Critical determinants of the interactions of capsule-expressing Neisseria meningitidis with host cells:: the role of receptor density in increased cellular targeting via the outer membrane Opa proteins
Critical determinants of the interactions of capsule-expressing Neisseria meningitidis with host cells:: the role of receptor density in increased cellular targeting via the outer membrane Opa proteins
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DOI：
10.1111/j.1462-5822.2005.00572.x
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发表时间：
2005-10-01
影响因子：
3.4
通讯作者：
Virji, M
中科院分区：
文献类型：
--
作者：
Bradley, CJ;Griffiths, NJ;Virji, M
脑膜炎奈瑟菌荚膜是在血液中存活所需的重要毒力决定因子，但据报道参与抑制脑膜炎球菌外膜粘附素介导的细胞相互作用。然而，来自我们先前研究的证据表明，宿主细胞上的靶受体密度可能决定荚膜细菌是否可以通过外膜蛋白如Opa粘附。为了证实这一点并评估胶囊化对细菌相互作用的影响，我们使用了胶囊化和无胶囊化脑膜炎球菌分离株的Opa（+）和Opa（-）衍生物以及表达CEACAM 1（Opa蛋白靶向的受体）的转染细胞系。为了评估细胞缔合的程度和速率，衍生了具有不同受体水平的稳定转染的中国仓鼠卵巢细胞亚群。证明了CEACAM 1水平与荚膜和无荚膜细菌两者的Opa依赖性结合的定量相关性，其在高受体密度下加速。然而，似乎只有当CEACAM密度达到阈值水平时，Opa（+）荚膜细菌的入侵才会发生。表达高水平CEACAM 1的靶细胞（MFI c. 400)结合3倍以上，但内化20倍以上的Opa（+）荚膜细菌比那些具有中间表达（MFI c. 100）。在内化群体中未观察到无囊表型的总体选择。这些观察结果证实，荚膜可能不是细胞相互作用的充分屏障，并证明了宿主因子的作用，可能决定荚膜细菌入侵的潜力。可响应于炎性细胞因子而发生的CEACAMs的上调可导致少量完全被囊化的细菌穿过粘膜上皮易位到血流中，足以引起播散性疾病的快速发作。因此，这些数据也为流行病学观察提供了一个新的理论基础，即先前患有感染/炎症性疾病的个体患侵袭性脑膜炎球菌病的风险很高。
Neisseria meningitidis capsule is an important virulence determinant required for survival in the blood but is reportedly involved in inhibiting cellular interactions mediated by meningococcal outer membrane adhesins. However, evidence from our previous studies suggested that target receptor density on host cells may determine whether or not capsulate bacteria can adhere via outer membrane proteins such as Opa. To confirm this and evaluate the impact of capsulation on bacterial interactions, we used Opa(+) and Opa(-) derivatives of capsulate and acapsulate meningococcal isolates and transfected cell lines expressing CEACAM1, a receptor targeted by Opa proteins. To assess the extent and rate of cell association, subpopulations of stably transfected Chinese hamster ovary cells with different receptor levels were derived. A quantitative correlation of CEACAM1 levels and Opa-dependent binding of both capsulate and acapsulate bacteria was demonstrated, which was accelerated at high receptor densities. However, it appears that invasion by Opa(+) capsulate bacteria only occurs when a threshold level of CEACAM density has been reached. Target cells expressing high levels of CEACAM1 (MFI c. 400) bound threefold more, but internalized 20-fold more Opa(+) capsulate bacteria than those with intermediate expression (MFI c. 100). No overall selection of acapsulate phenotype was observed in the internalized population. These observations confirm that capsule may not be an adequate barrier for cellular interactions and demonstrate the role of a host factor that may determine capsulate bacterial invasion potential. Upregulation of CEACAMs, which can occur in response to inflammatory cytokines, could lead to translocation of a small number of fully capsulate bacteria across mucosal epithelium into the bloodstream sufficient to cause a rapid onset of disseminated disease. Thus the data also suggest a novel rationale for the epidemiological observations that individuals with prior infectious/inflammatory conditions carry a high risk of invasive meningococcal disease.