Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0085437 (bacterial meningitis)
 4,038 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Pathogenic Neisseria species, the causative agents of gonorrhoea and bacterial meningitis, encode a family of polymorphic exo-proteins which are autoproteolytically processed into several distinct extracellular components, including an IgA1 protease and an alpha-protein. IgA1 protease, a putative virulence determinant, is a sequence-specific endopeptidase known to cleave human IgA1, but additional target proteins have been postulated. The physical linkage of IgA1 protease and alpha-protein suggests a functional relationship of both precursor components. Previous work has shown that alpha-protein is essential neither for extracellular transport nor for the proteolytic activity of IgA1 protease. Intriguingly, alpha-proteins carry amino acid sequences reminiscent of nuclear location signals of viral and eukaryotic proteins. Here we demonstrate the functionality of these nuclear location signal sequences in transfected eukaryotic cells. Chimeric alpha-proteins show nuclear transport and selectively associate with nucleolar structures. More importantly, native purified alpha-proteins are capable of entering certain human primary cells from the exterior via an endocytotic route and accumulate in the nuclei. The neisserial alpha-proteins share several features with eukaryotic transcription factors, such as the formation of dimers via a heptad repeat sequence. We propose a role for alpha-proteins in the regulation of host-cell functions. As the alpha-proteins are covalently connected with IgA1 protease they may also serve as carries for the IgA1 protease into human cells where additional proteolytic targets may exist. Neisseria meningitidis, which locally colonizes the nasopharyngeal mucosa of many human individuals without apparently causing symptoms, secretes this nucleus-targeted factor in large quantities.
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PMID:Uptake and nuclear transport of Neisseria IgA1 protease-associated alpha-proteins in human cells. 859 27

Neisseria meningitidis, a major cause of bacterial meningitis and septicaemia, secretes multiple virulence factors, including the adhesion and penetration protein (App) and meningococcal serine protease A (MspA). Both are conserved, immunogenic, type Va autotransporters harbouring S6-family serine endopeptidase domains. Previous work suggested that both could mediate adherence to human cells, but their precise contribution to meningococcal pathogenesis was unclear. Here, we confirm that App and MspA are in vivo virulence factors since human CD46-expressing transgenic mice infected with meningococcal mutants lacking App, MspA or both had improved survival rates compared with mice infected with wild type. Confocal imaging showed that App and MspA were internalized by human cells and trafficked to the nucleus. Cross-linking and enzyme-linked immuno assay (ELISA) confirmed that mannose receptor (MR), transferrin receptor 1 (TfR1) and histones interact with MspA and App. Dendritic cell (DC) uptake could be blocked using mannan and transferrin, the specific physiological ligands for MR and TfR1, whereas in vitro clipping assays confirmed the ability of both proteins to proteolytically cleave the core histone H3. Finally, we show that App and MspA induce a dose-dependent increase in DC death via caspase-dependent apoptosis. Our data provide novel insights into the roles of App and MspA in meningococcal infection.
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PMID:Nuclear trafficking, histone cleavage and induction of apoptosis by the meningococcal App and MspA autotransporters. 2560 Jan 71