A rare mutation in SPLUNC1 underlies meningococcal disease affecting bacterial adherence and invasion

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Title: A rare mutation in SPLUNC1 underlies meningococcal disease affecting bacterial adherence and invasion
Authors: Sancho Shimizu, V
Item Type: Journal Article
Abstract: Background Neisseriameningitidis (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 contribution of rare variants other than complement has not been determined. Methods 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 two patients with familial IMD. Candidate variants were further validated by in vitro assays. Results Exomes of two siblings with IMD identified a novel heterozygous missense mutation in BPIFA1/SPLUNC1. Sequencing of 186 other non-familial cases identified another unrelated IMD patient with the same mutation. SPLUNC1 is an innate immune defence protein expressed in the nasopharyngeal epithelia, however, its role in invasive infections is unknown. In vitro assays demonstrated that recombinant SPLUNC1 inhibits biofilm formation by Nm, and impedes Nm adhesion and invasion of human airway cells. The dominant negative mutant rSPLUNC1 (p.G22E) showed reduced anti-biofilm activity, increased meningococcal adhesion and invasion of cells compared with wild type SPLUNC1. Conclusions A mutation in SPLUNC1 affecting mucosal attachment, biofilm formation and invasion of mucosal epithelial cells is a new genetic cause of meningococcal disease.
Issue Date: 1-Jul-2019
Date of Acceptance: 28-Oct-2018
URI: http://hdl.handle.net/10044/1/71753
DOI: https://doi.org/10.1093/cid/ciz600
ISSN: 1058-4838
Publisher: Oxford University Press (OUP)
Journal / Book Title: Clinical Infectious Diseases
Copyright Statement: © The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.
Sponsor/Funder: Imperial College BRC
Imperial College Healthcare NHS Trust- BRC Funding
European Commission
Imperial College Healthcare NHS Trust- BRC Funding
Funder's Grant Number: P76547
Keywords: 06 Biological Sciences
11 Medical and Health Sciences
Publication Status: Accepted
Embargo Date: 2020-07-01
Open Access location: https://academic.oup.com/cid/advance-article/doi/10.1093/cid/ciz600/5526731
Online Publication Date: 2019-07-01
Appears in Collections:National Heart and Lung Institute
Department of Medicine

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