Helicobacter pylori Resists the Antimicrobial Activity of Calprotectin via Lipid A Modification and Associated Biofilm Formation
Helicobacter pylori Resists the Antimicrobial Activity of Calprotectin via Lipid A Modification and Associated Biofilm Formation
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DOI：
10.1128/mbio.01349-15
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发表时间：
2015-11-01
期刊：
影响因子：
6.4
通讯作者：
Algood, Holly M. S.
中科院分区：
文献类型：
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作者：
Gaddy, Jennifer A.;Radin, Jana N.;Algood, Holly M. S.
幽门螺杆菌是几种病原体之一，尽管有强大的免疫反应，但仍在宿主体内存在。H.幽门螺杆菌引起宿主上皮细胞的促炎反应，导致免疫细胞的募集，表现为胃炎。关于H.幽门螺杆菌存活的抗菌剂，包括钙卫蛋白（CP），这是存在于炎症反应。这里提供的数据表明，单向H。幽门螺杆菌是通过改变其外膜而在CP的营养隔离中存活的。CP处理的H. pylori证实了响应于进一步与CP共培养而增加的细菌适应性。CP处理的H.幽门螺杆菌培养物形成生物膜并显示细胞表面疏水性降低。H.幽门螺杆菌Lpx脂质A生物合成酶的功能不完全。在H.用CP处理的幽门螺杆菌培养物表明LpxF、LpxL和LpxR酶功能受到干扰。lpxF、lpxL和lpxR的转录分析表明，CP的金属限制并不通过转录调节来控制该途径。分析了H. pylori lpx突变体揭示了LpxF和LpxL的缺失导致适应性增加，类似于在CP存在下观察到的;此外，这些突变体具有显著增加的生物膜形成和降低的细胞表面疏水性。这些结果表明了H.幽门螺杆菌通过脂质A修饰策略对CP的抗微生物活性产生抗性并导致生物膜形成。重要性幽门螺杆菌通过修饰脂多糖的脂质A组分来逃避宿主免疫系统的识别。这些结果首次证明脂质A修饰途径受宿主营养免疫应答的影响。H.幽门螺杆菌暴露于宿主锰和锌结合蛋白钙卫蛋白干扰了脂质A修饰途径中涉及的3种酶的功能。CP处理H.幽门螺杆菌或具有改变的脂质A的突变体表现出增加的细菌适应性和增加的生物膜形成。这表明H.幽门螺杆菌改变其细胞表面结构，以在宿主免疫反应施加的压力下存活。这些结果提供了新的见解的分子机制，影响生物膜的生活方式，以及如何内毒素修饰，使H。幽门螺杆菌对阳离子抗菌肽具有抗性，可以响应于营养金属的螯合而失活。
Helicobacter pylori is one of several pathogens that persist within the host despite a robust immune response. H. pylori elicits a proinflammatory response from host epithelia, resulting in the recruitment of immune cells which manifests as gastritis. Relatively little is known about how H. pylori survives antimicrobials, including calprotectin (CP), which is present during the inflammatory response. The data presented here suggest that one way H. pylori survives the nutrient sequestration by CP is through alteration of its outer membrane. CP-treated H. pylori demonstrates increased bacterial fitness in response to further coculture with CP. Moreover, CP-treated H. pylori cultures form biofilms and demonstrate decreased cell surface hydrophobicity. In response to CP, the H. pylori Lpx lipid A biosynthetic enzymes are not fully functional. The lipid A molecules observed in H. pylori cultures treated with CP indicate that the LpxF, LpxL, and LpxR enzyme functions are perturbed. Transcriptional analysis of lpxF, lpxL, and lpxR indicates that metal restriction by CP does not control this pathway through transcriptional regulation. Analyses of H. pylori lpx mutants reveal that loss of LpxF and LpxL results in increased fitness, similar to what is observed in the presence of CP; moreover, these mutants have significantly increased biofilm formation and reduced cell surface hydrophobicity. Taken together, these results demonstrate a novel mechanism of H. pylori resistance to the antimicrobial activity of CP via lipid A modification strategies and resulting biofilm formation.IMPORTANCE Helicobacter pylori evades recognition of the host's immune system by modifying the lipid A component of lipopolysaccharide. These results demonstrate for the first time that the lipid A modification pathway is influenced by the host's nutritional immune response. H. pylori's exposure to the host Mn- and Zn-binding protein calprotectin perturbs the function of 3 enzymes involved in the lipid A modification pathway. Moreover, CP treatment of H. pylori, or mutants with an altered lipid A, exhibit increased bacterial fitness and increased biofilm formation. This suggests that H. pylori modifies its cell surface structure to survive under the stress imposed by the host immune response. These results provide new insights into the molecular mechanisms that influence the biofilm lifestyle and how endotoxin modification, which renders H. pylori resistant to cationic antimicrobial peptides, can be inactivated in response to sequestration of nutrient metals.