Salmonella enterica Serovar Typhimurium Uses PbgA/YejM To Regulate Lipopolysaccharide Assembly during Bacteremia
Salmonella enterica Serovar Typhimurium Uses PbgA/YejM To Regulate Lipopolysaccharide Assembly during Bacteremia
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DOI：
10.1128/iai.00758-19
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发表时间：
2020-01-01
影响因子：
3.1
通讯作者：
Dalebroux, Zachary D.
中科院分区：
文献类型：
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作者：
Cian, Melina;Giordano, Nicole;Dalebroux, Zachary D.
鼠伤寒沙门氏菌依靠内膜蛋白PbgA增强外膜完整性，提高小鼠的致病力。PbgA的跨膜结构域(残基1到190)是生存所必需的，而周质结构域(残基191到586)是必不可少的。碱性区域内的残基(残基191至245)与酸性磷酸盐结合在极性磷脂上，如心磷脂，是沙门氏菌OM完整性所必需的。鼠伤寒沙门氏菌在激活PhoPQ调节剂期间增加其OM心磷脂浓度。其机制涉及PbgA的周质球状区域(残基245至586)，但增加心磷脂表面的生物学作用尚不清楚。在pbgA Delta 191-586突变体中，LapB(也称为yciM)、FtsH和IpxC这三种重要的脂多糖合成调节因子的非同义多态不同程度地抑制了OM完整性、利福平耐药性、巨噬细胞存活率和小鼠全身定植方面的缺陷(该突变缺失了pbgA 191-586残基的周质区域)。与野生型沙门氏菌的OM相比，pbgA突变体的OM具有更高的脂A核心分子、心磷脂和磷脂酰乙醇胺水平，而环丙化脂肪酸降低了特定磷脂的水平。LapB和LpxC的互补和替换突变通常恢复了pbgA突变体的磷脂和脂多糖组装缺陷。在菌血症期间，感染pbgA突变体的小鼠存活并清除了细菌，而感染野生型沙门氏菌的动物在1周内死亡。值得注意的是，野生型小鼠在肝脏和脾中携带pbgA-IpxC沙门氏菌后无症状存活了几个月，但Toll样受体4缺陷的动物在大约一周内死于这些感染。综上所述，鼠伤寒沙门氏菌利用PbgA在胁迫过程中影响内毒素的组装，以便在宿主环境中生存、适应和增殖。
Salmonella enterica serovar Typhimurium (S. Typhimurium) relies upon the inner membrane protein PbgA to enhance outer membrane (OM) integrity and promote virulence in mice. The PbgA transmembrane domain (residues 1 to 190) is essential for viability, while the periplasmic domain (residues 191 to 586) is dispensable. Residues within the basic region (residues 191 to 245) bind acidic phosphates on polar phospholipids, like for cardiolipins, and are necessary for salmonella OM integrity. S. Typhimurium bacteria increase their OM cardiolipin concentrations during activation of the PhoPQ regulators. The mechanism involves PbgA's periplasmic globular region (residues 245 to 586), but the biological role of increasing cardiolipins on the surface is not understood. Nonsynonymous polymorphisms in three essential lipopolysaccharide (LPS) synthesis regulators, lapB (also known as yciM), ftsH, and IpxC, variably suppressed the defects in OM integrity, rifampin resistance, survival in macrophages, and systemic colonization of mice in the pbgA Delta 191-586 mutant (in which the PbgA periplasmic domain from residues 191 to 586 is deleted). Compared to the OMs of the wild-type salmonellae, the OMs of the pbgA mutants had increased levels of lipid A-core molecules, cardiolipins, and phosphatidylethano-lamines and decreased levels of specific phospholipids with cyclopropanated fatty acids. Complementation and substitution mutations in LapB and LpxC generally restored the phospholipid and LPS assembly defects for the pbgA mutants. During bacteremia, mice infected with the pbgA mutants survived and cleared the bacteria, while animals infected with wild-type salmonellae succumbed within 1 week. Remarkably, wild-type mice survived asymptomatically with pbgA-IpxC salmonellae in their livers and spleens for months, but Toll-like receptor 4-deficient animals succumbed to these infections within roughly 1 week. In summary, S. Typhimurium uses PbgA to influence LPS assembly during stress in order to survive, adapt, and proliferate within the host environment.