Whole-animal chemical screen identifies colistin as a new immunomodulator that targets conserved pathways.
Whole-animal chemical screen identifies colistin as a new immunomodulator that targets conserved pathways.
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DOI：
10.1128/mbio.01235-14
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发表时间：
2014-08-12
期刊：
影响因子：
6.4
通讯作者：
Aballay A
中科院分区：
文献类型：
--
作者：
Cai Y;Cao X;Aballay A
本研究的目的是利用线虫秀丽隐杆线虫进行全动物化学筛选，以确定潜在的免疫激活剂，可能会对细菌感染提供保护。我们从1，120种研究化合物中鉴定出45种市售药物，能够激活先天免疫所需的保守p38/PMK-1有丝分裂原活化蛋白激酶途径。这些药物中的一种，最后的抗生素粘菌素，可以防止革兰氏阴性病原体鼠疫耶尔森氏菌和铜绿假单胞菌的感染，但不能防止革兰氏阳性病原体粪肠球菌和金黄色葡萄球菌的感染。这种保护作用与粘菌素的抗菌活性无关，因为该药物在感染前是主动给药的，而且对耐药性细菌也有效。粘菌素的免疫激活不仅由p38/PMK-1途径介导，而且还由保守的FOXO转录因子β-16和转录因子SKN-1介导。此外，发现p38/PMK-1在肠中被粘菌素免疫激活所需。由粘菌素增强的p38/PMK-1介导的免疫应答并没有减少细菌负荷，表明该途径在宿主对革兰氏阴性菌感染的耐受性的发展中起作用。先天免疫系统代表了我们抵御入侵微生物的前线。鉴于细菌病原体对抗生素的耐药性不断增加，增强免疫防御的可能性是传统抗生素治疗的一种有趣的补充方法。在这里，我们报告说，抗生素粘菌素可以防止感染的机制，是独立于其杀菌活性。粘菌素的预防性治疗激活了肠道中保守的p38/PMK-1通路，有助于宿主更好地耐受细菌感染。由于p38/PMK-1介导的免疫反应似乎从植物到哺乳动物都是保守的，因此粘菌素也可以激活高等生物（包括人类）的免疫力。具有免疫调节特性的抗生素有可能改善慢性感染性疾病患者的长期结局。
The purpose of this study was to take advantage of the nematode Caenorhabditis elegans to perform a whole-animal chemical screen to identify potential immune activators that may confer protection against bacterial infections. We identified 45 marketed drugs, out of 1,120 studied compounds, that are capable of activating a conserved p38/PMK-1 mitogen-activated protein kinase pathway required for innate immunity. One of these drugs, the last-resort antibiotic colistin, protected against infections by the Gram-negative pathogens Yersinia pestis and Pseudomonas aeruginosa but not by the Gram-positive pathogens Enterococcus faecalis and Staphylococcus aureus. Protection was independent of the antibacterial activity of colistin, since the drug was administered prophylactically prior to the infections and it was also effective against antibiotic-resistant bacteria. Immune activation by colistin is mediated not only by the p38/PMK-1 pathway but also by the conserved FOXO transcription factor DAF-16 and the transcription factor SKN-1. Furthermore, p38/PMK-1 was found to be required in the intestine for immune activation by colistin. Enhanced p38/PMK-1-mediated immune responses by colistin did not reduce the bacterial burden, indicating that the pathway plays a role in the development of host tolerance to infections by Gram-negative bacteria. The innate immune system represents the front line of our defenses against invading microorganisms. Given the ever-increasing resistance to antibiotics developed by bacterial pathogens, the possibility of boosting immune defenses represents an interesting, complementary approach to conventional antibiotic treatments. Here we report that the antibiotic colistin can protect against infections by a mechanism that is independent of its microbicidal activity. Prophylactic treatment with colistin activates a conserved p38/PMK-1 pathway in the intestine that helps the host better tolerate a bacterial infection. Since p38/PMK-1-mediated immune responses appear to be conserved from plants to mammals, colistin may also activate immunity in higher organisms, including humans. Antibiotics with immunomodulatory properties have the potential of improving the long-term outcome of patients with chronic infectious diseases.