Victoria University

Identification of a meningococcal adhesin that inhibits epithelial cell migration

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dc.contributor.advisor MacKichan, Joanna
dc.contributor.advisor Carter, Philip Greig, Gabrielle 2020-03-19T03:32:59Z 2020-03-19T03:32:59Z 2020 2020
dc.description.abstract Neisseria meningitidis virulence is polygenic, therefore comparing many genomes may not yield strictly disease-associated virulence factors. An alternative approach is comparing closely related isolates, such as those from household contacts. Disease isolates have been shown to inhibit epithelial cell wound repair, while many carriage isolates do not. In this study, bacteria collected from disease patients and healthy household contacts were compared to identify the meningococcal factor responsible for wound repair inhibition and investigate how it contributes to invasive disease. Host cell wound repair inhibition was compared between disease-associated meningococcal isolate, NZ97/052, and isolates NZCM111 and NZCM112, from asymptomatic household contacts. Migrating bronchial airway cells were infected with meningococcal isolates and wound closure was evaluated by microscopy. NZ97/052 and NZCM111 both inhibited wound repair, whereas NZCM112 did not. To investigate if this was due to bacterial consumption of an important nutrient, infected cells were supplemented with nutrients known to be important for meningococcal growth and cell migration. Iron supplementation resulted in carriage associated isolates gaining the ability to inhibit wound repair. Genome and transcriptome comparisons were completed between NZ97/052 and NZCM112, which differ in wound repair inhibition. This analysis identified a frameshift mutation in NZCM112 in the haptoglobin-haemoglobin utilization gene, hpuA, which caused complete loss of expression. The hpuA gene was deleted by allelic replacement from NZ97/052, nullifying its ability to inhibit host cell migration. Furthermore, bacterial association and fluorescence microscopy assays suggested that HpuA contributes to meningococcal attachment to bronchial epithelial cells, as the hpuA mutant had significantly lower cell association. Heterologous expression of HpuA in E. coli resulted in higher levels of cell association, indicating that HpuA is sufficient to mediate bacterial adhesion to human bronchial epithelial cells. This work reveals novel roles for HpuA as a meningococcal adhesin and a bacterial factor that inhibits host cell migration. en_NZ
dc.language.iso en_NZ
dc.publisher Victoria University of Wellington en_NZ
dc.subject Neisseria meningitidis en_NZ
dc.subject HpuA en_NZ
dc.subject Molecular microbiology en_NZ
dc.subject Microbiology en_NZ
dc.subject Cell migration en_NZ
dc.subject Adhesin en_NZ
dc.subject Pathology en_NZ
dc.subject Invasive pathogen en_NZ
dc.subject Meningitis en_NZ
dc.subject Bacteria en_NZ
dc.title Identification of a meningococcal adhesin that inhibits epithelial cell migration en_NZ
dc.type Text en_NZ
vuwschema.contributor.unit School of Biological Sciences en_NZ
vuwschema.type.vuw Awarded Doctoral Thesis en_NZ Molecular Microbiology en_NZ Victoria University of Wellington en_NZ Doctoral en_NZ Doctor of Philosophy en_NZ
dc.rights.license Author Retains Copyright en_NZ 2020-03-14T10:22:37Z
vuwschema.subject.anzsrcfor 060501 Bacteriology en_NZ
vuwschema.subject.anzsrcfor 060599 Microbiology not elsewhere classified en_NZ
vuwschema.subject.anzsrcfor 060502 Infectious Agents en_NZ
vuwschema.subject.anzsrctoa 1 PURE BASIC RESEARCH en_NZ

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