PMID- 22919628
OWN - NLM
STAT- MEDLINE
DCOM- 20131211
LR  - 20211021
IS  - 2235-2988 (Electronic)
IS  - 2235-2988 (Linking)
VI  - 2
DP  - 2012
TI  - Characterization of the mechanism of protection mediated by CS-D7, a monoclonal 
      antibody to Staphylococcus aureus iron regulated surface determinant B (IsdB).
PG  - 36
LID - 10.3389/fcimb.2012.00036 [doi]
LID - 36
AB  - We previously reported the development of a human monoclonal antibody (CS-D7, 
      IgG(1)) with specificity and affinity for the iron regulated surface determinant 
      B (IsdB) of Staphylococcus aureus. CS-D7 mediates opsonophagocytic killing in 
      vitro and protection in a murine sepsis model. In light of recent data indicating 
      that IsdB specific T cells (CD4+, Th17), not Ab, mediate protection after 
      vaccination with IsdB, it is important to investigate the mechanism of protection 
      mediated by CS-D7. The mAb was examined to determine if it blocked heme binding 
      to IsdB in vitro. The mAb was not found to have heme blocking activity, nor did 
      it prevent bacterial growth under in vivo conditions, in an implanted growth 
      chamber. To assess the role of the mAb Fc a point mutation was introduced at aa 
      297 (CS-D7.N297A). This point mutation removes Fc effector functions. In vitro 
      analysis of the mutein confirmed that it lacked measurable binding to FcgammaR, and 
      that it did not fix complement. The mutein had dramatically reduced in vitro 
      opsonic OP activity compared to CS-D7. Nonetheless, the mutein conferred 
      protection equivalent to the wild type mAb in the murine sepsis model. Both wild 
      type and mutein mAbs were efficacious in FcgammaR deletion mice (including both 
      FcgammaRII(-/-) mice and FcgammaRIII(-/-) mice), indicating that these receptors were not 
      essential for mAb mediated protection in vivo. Protection mediated by CS-D7 was 
      lost in Balb/c mice depleted of C3 with cobra venom factor (CFV), was lost in 
      mice depleted of superoxide dismutase (SOD) in P47phox deletion mice, and as 
      previously reported, was absent in SCID mice (Joshi et al., 2012). Enhanced 
      clearance of S. aureus in the liver of CS-D7 treated mice and enhanced production 
      of IFN-gamma, but not of IL17, may play a role in the mechanism of protection 
      mediated by the mAb. CS-D7 apparently mediates survival in challenged mice 
      through a mechanism involving complement, phagocytes, and lymphocytes, but which 
      does not depend on interaction with FcgammaR, or on blocking heme uptake.
FAU - Pancari, Gregory
AU  - Pancari G
AD  - Department of Vaccine Basic Research, Merck Research Labs, Merck/MSD, West Point 
      PA, USA.
FAU - Fan, Hongxia
AU  - Fan H
FAU - Smith, Sharon
AU  - Smith S
FAU - Joshi, Amita
AU  - Joshi A
FAU - Haimbach, Robin
AU  - Haimbach R
FAU - Clark, Desmond
AU  - Clark D
FAU - Li, Yingzhe
AU  - Li Y
FAU - Hua, Jin
AU  - Hua J
FAU - McKelvey, Troy
AU  - McKelvey T
FAU - Ou, Yangsi
AU  - Ou Y
FAU - Drummond, James
AU  - Drummond J
FAU - Cope, Leslie
AU  - Cope L
FAU - Montgomery, Donna
AU  - Montgomery D
FAU - McNeely, Tessie
AU  - McNeely T
LA  - eng
PT  - Journal Article
DEP - 20120320
PL  - Switzerland
TA  - Front Cell Infect Microbiol
JT  - Frontiers in cellular and infection microbiology
JID - 101585359
RN  - 0 (Antibodies, Bacterial)
RN  - 0 (Antibodies, Monoclonal)
RN  - 0 (Cation Transport Proteins)
RN  - 0 (IsdB protein, Staphylococcus aureus)
RN  - 0 (Mutant Proteins)
RN  - 0 (Opsonin Proteins)
RN  - 42VZT0U6YR (Heme)
RN  - 9007-36-7 (Complement System Proteins)
SB  - IM
MH  - Animals
MH  - Antibodies, Bacterial/genetics/*immunology/metabolism
MH  - Antibodies, Monoclonal/genetics/*immunology/metabolism
MH  - Cation Transport Proteins/antagonists & inhibitors/*immunology
MH  - Complement System Proteins/immunology
MH  - Disease Models, Animal
MH  - Heme/metabolism
MH  - Mice
MH  - Mice, Inbred BALB C
MH  - Mutant Proteins/genetics/immunology/metabolism
MH  - Opsonin Proteins/*immunology/metabolism
MH  - Phagocytosis
MH  - Protein Binding
MH  - Sepsis/immunology/prevention & control
MH  - Staphylococcal Infections/immunology/prevention & control
MH  - Staphylococcus aureus/drug effects/growth & development/*immunology
MH  - Survival Analysis
PMC - PMC3417506
OTO - NOTNLM
OT  - Staphylococcus aureus
OT  - iron regulated surface determinant B (IsdB)
OT  - opsonophagocytosis
OT  - passive immunization
OT  - vaccination
EDAT- 2012/08/25 06:00
MHDA- 2012/08/25 06:01
PMCR- 2012/01/01
CRDT- 2012/08/25 06:00
PHST- 2011/12/13 00:00 [received]
PHST- 2012/03/03 00:00 [accepted]
PHST- 2012/08/25 06:00 [entrez]
PHST- 2012/08/25 06:00 [pubmed]
PHST- 2012/08/25 06:01 [medline]
PHST- 2012/01/01 00:00 [pmc-release]
AID - 10.3389/fcimb.2012.00036 [doi]
PST - epublish
SO  - Front Cell Infect Microbiol. 2012 Mar 20;2:36. doi: 10.3389/fcimb.2012.00036. 
      eCollection 2012.