Open AccessNuclear trafficking, histone cleavage and induction of apoptosis by the meningococcal A pp and M sp A autotransporters
Author(s) -
Khairalla Ahmed S.,
Omer Sherko A.,
Mahdavi Jafar,
Aslam Akhmed,
Dufailu Osman A.,
Self Tim,
Jonsson AnnBeth,
Geörg Miriam,
Sjölinder Hong,
Royer PierreJoseph,
MartinezPomares Luisa,
Ghaemmaghami Amir M.,
Wooldridge Karl G.,
Oldfield Neil J.,
Ala'Aldeen Dlawer A.A.
Publication year - 2015
Publication title -
cellular microbiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.542
H-Index - 138
eISSN - 1462-5822
pISSN - 1462-5814
DOI - 10.1111/cmi.12417
Subject(s) - biology , transferrin receptor , virulence , microbiology and biotechnology , neisseria meningitidis , serine protease , transferrin , protease , gene , genetics , biochemistry , bacteria , enzyme
Summary N eisseria meningitidis , a major cause of bacterial meningitis and septicaemia, secretes multiple virulence factors, including the adhesion and penetration protein ( A pp) and meningococcal serine protease A ( MspA ). Both are conserved, immunogenic, type V a autotransporters harbouring S 6‐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 A pp and MspA are in vivo virulence factors since human CD 46‐expressing transgenic mice infected with meningococcal mutants lacking A pp, MspA or both had improved survival rates compared with mice infected with wild type. Confocal imaging showed that A pp 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 ( TfR 1) and histones interact with MspA and A pp. Dendritic cell ( DC ) uptake could be blocked using mannan and transferrin, the specific physiological ligands for MR and TfR 1, whereas in vitro clipping assays confirmed the ability of both proteins to proteolytically cleave the core histone H 3. Finally, we show that A pp and MspA induce a dose‐dependent increase in DC death via caspase‐dependent apoptosis. Our data provide novel insights into the roles of A pp and MspA in meningococcal infection.