一个成年人虽然有超过70兆个细胞，但却有许多特征跟仅有959个细胞的线虫极为相似，杜克大学(Duke University)的Alejandro Aballay教授发现两个先天性免疫力(innate immunity)的讯息传递路径，在人类与线虫之间有高度的保守性(highly conserved)。而这些讯息传递诱发的免疫力，保护着人类或线虫免于外敌的入侵。
第一个讯息传递路径是p38 MAPK/CED-3，这个路径也与细胞的计划性死亡(programmed cell death)有关，另一个是heat shock transcription factor-1 (简称HSF-1)，这个讯息传递受到高温而诱发。Aballay利用荧光标定的转殖线虫，发现了这两个路径中的免疫受动分子(immunity effector)、相关的讯息传递分子以及转录因子。并描绘出这两个免疫讯息传递路径是如何直接的对抗病源菌。
最令人惊讶的发现是线虫的HSF-1路径所引发的免疫反应，竟能对抗绿脓杆菌、沙门氏菌、鼠疫耶辛菌以及肠球菌等。证明了HSF-1是一种广效、多重功能的抗病源菌的路径。也间接让人联想到这个免疫反应路径可能与发烧(fever)有关。因为当生物受到病菌感染，发烧是一个典型反应，恒温动物(homeotherms)，如老鼠或人，会增加体内温度以告知受到感染；而冷血动物(poikiotherms)，如线虫则会游动到较温暖的环境，表示其受到感染。而当体内或环境温度上升时，便会活化HSF-1的免疫讯息传递路径，这可以同时解释HSF-1路径的功能是用来抵御外敌的感染，同时也能解释为何生物遭受感染就可能会发烧。
用相同的道理来看，当人类受到感染而发烧，常会吃退烧药，但会不会因此而造成HSF-1的不活化，而使情况变得更糟呢？只有少数像阿司匹林等抗发炎药，能够退烧又能活化HSF-1讯号，才是较好的治疗方法。目前设计用来活化HSF-1的新药已进入临床试验，Aballay教授的研究让我们了解为何生物受到感染会以发烧作为警示，同时也让更多的研究人员投入增加HSF-1活性的新药研究，藉由提高身体内的免疫反应来战胜病菌的感染。
英文原文：
Worms produce surprise insight into human fever
Patients fighting infections may be taking wrong fever-reducing drugs.
Give or take a few dozen trillions, a human adult has about 70 trillion cells. An adult Caenorhabditis elegans roundworm has exactly 959 cells.
Yet we have an awful lot in common, says Alejandro Aballay of Duke University, who has been exploring two “highly conserved” cell-signaling pathways for innate immunity shared by worms and humans. For one, we have a lot of common enemies, particularly soil-borne pathogens. C. elegans, of course, lives in the soil. Human populations merely ingest soil by the ton in our food, on our hands, and suspended in our drinking water.
Some of these basic pathways that set off the worm’s innate immune defenses have homologs—similar proteins in mammal cells, including ours. These conserved pathways are involved in many similar “effector” strategies against hostile bugs peristalsis, low gut pH, lytic enzymes, and antimicrobial peptides to prevent microbial colonization of the intestine.
In dissecting two conserved pathways required for C. elegans immunity to bacteria, Aballay found a wealth of data on innate immunity plus a surprising insight into another classic metazoan response to infection fever.
The first pathway was p38 MAPK/CED-3, which is also required for the activation of programmed cell death under certain stresses. The other was a heat shock transcription factor-1 (HSF-1) pathway, which is elicited by increased temperature independently of p38 MAPK/CED-3. Aballay identified genes in both pathways that encoded immunity effector molecules plus relevant signaling molecules and transcription factors. In fluorescently labeled transgenic worms, he mapped gene expression in the two target pathways as they came into direct contact with a small zoo of pathogenic microbes.
The big surprise was the discovery that the HSF-1 pathway was required for C. elegans immunity against Pseudomonas aeruginosa, Salmonella enterica, Yersinia pestis, and Enterococcus faecalis. It indicated that HSF-1 is part of a broad, multi-pathogen defense pathway. And it also suggested something new about fever, says Aballay.
Fever is an ancient immune mechanism used by metazoans in response to microbial infections. Warm-blooded “homeotherms” like rats (and people) can increase their internal body temperature in response to infection, yet even cold-blooded “poikilotherms” like worms migrate toward warmer environments in response to infections. But the mechanism of fever as a response to infection is still largely unknown. The activation of the HSF-1 pathways by heat shock and its function in C. elegans immunity provides both a molecular explanation for the beneficial role of behavioral fevers in poikilotherms and a mechanism by which fever works in metazoans, says Aballay.
It also raises questions about the HSF-1 pathway in humans and whether drugs currently used to reduce fever in infected patients may make matters worse by preventing activation of the HSF-1 pathway. Aspirin and similar anti-inflammatory drugs, which reduce fever but also activate HSF-1 signaling, could offer the best of both worlds, says Aballay. He also points out that new drugs designed to activate HSF-1 are already in clinical trials for treating neurodegenerative diseases. “Our work opens the possibility of using co-inducers of HSF-1 to boost immunity to treat infectious diseases and immunodeficiencies,” says Aballay.
