Pseudomonas aeruginosa Elastase Contributes to the Establishment of Chronic Lung Colonization and Modulates the Immune Response in a Murine Model.
Pseudomonas aeruginosa Elastase Contributes to the Establishment of Chronic Lung Colonization and Modulates the Immune Response in a Murine Model.
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DOI：
10.3389/fmicb.2020.620819
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发表时间：
2020
影响因子：
5.2
通讯作者：
Everett M
中科院分区：
文献类型：
--
作者：
Cigana C;Castandet J;Sprynski N;Melessike M;Beyria L;Ranucci S;Alcalá-Franco B;Rossi A;Bragonzi A;Zalacain M;Everett M
囊性纤维化(CF)患者慢性铜绿假单胞菌感染是进行性肺损伤的主要原因，现有的抗生素治疗效果不佳。开发其他抗生素治疗方法的另一种方法是确定针对建立和/或维持慢性感染所必需的细菌毒力因子的补充治疗方法。铜绿假单胞菌弹性蛋白酶(LasB)由于其胞外定位、对宿主组织和免疫系统的有害降解作用以及使用小分子抑制剂抑制其活性的潜力，已被认为是一个有吸引力的抗毒力靶点。然而，虽然LasB在急性铜绿假单胞菌感染中的相关性已被证明，但该弹性蛋白酶是否也可能在慢性肺部定植的早期阶段发挥作用仍不清楚。通过对1例CF患者临床分离的铜绿假单胞菌克隆株的分析，我们发现，在持续早期收集的RP45菌株能够产生大量的活性LasB，而其克隆变体RP73在多年的定植后收集到的RP73不产生LasB。当使用持续性肺炎的小鼠模型时，与感染野生型(Wt)RP45的小鼠相比，RP45中lasB基因的缺失导致攻击后第7天的平均细菌数量和慢性肺部定植发生率显著降低。此外，菌株RP45中lasB的缺失还导致感染动物中与先天和获得性免疫反应相关的免疫调节剂的增加。相反，RP73中lasB基因的缺失并不影响慢性感染的建立。总体而言，这些结果表明LasB有助于铜绿假单胞菌适应持续的生活方式。此外，这些发现支持LasB的药理抑制作用，作为一种在慢性感染建立之前对铜绿假单胞菌感染的CF患者进行潜在有用的治疗干预。
Chronic infection by Pseudomonas aeruginosa in cystic fibrosis (CF) patients is a major contributor to progressive lung damage and is poorly treated by available antibiotic therapy. An alternative approach to the development of additional antibiotic treatments is to identify complementary therapies which target bacterial virulence factors necessary for the establishment and/or maintenance of the chronic infection. The P. aeruginosa elastase (LasB) has been suggested as an attractive anti-virulence target due to its extracellular location, its harmful degradative effects on host tissues and the immune system, and the potential to inhibit its activity using small molecule inhibitors. However, while the relevance of LasB in acute P. aeruginosa infection has been demonstrated, it is still unclear whether this elastase might also play a role in the early phase of chronic lung colonization. By analyzing clinical P. aeruginosa clonal isolates from a CF patient, we found that the isolate RP45, collected in the early phase of persistence, produces large amounts of active LasB, while its clonal variant RP73, collected after years of colonization, does not produce it. When a mouse model of persistent pneumonia was used, deletion of the lasB gene in RP45 resulted in a significant reduction in mean bacterial numbers and incidence of chronic lung colonization at Day 7 post-challenge compared to those mice infected with wild-type (wt) RP45. Furthermore, deletion of lasB in strain RP45 also resulted in an increase in immunomodulators associated with innate and adaptive immune responses in infected animals. In contrast, deletion of the lasB gene in RP73 did not affect the establishment of chronic infection. Overall, these results indicate that LasB contributes to the adaptation of P. aeruginosa to a persistent lifestyle. In addition, these findings support pharmacological inhibition of LasB as a potentially useful therapeutic intervention for P. aeruginosa-infected CF patients prior to the establishment of a chronic infection.
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影响因子：
4.6
作者：
Lorè NI;Cigana C;Riva C;De Fino I;Nonis A;Spagnuolo L;Sipione B;Cariani L;Girelli D;Rossi G;Basso V;Colombo C;Mondino A;Bragonzi A
通讯作者：
Bragonzi A
影响因子：
6.7
作者：
Golovkine G;Faudry E;Bouillot S;Voulhoux R;Attrée I;Huber P
通讯作者：
Huber P
影响因子：
3.1
作者：
Lee, Kang-Mu;Yoon, Mi Young;Yoon, Sang Sun
通讯作者：
Yoon, Sang Sun
影响因子：
4.6
作者：
Cigana C;Lorè NI;Riva C;De Fino I;Spagnuolo L;Sipione B;Rossi G;Nonis A;Cabrini G;Bragonzi A
通讯作者：
Bragonzi A
影响因子：
24.3
作者：
Cigana, Cristina;Ranucci, Serena;Bragonzi, Alessandra
通讯作者：
Bragonzi, Alessandra