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上海士鋒生物：蛋白NLRP6抵御細(xì)菌感染
點(diǎn)擊次數(shù)：860 發(fā)布時(shí)間：2013-7-4
研究者表示，這項(xiàng)研究的亮點(diǎn)在于如果可以產(chǎn)生出單克隆中和抗體來(lái)中和這種蛋白質(zhì)，就能有效抵御細(xì)菌的感染。盡管目前部分抗生素對(duì)于抵御細(xì)菌感染有效，可是細(xì)菌的變異會(huì)慢慢產(chǎn)生耐藥性，這給人類的健康和財(cái)產(chǎn)帶來(lái)了巨大損失。更好地理解免疫系統(tǒng)如何識(shí)別以及對(duì)于病原體產(chǎn)生效應(yīng)，對(duì)于我們開發(fā)出新的有效療法會(huì)帶來(lái)巨大幫助。
研究者前期重點(diǎn)研究了類似NOD的受體蛋白6（NLRP6），NLRP6屬于先天免疫應(yīng)答的部分組分蛋白家族，這些蛋白質(zhì)在細(xì)胞內(nèi)部充當(dāng)了哨兵的角色，可以識(shí)別并且對(duì)于病原體感染產(chǎn)生效應(yīng)，截至到現(xiàn)在沒有人知道NLRP6所扮演的角色。通過(guò)研究有無(wú)Nlrp6基因的小鼠，研究者研究了小鼠對(duì)于不同細(xì)菌的免疫效應(yīng)，這些細(xì)菌包括單核李斯特氏菌、鼠傷寒沙門菌以及大腸桿菌。結(jié)果顯示，無(wú)Nlrp6基因的小鼠在注射致死劑量的細(xì)菌菌液之后更容易生存，而且這種小鼠的肝臟和脾臟在感染細(xì)菌一天和三天之后含有少量的細(xì)菌，而且其體內(nèi)含有高水平的單核細(xì)胞和中性白細(xì)胞，綜上所述，缺失NLRP6的小鼠表現(xiàn)出了更強(qiáng)效應(yīng)的免疫效應(yīng)。
研究者進(jìn)而揭示了NLRP6受壓制的活性可以觸發(fā)細(xì)胞因子等蛋白質(zhì)的產(chǎn)生，這將促進(jìn)炎癥來(lái)抵御感染，結(jié)果揭示出NLRP6可以調(diào)節(jié)核因子κB和胞外信號(hào)調(diào)節(jié)激酶途徑。研究者Paras表示，研究結(jié)果*出乎意料，這是NLR家族的*個(gè)成員被報(bào)道可以抑制而并非激活先天性免疫效應(yīng)。這項(xiàng)研究由國(guó)立衛(wèi)生研究院和ALSAC支持。
編譯自：Innate Immune System Protein Provides a New Target in War Against Bacterial Infections
原文摘要：
NLRP6 negatively regulates innate immunity and host defence against bacterial pathogens
Members of the intracellular nucleotide-binding and oligomerization domain （NOD）-like receptor （NLR） family contribute to immune responses through activation of nuclear factor-κB （NF-κB）, type I interferon and inflammasome signalling. Mice lacking the NLR family member NLRP6 were recently shown to be susceptible to colitis and colorectal tumorigenesis, but the role of NLRP6 in microbial infections and the nature of the inflammatory signalling pathways regulated by NLRP6 remain unclear. Here we show thatNlrp6-deficient mice are highly resistant to infection with the bacterial pathogens Listeria monocytogenes, Salmonella typhimurium and Escherichia coli. Infected Nlrp6-deficient mice had increased numbers of monocytes and neutrophils in circulation, and NLRP6 signalling in both haematopoietic and radioresistant cells contributed to increased susceptibility. Nlrp6 deficiency enhanced activation of mitogen-activated protein kinase （MAPK） and the canonical NF-κB pathway after Toll-like receptor ligation, but not cytosolic /2 ligation, in vitro. Consequently, infected Nlrp6-deficient cells produced increased levels of NF-κB- and MAPK-dependent cytokines and chemokines. Thus, our results reveal NLRP6 as a negative regulator of inflammatory signalling, and demonstrate a role for this NLR in impeding clearance of both Gram-positive and -negative bacterial pathogens.