如果现代抗生素都杀灭不了一些致命的细菌，我们该怎么办？很简单：激发免疫系统完成自身的使命。加拿大不列颠-哥伦比亚大学免疫学家Robert Hancock的研究小组最近开发出一种新的化合物，它能够激发起免疫系统的首道防线，使小鼠死于抗药细菌感染的几率减少。该研究成果发表在最新一期的《自然—生物技术》上。
抗药性细菌引发的疾病是全球性问题，其中威胁最大的是耐万古霉素肠球菌（VRE）和耐甲氧西林金黄色葡萄球菌（MRSA），它们都是普通抗生素无法对付的“超级细菌”。为了寻找有效杀灭这些“超级细菌”的新办法，Hancock研究了一组短蛋白（多肽）。
考虑到多肽可能会引发败血症，Hancock现在小鼠身上进行实验。出乎意料的是，这些多肽反而能使败血症有所好转。唯一的问题是它们导致了过敏反应，引起一些健康的肠细胞死亡。因此，Hancock和同事设计出更短的多肽，既能阻止败血症，又不会引起其他并发症。
研究人员偶然发现一种13个氨基酸长度的多肽，并将其称为先天防御调节器（Innate Defense Regulator ，简称IDR-1）。为了检验其效果，研究人员将IDR-1注射入小鼠体内，这些小鼠要么尚未感染VRE或MRSA，要么感染不超过4小时。结果发现，这些小鼠存活率是之前的两倍。
Hancock表示，并不是这些多肽直接杀死了“超级细菌”。它似乎使人体自身先天免疫系统作了某种“事先准备”，随后的细菌感染会使体内产生过剩的单核白细胞和巨噬细胞，吞噬入侵的病原体。同时，由于体内产生的更具侵略性的噬中性白细胞较少，因此不会导致败血症。
Hancock表示，IDR-1的临床实验将在12到15个月后开始，而且已经有初步证据表明，即使是在对抗“超级细菌”时，该多肽也能够提高小鼠体内抗生素的效力。
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 bob@cmdr.ubc.ca
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.
