title: Meningococcal outer membrane protein NhhA triggers apoptosis in macrophages.
abstract: Phagocytotic cells play a fundamental role in the defense against bacterial pathogens. One mechanism whereby bacteria evade phagocytosis is to produce factors that trigger apoptosis. Here we identify for the first time a meningococcal protein capable of inducing macrophage apoptosis. The conserved meningococcal outer membrane protein NhhA (Neisseria hia/hsf homologue A, also known as Hsf) mediates bacterial adhesion and interacts with extracellular matrix components heparan sulphate and laminin. Meningococci lacking NhhA fail to colonise nasal mucosa in a mouse model of meningococcal disease. We found that exposure of macrophages to NhhA resulted in a highly increased rate of apoptosis that proceeded through caspase activation. Exposure of macrophages to NhhA also led to iNOS induction and nitric oxide production. However, neither nitric oxide production nor TNF-α signaling was found to be a prerequisite for NhhA-induced apoptosis. Macrophages exposed to wildtype NhhA-expressing meningococci were also found to undergo apoptosis whereas NhhA-deficient meningococci had a markedly decreased capacity to induce macrophage apoptosis. These data provide new insights on the role of NhhA in meningococcal disease. NhhA-induced macrophage apoptosis could be a mechanism whereby meningococci evade immunoregulatory and phagocytotic actions of macrophages.
authors.affiliation: Department of Genetics, Microbiology and Toxicology, Stockholm University, Stockholm, Sweden.
authors.forename: Mikael
authors.initials: M
authors.lastname: Sjölinder
authors.forename: Georg
authors.initials: G
authors.lastname: Altenbacher
authors.forename: Matthias
authors.initials: M
authors.lastname: Hagner
authors.forename: Wei
authors.initials: W
authors.lastname: Sun
authors.forename: Sophia
authors.initials: S
authors.lastname: Schedin-Weiss
authors.forename: Hong
authors.initials: H
authors.lastname: Sjölinder
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D001425:Bacterial Outer Membrane Proteins / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology / Q000502:physiology*; D019070:Cell Lineage; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D008589:Meningococcal Infections / Q000276:immunology / Q000473:pathology*; D051379:Mice; D009000:Monocytes / Q000166:cytology / Q000502:physiology; D009345:Neisseria meningitidis / Q000235:genetics / Q000378:metabolism*; D009569:Nitric Oxide / Q000378:metabolism / Q000502:physiology; D011485:Protein Binding; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D001425:Bacterial Outer Membrane Proteins; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide