近日,，國際著名雜志PLoS One在線刊登了加拿大多倫多大學(xué)研究人員的最新研究成果“Identifying Mechanisms by Which Escherichia coli O157：H7 Subverts Interferon-γ Mediated Signal Transducer and Activator of Transcription-1 Activation，”,，文章中,，研究者揭示了EHEC破壞人類細(xì)胞的IFNγ信號(hào)途徑的一種可能性機(jī)制。
O157：H7是腸出血性大腸桿菌（EHEC）最為常見的一種分型,，也是一種非侵入型的腸細(xì)菌病原體,，這種病原菌一般會(huì)促使人類的出血性大腸炎和溶血性尿毒癥綜合征以及個(gè)別的散發(fā)病例，人和動(dòng)物之間EHEC的傳染一般通過攝入被污染的食物和飲水,，而且可以通過人和人之間微生物的傳播來進(jìn)行傳染,。
人類對于細(xì)菌感染的防御一般是先天的適應(yīng)性的免疫系統(tǒng)的激活，致炎細(xì)胞因子，包括干擾素γ（IFNγ）,，一般情況下,，當(dāng)細(xì)菌感染時(shí)，該細(xì)胞因子被分泌至胞外大環(huán)境并且激活人體達(dá)到抗菌的狀態(tài),，巨噬細(xì)胞產(chǎn)生的IFNγ,、自然殺傷T細(xì)胞、活化的T細(xì)胞通過結(jié)合至IFNγ的受體來觸發(fā)機(jī)體使得機(jī)體進(jìn)入抵御微生物的狀態(tài),，隨后引起信號(hào)轉(zhuǎn)換器的酪氨酸磷酸化以及轉(zhuǎn)錄因子STAT1分子的活化,，這種活化導(dǎo)致STAT1的二聚化，從細(xì)胞溶質(zhì)轉(zhuǎn)移至細(xì)胞核,，在細(xì)胞核中,，STAT1結(jié)合至伽馬激活序列上（GAS），隨后上調(diào)2000多個(gè)致炎細(xì)胞因子基因,，包括誘生型一氧化氮合酶（iNOS）,，單核細(xì)胞化學(xué)吸引蛋白質(zhì)1(MCP-1)，淋巴細(xì)胞吸附蛋白ICAM-1,。一個(gè)完整的IFNγ途徑對于應(yīng)對一次病原菌的感染時(shí)非常有必要的,，因此，STAT1信號(hào)缺失的遺傳缺陷病人對于微生物的感染時(shí)非常敏感的,。
IFNγ/STAT1信號(hào)轉(zhuǎn)導(dǎo)通路的破壞可以促使微生物病原菌的繁殖定居,，而且妨礙了宿主對病原菌的徹底清除，EHEC依靠一種目前尚未知的因子摧毀了IFNγ途徑,，作者文章中的研究重點(diǎn)就是想證實(shí)EHEC是如何通過破壞人類細(xì)胞的IFNγ信號(hào)途徑從而來輕而易舉進(jìn)行感染的,，作者的研究結(jié)果首次證實(shí)了，STAT1的酪氨酸磷酸化被大腸桿菌O157：H7分泌的蛋白所抑制,，運(yùn)用連續(xù)陰離子交換和分子排阻色譜法,，作者識(shí)別出了YodA基因，但是通過等基因突變分析,，發(fā)現(xiàn)該基因并不介導(dǎo)STAT1信號(hào)通路,，由此，作者認(rèn)為大腸桿菌O157：H7破壞STAT1的酪氨酸磷酸化途徑仍然是通過一個(gè)未知的細(xì)菌分泌蛋白來完成的,，作者指出,，他們需要進(jìn)行進(jìn)一步的研究來確定EHEC破壞人類細(xì)胞的IFNγ信號(hào)途徑的詳細(xì)機(jī)制。（生物谷：T.Shen編譯）
doi:10.1371/journal.pone.0030145
PMC:
PMID:
Identifying Mechanisms by Which Escherichia coli O157:H7 Subverts Interferon-γ Mediated Signal Transducer and Activator of Transcription-1 Activation
Nathan K. Ho1,3, Ian Crandall2, Philip M. Sherman1,3*
Enterohemorrhagic Escherichia coli serotype O157:H7 is a food borne enteric bacterial pathogen that causes significant morbidity and mortality in both developing and industrialized nations. E. coli O157:H7 infection of host epithelial cells inhibits the interferon gamma pro-inflammatory signaling pathway, which is important for host defense against microbial pathogens, through the inhibition of Stat-1 tyrosine phosphorylation. The aim of this study was to determine which bacterial factors are involved in the inhibition of Stat-1 tyrosine phosphorylation. Human epithelial cells were challenged with either live bacteria or bacterial-derived culture supernatants, stimulated with interferon-gamma, and epithelial cell protein extracts were then analyzed by immunoblotting. The results show that Stat-1 tyrosine phosphorylation was inhibited by E. coli O157:H7 secreted proteins. Using sequential anion exchange and size exclusion chromatography, YodA was identified, but not confirmed to mediate subversion of the Stat-1 signaling pathway using isogenic mutants. We conclude that E. coli O157:H7 subverts Stat-1 tyrosine phosphorylation in response to interferon-gamma through a still as yet unidentified secreted bacterial protein.
