A Rare Mutation in SPLUNC1 Affects Bacterial Adherence and Invasion in Meningococcal Disease
| Autor: | Bayarchimeg Mashbat, Evangelos Bellos, Stephanie Hodeib, Fadil Bidmos, Ryan S Thwaites, Yaxuan Lu, Victoria J Wright, Jethro A Herberg, Daniela S Klobassa, William G Walton, Werner Zenz, Trevor T Hansel, Simon Nadel, Paul R Langford, Luregn J Schlapbach, Ming-Shi Li, Matthew R Redinbo, Y Peter Di, Michael Levin, Vanessa Sancho-Shimizu |
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| Přispěvatelé: | University of Zurich |
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Microbiology (medical) human genetics 610 Medicine & health Neisseria meningitidis Dominant-Negative Mutation Meningococcal disease medicine.disease_cause severe infectious disease Microbiology sepsis 03 medical and health sciences 0302 clinical medicine medicine Humans media_common.cataloged_instance Missense mutation European union Articles and Commentaries Exome sequencing Glycoproteins media_common meningococcal disease Innate immune system business.industry Epithelial Cells Complement System Proteins Phosphoproteins medicine.disease Meningococcal Infections AcademicSubjects/MED00290 030104 developmental biology Infectious Diseases 10036 Medical Clinic Infectious disease (medical specialty) Mutation mucosal immunity business 030215 immunology |
| Zdroj: | Clinical Infectious Diseases: An Official Publication of the Infectious Diseases Society of America |
| ISSN: | 1537-6591 1058-4838 |
| DOI: | 10.1093/cid/ciz600 |
| Popis: | Background 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. 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 2 patients with familial IMD. Candidate variants were further validated by in vitro assays. Results 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. Conclusions A mutation in SPLUNC1 affecting mucosal attachment, biofilm formation, and invasion of mucosal epithelial cells is a new genetic cause of meningococcal disease. Severe meningococcal disease may result from single-gene inborn errors of immunity, affecting bacterial colonization, biofilm formation, and invasion. Our findings demonstrate the host protective role SPLUNC1 plays in maintaining mucosal immunity in the upper respiratory tract, and preventing invasive disease. |
| Databáze: | OpenAIRE |
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