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Title: Structural, functional and immunogenic insights on Cu,Zn superoxide dismutase pathogenic virulence factors from Neisseria meningitidis and Brucella abortus

Abstract

Bacterial pathogens Neisseria meningitidis and Brucella abortus pose threats to human and animal health worldwide, causing meningococcal disease and brucellosis, respectively. Mortality from acute N. meningitidis infections remains high despite antibiotics, and brucellosis presents alimentary and health consequences. Superoxide dismutases are master regulators of reactive oxygen and general pathogenicity factors and are therefore therapeutic targets. Cu,Zn superoxide dismutases (SODs) localized to the periplasm promote survival by detoxifying superoxide radicals generated by major host antimicrobial immune responses. We discovered that passive immunization with an antibody directed at N. meningitidis SOD (NmSOD) was protective in a mouse infection model. To define the relevant atomic details and solution assembly states of this important virulence factor, we report high-resolution and X-ray scattering analyses of NmSOD and of SOD from B. abortus (BaSOD). The NmSOD structures revealed an auxiliary tetrahedral Cu-binding site bridging the dimer interface; mutational analyses suggested that this metal site contributes to protein stability, with implications for bacterial defense mechanisms. Biochemical and structural analyses informed us about electrostatic substrate guidance, dimer assembly, and an exposed C-terminal epitope in the NmSOD dimer. In contrast, the monomeric BaSOD structure provided insights for extending immunogenic peptide epitopes derived from the protein. These collective results revealmore » unique contributions of SOD to pathogenic virulence, refine predictive motifs for distinguishing SOD classes, and suggest general targets for antibacterial immune responses. Furthermore, the identified functional contributions, motifs, and targets distinguishing bacterial and eukaryotic SOD assemblies presented here provide a foundation for efforts to develop SOD-specific inhibitors of or vaccines against these harmful pathogens.« less

Authors:
 [1];  [2];  [1];  [3];  [2];  [4];  [5];  [6];  [4];  [6];  [7];  [2]
  1. The Scripps Research Institute, La Jolla, CA (United States); Lawrence Berkeley National Lab., Berkeley, CA (United States)
  2. The Scripps Research Institute, La Jolla, CA (United States)
  3. Brookhaven National Lab. (BNL), Upton, NY (United States)
  4. National Animal Disease Center, Ames, IA (United States)
  5. Public Health England (previously The Health Protection Agency), Salisbury (United Kingdom)
  6. Imperial College, London (United Kingdom)
  7. Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States); Univ. of Texas M.D. Anderson Cancer Center, Houston, TX (United States)
Publication Date:
Research Org.:
Brookhaven National Laboratory (BNL), Upton, NY (United States)
Sponsoring Org.:
USDOE Office of Science (SC), Basic Energy Sciences (BES)
OSTI Identifier:
1224775
Alternate Identifier(s):
OSTI ID: 1235891
Report Number(s):
BNL-108508-2015-JA; BNL-111744-2016-JA
Journal ID: ISSN 0021-9193; R&D Project: CO004; KC0304030
Grant/Contract Number:  
SC0012704
Resource Type:
Journal Article: Accepted Manuscript
Journal Name:
Journal of Bacteriology
Additional Journal Information:
Journal Volume: 197; Journal Issue: 24; Journal ID: ISSN 0021-9193
Publisher:
American Society for Microbiology
Country of Publication:
United States
Language:
English
Subject:
38 RADIATION CHEMISTRY, RADIOCHEMISTRY, AND NUCLEAR CHEMISTRY; Laser Electron Accelerator Facility (LEAF)

Citation Formats

Pratt, Ashley J., DiDonato, Michael, Shin, David S., Cabelli, Diane E., Bruns, Cami K., Belzer, Carol A., Gorringe, Andrew R., Langford, Paul R., Tabatabai, Louisa B., Kroll, J. Simon, Tainer, John A., and Getzoff, Elizabeth D. Structural, functional and immunogenic insights on Cu,Zn superoxide dismutase pathogenic virulence factors from Neisseria meningitidis and Brucella abortus. United States: N. p., 2015. Web. doi:10.1128/JB.00343-15.
Pratt, Ashley J., DiDonato, Michael, Shin, David S., Cabelli, Diane E., Bruns, Cami K., Belzer, Carol A., Gorringe, Andrew R., Langford, Paul R., Tabatabai, Louisa B., Kroll, J. Simon, Tainer, John A., & Getzoff, Elizabeth D. Structural, functional and immunogenic insights on Cu,Zn superoxide dismutase pathogenic virulence factors from Neisseria meningitidis and Brucella abortus. United States. https://doi.org/10.1128/JB.00343-15
Pratt, Ashley J., DiDonato, Michael, Shin, David S., Cabelli, Diane E., Bruns, Cami K., Belzer, Carol A., Gorringe, Andrew R., Langford, Paul R., Tabatabai, Louisa B., Kroll, J. Simon, Tainer, John A., and Getzoff, Elizabeth D. 2015. "Structural, functional and immunogenic insights on Cu,Zn superoxide dismutase pathogenic virulence factors from Neisseria meningitidis and Brucella abortus". United States. https://doi.org/10.1128/JB.00343-15. https://www.osti.gov/servlets/purl/1224775.
@article{osti_1224775,
title = {Structural, functional and immunogenic insights on Cu,Zn superoxide dismutase pathogenic virulence factors from Neisseria meningitidis and Brucella abortus},
author = {Pratt, Ashley J. and DiDonato, Michael and Shin, David S. and Cabelli, Diane E. and Bruns, Cami K. and Belzer, Carol A. and Gorringe, Andrew R. and Langford, Paul R. and Tabatabai, Louisa B. and Kroll, J. Simon and Tainer, John A. and Getzoff, Elizabeth D.},
abstractNote = {Bacterial pathogens Neisseria meningitidis and Brucella abortus pose threats to human and animal health worldwide, causing meningococcal disease and brucellosis, respectively. Mortality from acute N. meningitidis infections remains high despite antibiotics, and brucellosis presents alimentary and health consequences. Superoxide dismutases are master regulators of reactive oxygen and general pathogenicity factors and are therefore therapeutic targets. Cu,Zn superoxide dismutases (SODs) localized to the periplasm promote survival by detoxifying superoxide radicals generated by major host antimicrobial immune responses. We discovered that passive immunization with an antibody directed at N. meningitidis SOD (NmSOD) was protective in a mouse infection model. To define the relevant atomic details and solution assembly states of this important virulence factor, we report high-resolution and X-ray scattering analyses of NmSOD and of SOD from B. abortus (BaSOD). The NmSOD structures revealed an auxiliary tetrahedral Cu-binding site bridging the dimer interface; mutational analyses suggested that this metal site contributes to protein stability, with implications for bacterial defense mechanisms. Biochemical and structural analyses informed us about electrostatic substrate guidance, dimer assembly, and an exposed C-terminal epitope in the NmSOD dimer. In contrast, the monomeric BaSOD structure provided insights for extending immunogenic peptide epitopes derived from the protein. These collective results reveal unique contributions of SOD to pathogenic virulence, refine predictive motifs for distinguishing SOD classes, and suggest general targets for antibacterial immune responses. Furthermore, the identified functional contributions, motifs, and targets distinguishing bacterial and eukaryotic SOD assemblies presented here provide a foundation for efforts to develop SOD-specific inhibitors of or vaccines against these harmful pathogens.},
doi = {10.1128/JB.00343-15},
url = {https://www.osti.gov/biblio/1224775}, journal = {Journal of Bacteriology},
issn = {0021-9193},
number = 24,
volume = 197,
place = {United States},
year = {Mon Oct 12 00:00:00 EDT 2015},
month = {Mon Oct 12 00:00:00 EDT 2015}
}

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Works referencing / citing this record:

Immune Response to Mucosal Brucella Infection
journal, August 2019


Antigenicity of Brucella Proteins by the Elisa test
journal, March 2019