摘要
During infections,bacteria stimulate host cells to produce and release histamine,which is a key mediator of vital cellular processes in animals.However,the mechanisms underlying the bacterial cell’s ability to sense and respond to histamine are poorly understood.Herein,we show that HinK,a Lys R-type transcriptional regulator,is required to evoke responses to histamine in Pseudomonas aeruginosa,an important human pathogen.HinK directly binds to and activates the promoter of genes involved in histamine uptake and metabolism,iron acquisition,and Pseudomonas quinolone signal(PQS)biosynthesis.The transcriptional regulatory activity of HinK is induced when histamine is present,and it occurs when HinK binds with imidazole-4-acetic acid(Im AA),a histamine metabolite whose production in P.aeruginosa depends on the HinK-activated histamine uptake and utilization operon hin DAC-pa0222.Importantly,the inactivation of HinK inhibits diverse pathogenic phenotypes of P.aeruginosa.These results suggest that histamine acts as an interkingdom signal and provide insights into the mechanism used by pathogenic bacteria to exploit host regulatory signals to promote virulence.
在感染过程中,细菌刺激宿主的免疫细胞产生和释放组胺.然而,细菌如何对组胺进行应答及其在细菌感染中的作用尚不清楚.本研究发现铜绿假单胞菌的转录调节因子HinK在细菌对组胺进行应答的过程中起着决定性的作用.HinK直接激活组胺摄取和代谢、铁获取及假单胞菌喹诺酮类信号生物合成等相关基因的表达.在含组胺的培养基中,HinK的转录激活活性受到强烈的诱导;进一步的研究发现组胺代谢物咪唑-4-乙酸与HinK结合从而激活HinK的转录调控活性.基于细菌感染动物模型,发现组胺可增强铜绿假单胞菌的致病能力,同时,HinK基因的缺失导致铜绿假单胞菌的致病能力显著下降.这些结果揭示了细菌利用宿主调节信号分子促进致病力的一种新机制.
作者
Yaya Wang
Qiao Cao
Qin Cao
Jianhua Gan
Ning Sun
Cai-Guang Yang
Taeok Bae
Min Wu
Lefu Lan
王娅娅;曹荞;曹芹;甘建华;孙宁;杨财广;Taeok Bae;吴敏;蓝乐夫(State Key Laboratory of Drug Research,Shanghai Institute of Materia Medica,Chinese Academy of Sciences,Shanghai 201203,China;College of Life Science,Northwest University,Xi'an 710069,China;University of Chinese Academy of Sciences,Beijing 100049,China;State Key Laboratory of Genetic Engineering,Shanghai Public Health Clinical Center,Collaborative Innovation Center of Genetics and Development,School of Life Sciences,Hehai University,Shanghai 201438,China;The State Key Laboratory of Chemical Biology and Drug Discovery,Department of Applied Biology and Chemical Technology,The Hong Kong Polytechnic University,Hong Kong 999077,China;School of Pharmaceutical Science and Technology,Hangzhou Institute for Advanced Study,University of Chinese Academy of Sciences,Hangzhou 310024,China;Department of Microbiology and Immunology,Indiana University School of Medicine-Northwest,Gary IN 46408,USA;Department of Biomedical Sciences,University of North Dakota,Grand Forks ND 58203-9037,USA;NMPA Key Laboratory for Testing Technology of Pharmaceutical Microbiology,Shanghai Institute for Food and Drug Control,Shanghai 201203,China)
基金
supported by the Ministry of Science and Technology(MOST)of China(2016YFA0501503 and 2019ZX09721001-004-003)
the National Natural Science Foundation of China(31670136,31870127,and 81861138047)
the Science and Technology Commission of Shanghai Municipality(19JC1416400)
the State Key Laboratory of Drug Research(SIMM2003ZZ-03)。
