Gaddy Jennifer A, Radin Jana N, Loh John T, Piazuelo M Blanca, Kehl-Fie Thomas E, Delgado Alberto G, Ilca Florin T, Peek Richard M, Cover Timothy L, Chazin Walter J, Skaar Eric P, Scott Algood Holly M
Veterans Affairs Tennessee Valley Healthcare Services, Nashville, Tennessee, United States of America; Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America.
Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America.
PLoS Pathog. 2014 Oct 16;10(10):e1004450. doi: 10.1371/journal.ppat.1004450. eCollection 2014 Oct.
Transition metals are necessary for all forms of life including microorganisms, evidenced by the fact that 30% of all proteins are predicted to interact with a metal cofactor. Through a process termed nutritional immunity, the host actively sequesters essential nutrient metals away from invading pathogenic bacteria. Neutrophils participate in this process by producing several metal chelating proteins, including lactoferrin and calprotectin (CP). As neutrophils are an important component of the inflammatory response directed against the bacterium Helicobacter pylori, a major risk factor for gastric cancer, it was hypothesized that CP plays a role in the host response to H. pylori. Utilizing a murine model of H. pylori infection and gastric epithelial cell co-cultures, the role CP plays in modifying H. pylori -host interactions and the function of the cag Type IV Secretion System (cag T4SS) was investigated. This study indicates elevated gastric levels of CP are associated with the infiltration of neutrophils to the H. pylori-infected tissue. When infected with an H. pylori strain harboring a functional cag T4SS, calprotectin-deficient mice exhibited decreased bacterial burdens and a trend toward increased cag T4SS -dependent inflammation compared to wild-type mice. In vitro data demonstrate that culturing H. pylori with sub-inhibitory doses of CP reduces the activity of the cag T4SS and the biogenesis of cag T4SS-associated pili in a zinc-dependent fashion. Taken together, these data indicate that zinc homeostasis plays a role in regulating the proinflammatory activity of the cag T4SS.
过渡金属对于包括微生物在内的所有生命形式都是必需的，这一点可由以下事实证明：预计所有蛋白质中有30%会与金属辅因子相互作用。通过一种称为营养免疫的过程，宿主会主动将必需的营养金属从入侵的病原菌中隔离出来。中性粒细胞通过产生几种金属螯合蛋白参与这一过程，包括乳铁蛋白和钙卫蛋白（CP）。由于中性粒细胞是针对幽门螺杆菌（胃癌的主要危险因素）的炎症反应的重要组成部分，因此推测CP在宿主对幽门螺杆菌的反应中起作用。利用幽门螺杆菌感染的小鼠模型和胃上皮细胞共培养，研究了CP在改变幽门螺杆菌与宿主相互作用以及cag IV型分泌系统（cag T4SS）功能方面所起的作用。这项研究表明，胃中CP水平升高与中性粒细胞向幽门螺杆菌感染组织的浸润有关。当感染携带功能性cag T4SS的幽门螺杆菌菌株时，与野生型小鼠相比，缺乏钙卫蛋白的小鼠细菌载量降低，并且cag T4SS依赖性炎症有增加的趋势。体外数据表明，用亚抑制剂量的CP培养幽门螺杆菌会以锌依赖的方式降低cag T4SS的活性以及cag T4SS相关菌毛的生物合成。综上所述，这些数据表明锌稳态在调节cag T4SS的促炎活性中起作用。
