%0 Journal Article %1 madico_meningococcal_2006 %A Madico, Guillermo %A Welsch, Jo Anne %A Lewis, Lisa A %A McNaughton, Anne %A Perlman, David H %A Costello, Catherine E %A Ngampasutadol, Jutamas %A Vogel, Ulrich %A Granoff, Dan M %A Ram, Sanjay %D 2006 %J Journal of Immunology (Baltimore, Md.: 1950) %K Acid Activity, Adhesion, Adjuvants, Adult, Alternative, Amino Antibodies, Antibody, Antigens, Bacterial Bacterial, Bactericidal Binding Binding, Blood Competitive, Complement Data, Deletion, Factor Gene Genetic H, Humans, Immunologic, Ligands, Membrane Meningococcal Molecular Monoclonal, Neisseria Outer Pathway, Porins, Proteins, Sequence Sequence, Sites, Vaccines, Variation, meningitidis, {DNA} %N 1 %P 501--510 %T The meningococcal vaccine candidate GNA1870 binds the complement regulatory protein factor H and enhances serum resistance %U http://www.ncbi.nlm.nih.gov/pubmed/16785547 %V 177 %X Neisseria meningitidis binds factor H (fH), a key regulator of the alternative complement pathway. A approximately 29 kD fH-binding protein expressed in the meningococcal outer membrane was identified by mass spectrometry as GNA1870, a lipoprotein currently under evaluation as a broad-spectrum meningococcal vaccine candidate. GNA1870 was confirmed as the fH ligand on intact bacteria by 1) abrogation of fH binding upon deleting GNA1870, and 2) blocking fH binding by anti-GNA1870 mAbs. fH bound to whole bacteria and purified rGNA1870 representing each of the three variant GNA1870 families. We showed that the amount of fH binding correlated with the level of bacterial GNA1870 expression. High levels of variant 1 GNA1870 expression (either by allelic replacement of gna1870 or by plasmid-driven high-level expression) in strains that otherwise were low-level GNA1870 expressers (and bound low amounts of fH by flow cytometry) restored high levels of fH binding. Diminished fH binding to the GNA1870 deletion mutants was accompanied by enhanced C3 binding and increased killing of the mutants. Conversely, high levels of GNA1870 expression and fH binding enhanced serum resistance. Our findings support the hypothesis that inhibiting the binding of a complement down-regulator protein to the neisserial surface by specific Ab may enhance intrinsic bactericidal activity of the Ab, resulting in two distinct mechanisms of Ab-mediated vaccine efficacy. These data provide further support for inclusion of this molecule in a meningococcal vaccine. To reflect the critical function of this molecule, we suggest calling it fH-binding protein.

@article{madico_meningococcal_2006, abstract = {Neisseria meningitidis binds factor H {(fH)}, a key regulator of the alternative complement pathway. A approximately 29 {kD} {fH-binding} protein expressed in the meningococcal outer membrane was identified by mass spectrometry as {GNA1870}, a lipoprotein currently under evaluation as a broad-spectrum meningococcal vaccine candidate. {GNA1870} was confirmed as the {fH} ligand on intact bacteria by 1) abrogation of {fH} binding upon deleting {GNA1870}, and 2) blocking {fH} binding by {anti-GNA1870} {mAbs.} {fH} bound to whole bacteria and purified {rGNA1870} representing each of the three variant {GNA1870} families. We showed that the amount of {fH} binding correlated with the level of bacterial {GNA1870} expression. High levels of variant 1 {GNA1870} expression (either by allelic replacement of gna1870 or by plasmid-driven high-level expression) in strains that otherwise were low-level {GNA1870} expressers (and bound low amounts of {fH} by flow cytometry) restored high levels of {fH} binding. Diminished {fH} binding to the {GNA1870} deletion mutants was accompanied by enhanced C3 binding and increased killing of the mutants. Conversely, high levels of {GNA1870} expression and {fH} binding enhanced serum resistance. Our findings support the hypothesis that inhibiting the binding of a complement down-regulator protein to the neisserial surface by specific Ab may enhance intrinsic bactericidal activity of the Ab, resulting in two distinct mechanisms of Ab-mediated vaccine efficacy. These data provide further support for inclusion of this molecule in a meningococcal vaccine. To reflect the critical function of this molecule, we suggest calling it {fH-binding} protein.}, added-at = {2011-06-24T11:21:47.000+0200}, author = {Madico, Guillermo and Welsch, Jo Anne and Lewis, Lisa A and {McNaughton}, Anne and Perlman, David H and Costello, Catherine E and Ngampasutadol, Jutamas and Vogel, Ulrich and Granoff, Dan M and Ram, Sanjay}, biburl = {https://www.bibsonomy.org/bibtex/29e305f108b2b87dfc4298cfbc891ac2e/ag_vogel}, interhash = {da5865e0f2fc760c932458ef542e560d}, intrahash = {9e305f108b2b87dfc4298cfbc891ac2e}, issn = {0022-1767}, journal = {Journal of Immunology {(Baltimore}, Md.: 1950)}, keywords = {Acid Activity, Adhesion, Adjuvants, Adult, Alternative, Amino Antibodies, Antibody, Antigens, Bacterial Bacterial, Bactericidal Binding Binding, Blood Competitive, Complement Data, Deletion, Factor Gene Genetic H, Humans, Immunologic, Ligands, Membrane Meningococcal Molecular Monoclonal, Neisseria Outer Pathway, Porins, Proteins, Sequence Sequence, Sites, Vaccines, Variation, meningitidis, {DNA}}, month = jul, note = {{PMID:} 16785547}, number = 1, pages = {501--510}, timestamp = {2011-06-24T11:21:50.000+0200}, title = {The meningococcal vaccine candidate {GNA1870} binds the complement regulatory protein factor H and enhances serum resistance}, url = {http://www.ncbi.nlm.nih.gov/pubmed/16785547}, volume = 177, year = 2006 }