一個成年人雖然有超過70兆個細(xì)胞，但卻有許多特征跟僅有959個細(xì)胞的線蟲極為相似,，杜克大學(xué)(Duke University)的Alejandro Aballay教授發(fā)現(xiàn)兩個先天性免疫力(innate immunity)的訊息傳遞路徑，在人類與線蟲之間有高度的保守性(highly conserved),。而這些訊息傳遞誘發(fā)的免疫力,，保護(hù)著人類或線蟲免于外敵的入侵。
第一個訊息傳遞路徑是p38 MAPK/CED-3,，這個路徑也與細(xì)胞的計劃性死亡(programmed cell death)有關(guān),，另一個是heat shock transcription factor-1 (簡稱HSF-1)，這個訊息傳遞受到高溫而誘發(fā),。Aballay利用熒光標(biāo)定的轉(zhuǎn)殖線蟲,，發(fā)現(xiàn)了這兩個路徑中的免疫受動分子(immunity effector),、相關(guān)的訊息傳遞分子以及轉(zhuǎn)錄因子。并描繪出這兩個免疫訊息傳遞路徑是如何直接的對抗病源菌,。
最令人驚訝的發(fā)現(xiàn)是線蟲的HSF-1路徑所引發(fā)的免疫反應(yīng),，竟能對抗綠膿桿菌、沙門氏菌,、鼠疫耶辛菌以及腸球菌等,。證明了HSF-1是一種廣效、多重功能的抗病源菌的路徑,。也間接讓人聯(lián)想到這個免疫反應(yīng)路徑可能與發(fā)燒(fever)有關(guān),。因為當(dāng)生物受到病菌感染，發(fā)燒是一個典型反應(yīng),，恒溫動物(homeotherms),，如老鼠或人，會增加體內(nèi)溫度以告知受到感染,；而冷血動物(poikiotherms),，如線蟲則會游動到較溫暖的環(huán)境，表示其受到感染,。而當(dāng)體內(nèi)或環(huán)境溫度上升時,，便會活化HSF-1的免疫訊息傳遞路徑，這可以同時解釋HSF-1路徑的功能是用來抵御外敵的感染,，同時也能解釋為何生物遭受感染就可能會發(fā)燒,。
用相同的道理來看，當(dāng)人類受到感染而發(fā)燒,，常會吃退燒藥,，但會不會因此而造成HSF-1的不活化，而使情況變得更糟呢,？只有少數(shù)像阿司匹林等抗發(fā)炎藥,，能夠退燒又能活化HSF-1訊號，才是較好的治療方法,。目前設(shè)計用來活化HSF-1的新藥已進(jìn)入臨床試驗,，Aballay教授的研究讓我們了解為何生物受到感染會以發(fā)燒作為警示，同時也讓更多的研究人員投入增加HSF-1活性的新藥研究,，藉由提高身體內(nèi)的免疫反應(yīng)來戰(zhàn)勝病菌的感染,。
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.
