Imperial College London
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DrRyanThwaites

Faculty of Medicine, National Heart & Lung Institute

Lecturer in Respiratory Immunology
 
 
 
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r.thwaites

 
 
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Respiratory InfectionsMedical SchoolSt Mary's Campus

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Summary

 

Publications

Citation

BibTex format

@article{Mashbat:2020:cid/ciz600,
author = {Mashbat, B and Bellos, E and Hodeib, S and Bidmos, F and Thwaites, RS and Lu, Y and Wright, VJ and Herberg, JA and Klobassa, DS and Zenz, W and Hansel, TT and Nadel, S and Langford, PR and Schlapbach, LJ and Li, M-S and Redinbo, MR and Di, YP and Levin, M and Sancho-Shimizu, V},
doi = {cid/ciz600},
journal = {Clinical Infectious Diseases},
pages = {2045--2053},
title = {A rare mutation in SPLUNC1 underlies meningococcal disease affecting bacterial adherence and invasion},
url = {http://dx.doi.org/10.1093/cid/ciz600},
volume = {70},
year = {2020}
}
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RIS format (EndNote, RefMan)

TY  - JOUR
AB  - BackgroundNeisseriameningitidis (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.MethodsWe 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.ResultsExomes 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.ConclusionsA mutation in SPLUNC1 affecting mucosal attachment, biofilm formation and invasion of mucosal epithelial cells is a new genetic cause of meningococcal disease.
AU  - Mashbat,B
AU  - Bellos,E
AU  - Hodeib,S
AU  - Bidmos,F
AU  - Thwaites,RS
AU  - Lu,Y
AU  - Wright,VJ
AU  - Herberg,JA
AU  - Klobassa,DS
AU  - Zenz,W
AU  - Hansel,TT
AU  - Nadel,S
AU  - Langford,PR
AU  - Schlapbach,LJ
AU  - Li,M-S
AU  - Redinbo,MR
AU  - Di,YP
AU  - Levin,M
AU  - Sancho-Shimizu,V
DO  - cid/ciz600
EP  - 2053
PY  - 2020///
SN  - 1058-4838
SP  - 2045
TI  - A rare mutation in SPLUNC1 underlies meningococcal disease affecting bacterial adherence and invasion
T2  - Clinical Infectious Diseases
UR  - http://dx.doi.org/10.1093/cid/ciz600
UR  - https://academic.oup.com/cid/advance-article/doi/10.1093/cid/ciz600/5526731
UR  - http://hdl.handle.net/10044/1/71753
VL  - 70
ER  -
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