Department of Paediatric Infectious Diseases, Division of Medicine, Imperial College London, Norfolk Place, United Kingdom.
National Heart and Lung Institute, Imperial College London, United Kingdom.
Clin Infect Dis. 2020 May 6;70(10):2045-2053. doi: 10.1093/cid/ciz600.
Neisseria meningitidis (Nm) is a nasopharyngeal commensal carried by healthy individuals. However, invasive infections occurs in a minority of individuals, with devastating consequences. There is evidence that common polymorphisms are associated with invasive meningococcal disease (IMD), but the contributions of rare variants other than those in the complement system have not been determined.
We identified familial cases of IMD in the UK meningococcal disease study and the European Union Life-Threatening Infectious Disease Study. Candidate genetic variants were identified by whole-exome sequencing of 2 patients with familial IMD. Candidate variants were further validated by in vitro assays.
Exomes of 2 siblings with IMD identified a novel heterozygous missense mutation in BPIFA1/SPLUNC1. Sequencing of 186 other nonfamilial cases identified another unrelated IMD patient with the same mutation. SPLUNC1 is an innate immune defense protein expressed in the nasopharyngeal epithelia; however, its role in invasive infections is unknown. In vitro assays demonstrated that recombinant SPLUNC1 protein inhibits biofilm formation by Nm, and impedes Nm adhesion and invasion of human airway cells. The dominant negative mutant recombinant SPLUNC1 (p.G22E) showed reduced antibiofilm activity, increased meningococcal adhesion, and increased invasion of cells, compared with wild-type SPLUNC1.
A mutation in SPLUNC1 affecting mucosal attachment, biofilm formation, and invasion of mucosal epithelial cells is a new genetic cause of meningococcal disease.
脑膜炎奈瑟菌（Nm）是一种存在于健康个体鼻咽部的共生菌。然而，侵袭性感染仅发生在少数个体中，会产生毁灭性的后果。有证据表明常见的多态性与侵袭性脑膜炎球菌病（IMD）有关，但尚未确定除补体系统以外的稀有变异体的贡献。
我们在英国脑膜炎球菌病研究和欧盟危及生命的传染病研究中确定了 IMD 的家族病例。通过对 2 例家族性 IMD 患者的全外显子组测序鉴定候选遗传变异。通过体外实验进一步验证候选变异。
2 例 IMD 同胞的外显子组鉴定出 BPIFA1/SPLUNC1 中的一种新型杂合错义突变。对 186 例其他非家族性病例的测序确定了另一位患有相同突变的无关 IMD 患者。SPLUNC1 是一种在鼻咽上皮细胞中表达的固有免疫防御蛋白，但它在侵袭性感染中的作用尚不清楚。体外实验表明，重组 SPLUNC1 蛋白抑制 Nm 的生物膜形成，并阻碍 Nm 对人气道细胞的黏附和侵袭。与野生型 SPLUNC1 相比，显性负突变重组 SPLUNC1（p.G22E）表现出降低的抗生物膜活性、增加的脑膜炎球菌黏附性和增加的细胞侵袭性。
影响黏膜附着、生物膜形成和黏膜上皮细胞侵袭的 SPLUNC1 突变是脑膜炎球菌病的一个新的遗传病因。
