. This study highlights the potential in therapeutically targeting the VacJ/Mla pathway in sensitizing P. aeruginosa to killing by the host innate immune response.
• The Mla pathway regulates outer membrane dynamics in human pathogen Pseudomonas aeruginosa (PA). • Disruption of Mla pathway gene vacJ sensitizes PA to host cathelicidin antimicrobial peptide LL-37. • Loss of vacJ expression renders PA more sensitive to human whole blood and serum killing. • Loss of vacJ expression reduces PA survival and virulence in a murine lung infection model. • The Mla pathway merits exploration as a pharmacologic target to sensitize PA to host innate immunity.
铜绿假单胞菌是一种重要的机会性病原体，由于抗生素耐药率的增加，它已成为一个严重的问题。由于这一点以及新型抗生素，特别是针对革兰氏阴性病原体的抗生素的开发不足，需要新的治疗策略来防止抗生素后时代的到来。在这里，我们描述了 VacJ/Mla 途径在抵抗宿主固有免疫反应杀菌作用中的重要性。与野生型亲本菌株相比，铜绿假单胞菌 tn5 转座子突变体在 VacJ/Mla 途径中的基因对宿主抗菌肽 LL-37 的杀伤作用表现出更高的敏感性。铜绿假单胞菌 vacJ 突变体在受到损伤时表现出更高的膜通透性，并且在去污剂十二烷基硫酸钠和二价阳离子螯合剂 EDTA 的存在下对杀伤作用更敏感。当暴露于人全血和血清补体时，与野生型亲本菌株和互补突变体相比，vacJ 突变体更快地被杀死。最后，在体内小鼠肺感染模型中，与野生型菌株相比，感染 vacJ 突变体导致死亡率降低、细菌负荷降低和肺损伤减轻。这项研究强调了在治疗上靶向 VacJ/Mla 途径以增强铜绿假单胞菌对宿主固有免疫反应杀伤作用的潜力。
• Mla 途径调节人类病原体铜绿假单胞菌 (PA) 的外膜动力学。• Mla 途径基因 vacJ 的缺失使 PA 对宿主抗菌肽 LL-37 敏感。• vacJ 表达的丧失使 PA 对人全血和血清杀伤更为敏感。• vacJ 表达的丧失降低了 PA 在小鼠肺感染模型中的存活和毒力。• Mla 途径值得探索作为一种药理学靶点，以增强 PA 对宿主固有免疫的敏感性。
