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

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, general pathogenicity factors and 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 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 ofmore » SOD to pathogenic virulence, refine predictive motifs for distinguishing SOD classes and suggest general targets for anti-bacterial immune responses. 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 or vaccines against these harmful pathogens. IMPORTANCE By protecting microbes against reactive oxygen insults, Cu,Zn superoxide dismutases (SODs) aid survival of many bacteria within their hosts. Despite the ubiquity and conservation of these key enzymes, notable species-specific differences relevant to pathogenesis remain undefined. To probe mechanisms that govern the functioning of Neisseria meningitidis and Brucella abortus SODs, we used X-ray structures, enzymology, modeling and murine infection experiments. We identified virulence determinants common to both homologs, assembly differences and a unique metal reservoir within meningococcal SOD that stabilizes the enzyme and may provide a safeguard against copper toxicity. The insights reported here provide a rationale and basis for SOD-specific drugs and extension of immunogen design to target two important pathogens that continue to pose global health threats.« less
 [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:
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; AC02-05CH11231
Accepted Manuscript
Journal Name:
Journal of Bacteriology
Additional Journal Information:
Journal Volume: 197; Journal Issue: 24; Journal ID: ISSN 0021-9193
American Society for Microbiology
Research Org:
Brookhaven National Laboratory (BNL), Upton, NY (United States); Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States)
Sponsoring Org:
USDOE Office of Science (SC), Basic Energy Sciences (BES) (SC-22)
Country of Publication:
United States
OSTI Identifier:
Alternate Identifier(s):
OSTI ID: 1235891; OSTI ID: 1407285