如果現(xiàn)代抗生素都?xì)绮涣艘恍┲旅募?xì)菌,，我們該怎么辦,？很簡單：激發(fā)免疫系統(tǒng)完成自身的使命。加拿大不列顛-哥倫比亞大學(xué)免疫學(xué)家Robert Hancock的研究小組最近開發(fā)出一種新的化合物,，它能夠激發(fā)起免疫系統(tǒng)的首道防線,，使小鼠死于抗藥細(xì)菌感染的幾率減少。該研究成果發(fā)表在最新一期的《自然—生物技術(shù)》上,。
抗藥性細(xì)菌引發(fā)的疾病是全球性問題,，其中威脅最大的是耐萬古霉素腸球菌（VRE）和耐甲氧西林金黃色葡萄球菌（MRSA），它們都是普通抗生素?zé)o法對付的“超級細(xì)菌”,。為了尋找有效殺滅這些“超級細(xì)菌”的新辦法,，Hancock研究了一組短蛋白（多肽）。
考慮到多肽可能會引發(fā)敗血癥,，Hancock現(xiàn)在小鼠身上進(jìn)行實驗,。出乎意料的是，這些多肽反而能使敗血癥有所好轉(zhuǎn),。唯一的問題是它們導(dǎo)致了過敏反應(yīng),，引起一些健康的腸細(xì)胞死亡。因此,，Hancock和同事設(shè)計出更短的多肽,，既能阻止敗血癥，又不會引起其他并發(fā)癥,。
研究人員偶然發(fā)現(xiàn)一種13個氨基酸長度的多肽,，并將其稱為先天防御調(diào)節(jié)器（Innate Defense Regulator ，簡稱IDR-1）,。為了檢驗其效果,，研究人員將IDR-1注射入小鼠體內(nèi)，這些小鼠要么尚未感染VRE或MRSA,，要么感染不超過4小時,。結(jié)果發(fā)現(xiàn)，這些小鼠存活率是之前的兩倍,。
Hancock表示,，并不是這些多肽直接殺死了“超級細(xì)菌”。它似乎使人體自身先天免疫系統(tǒng)作了某種“事先準(zhǔn)備”,，隨后的細(xì)菌感染會使體內(nèi)產(chǎn)生過剩的單核白細(xì)胞和巨噬細(xì)胞,，吞噬入侵的病原體。同時,，由于體內(nèi)產(chǎn)生的更具侵略性的噬中性白細(xì)胞較少,，因此不會導(dǎo)致敗血癥,。
Hancock表示，IDR-1的臨床實驗將在12到15個月后開始,，而且已經(jīng)有初步證據(jù)表明,，即使是在對抗“超級細(xì)菌”時，該多肽也能夠提高小鼠體內(nèi)抗生素的效力,。
部分英文原文
Nature Biotechnology,，Published online: 25 March 2007; | doi:10.1038/nbt1288
An anti-infective peptide that selectively modulates the innate immune response
Monisha G Scott1, Edie Dullaghan1, 4, Neeloffer Mookherjee2, 4, Natalie Glavas1, Matthew Waldbrook2, Annick Thompson1, Aikun Wang1, Ken Lee1, Silvana Doria2, Pam Hamill2, Jie Jessie Yu2, Yuexin Li2, Oreola Donini1, M Marta Guarna1, B Brett Finlay3, John R North1 & Robert E W Hancock2
1 Inimex Pharmaceuticals Inc., 3650 Wesbrook Mall, Vancouver, British Columbia, Canada V6S 2L2.
2 Centre for Microbial Diseases and Immunity Research, University of British Columbia, Vancouver, British Columbia, Canada, V6T 1Z4
3 Michael Smith Laboratories, 2259 Lower Mall Research Station, University of British Columbia, Vancouver, British Columbia, Canada, V6T 1Z4.
4 These authors contributed equally to this work.
Correspondence should be addressed to Robert E W Hancock [email protected]
We show that an innate defense–regulator peptide (IDR-1) was protective in mouse models of infection with important Gram-positive and Gram-negative pathogens, including methicillin-resistant Staphylococcus aureus, vancomycin-resistant Enterococcus and Salmonella enterica serovar Typhimurium. When given from 48 h before to 6 h after infection, the peptide was effective by both local and systemic administration. Because protection by IDR-1 was prevented by in vivo depletion of monocytes and macrophages, but not neutrophils or B- and T-lymphocytes, we conclude that monocytes and macrophages are key effector cells. IDR-1 was not directly antimicrobial: gene and protein expression analysis in human and mouse monocytes and macrophages indicated that IDR-1, acting through mitogen-activated protein kinase and other signaling pathways, enhanced the levels of monocyte chemokines while reducing pro-inflammatory cytokine responses. To our knowledge, an innate defense regulator that counters infection by selective modulation of innate immunity without obvious toxicities has not been reported previously.
