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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.

Nuclear trafficking, histone cleavage and induction of apoptosis by the meningococcal A pp and M sp A autotransporters