Helicobacter pylori versus the host: remodeling of the bacterial outer membrane is required for survival in the gastric mucosa.
Helicobacter pylori versus the host: remodeling of the bacterial outer membrane is required for survival in the gastric mucosa.
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DOI：
10.1371/journal.ppat.1002454
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发表时间：
2011-12
期刊：
影响因子：
6.7
通讯作者：
Trent MS
中科院分区：
文献类型：
--
作者：
Cullen TW;Giles DK;Wolf LN;Ecobichon C;Boneca IG;Trent MS
细菌表面结构的修饰，如脂多糖（LPS）的脂质A部分，被许多病原菌用来帮助逃避宿主的先天免疫反应。幽门螺杆菌是一种革兰氏阴性菌，能够在人胃中长期定植，通过从脂质A骨架的1-和4′-位去除磷酸基团来修饰其脂质A。在这项研究中，我们确定的酶负责的脂质A4 ′-磷酸基团的去磷酸化的H。pylori，Jhp1487（LpxF）。目的探讨这些修饰在H. pylori中，我们创建了lpxE（1-磷酸酶）、lpxF（4′-磷酸酶）突变体和lpxE/F双突变体。从lpxE和lpxF突变体中分离的脂质A的分析显示脂质A分别具有1或4′-磷酸基团，而双lpxE/F突变体显示双磷酸化脂质A。缺乏lpxE、lpxF或lpxE/F的突变体显示对阳离子抗微生物肽多粘菌素B的敏感性分别增加16、360和1020倍。此外，对人体中发现的多种CAMP，包括LL 37、β-防御素2和P-113，也观察到类似的抗性丧失。使用多粘菌素的荧光衍生物，我们证明，与野生型细菌不同，多粘菌素容易与lpxE/F突变体。推测H. pylori LPS允许肽与细菌表面结合。有趣的是，LpxE和LpxF的作用显示出减少先天免疫受体Toll样受体4对螺杆菌LPS的识别。此外，与野生型H相比，lpxE/F突变体不能定殖于C57 BL/6 J和C57 BL/6 J tlr 4-/-小鼠的胃粘膜。幽门。我们的结果表明，去磷酸化的脂质A结构域的H。pylori LPS通过LpxE和LpxF是其能够定殖哺乳动物宿主的关键。自1982年发现以来，幽门螺杆菌已被确定为胃炎和消化性溃疡疾病的主要原因，感染了约50%的世界人口。受感染的患者患胃癌的风险增加，这使得H。幽门螺旋杆菌列为I类致癌物。H.幽门螺杆菌只有一个明确的小生境，即人的胃。由于不存在其他宿主，因此在感染期间必须建立一种独特的平衡，使细菌及其人类宿主能够长期存活。在这里，我们表明，H。幽门螺杆菌改变其主要表面成分脂多糖（LPS），使细菌不能被先天免疫系统的成分检测到，并且对宿主细胞分泌的抗微生物化合物具有高度抗性。突变株H.不能修饰其表面的幽门螺杆菌显示出对抗菌肽的敏感性增加（1000倍）和先天免疫系统组分的识别增加。H. pylori突变体不能在小鼠模型中定殖，这表明LPS的重塑对于胃粘膜内的存活是必不可少的。理解H.幽门螺杆菌在人类宿主中存活和持续存在是解开这种独特生物体如何影响胃病的关键。
Modification of bacterial surface structures, such as the lipid A portion of lipopolysaccharide (LPS), is used by many pathogenic bacteria to help evade the host innate immune response. Helicobacter pylori, a gram-negative bacterium capable of chronic colonization of the human stomach, modifies its lipid A by removal of phosphate groups from the 1- and 4′-positions of the lipid A backbone. In this study, we identify the enzyme responsible for dephosphorylation of the lipid A 4′-phosphate group in H. pylori, Jhp1487 (LpxF). To ascertain the role these modifications play in the pathogenesis of H. pylori, we created mutants in lpxE (1-phosphatase), lpxF (4′-phosphatase) and a double lpxE/F mutant. Analysis of lipid A isolated from lpxE and lpxF mutants revealed lipid A species with a 1 or 4′-phosphate group, respectively while the double lpxE/F mutant revealed a bis-phosphorylated lipid A. Mutants lacking lpxE, lpxF, or lpxE/F show a 16, 360 and 1020 fold increase in sensitivity to the cationic antimicrobial peptide polymyxin B, respectively. Moreover, a similar loss of resistance is seen against a variety of CAMPs found in the human body including LL37, β-defensin 2, and P-113. Using a fluorescent derivative of polymyxin we demonstrate that, unlike wild type bacteria, polymyxin readily associates with the lpxE/F mutant. Presumably, the increase in the negative charge of H. pylori LPS allows for binding of the peptide to the bacterial surface. Interestingly, the action of LpxE and LpxF was shown to decrease recognition of Helicobacter LPS by the innate immune receptor, Toll-like Receptor 4. Furthermore, lpxE/F mutants were unable to colonize the gastric mucosa of C57BL/6J and C57BL/6J tlr4 -/- mice when compared to wild type H. pylori. Our results demonstrate that dephosphorylation of the lipid A domain of H. pylori LPS by LpxE and LpxF is key to its ability to colonize a mammalian host. Since its discovery in 1982 Helicobacter pylori has been identified as the leading cause of gastritis and peptic ulcer disease, infecting around 50% of the world's population. Infected patients are at increased risk for gastric cancers, allowing for classification of H. pylori as a class I carcinogen by the World Health Organization. H. pylori has only one well defined niche, the human stomach. Since no other reservoirs exist, a unique balance must be established during infection permitting long-term survival of both the bacterium and its human host. Here, we show that H. pylori modifies its primary surface component, lipopolysaccharide (LPS), making the bacterium undetectable by components of the innate immune system and highly resistant to antimicrobial compounds secreted by host cells. Mutant strains of H. pylori unable to modify their surface show increased sensitivity to antimicrobial peptides (∼1000 fold) and increased recognition by components of the innate immune system. H. pylori mutants were unable to colonize mouse models, suggesting that remodeling of LPS is essential for survival within the gastric mucosa. Understanding the adaptations used by H. pylori to survive and persist within the human host is key towards unraveling how this unique organism impacts gastric disease.
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影响因子：
3.4
作者：
Coats SR;Jones JW;Do CT;Braham PH;Bainbridge BW;To TT;Goodlett DR;Ernst RK;Darveau RP
通讯作者：
Darveau RP
影响因子：
3.6
作者：
Gunn, JS;Lim, KB;Miller, SI
通讯作者：
Miller, SI
影响因子：
64.8
作者：
Park, Beom Seok;Song, Dong Hyun;Lee, Jie-Oh
通讯作者：
Lee, Jie-Oh
影响因子：
15.9
作者：
Israel, DA;Salama, N;Peek, RM
通讯作者：
Peek, RM
DOI：
10.1084/jem.188.12.2277
发表时间：
1998-12-21
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Ermak TH;Giannasca PJ;Nichols R;Myers GA;Nedrud J;Weltzin R;Lee CK;Kleanthous H;Monath TP
通讯作者：
Monath TP