Staphylococcus aureus, the causative agent of recurrent skin and soft tissue infections, is the most frequent cause of infectious disease morbidity and mortality in the United States. Methicillin-resistant S. aureus strains are associated with failure of antibiotic therapy, a public health crisis that must be addressed by developing new preventive strategies. S. aureus infection does not establish protective immunity, however the key mechanisms of immune evasion for this pathogen were previously not known. We show here that the immunoglobulin Fc-gamma and Fab binding attributes of staphylococcal protein A (SpA) allow S. aureus to escape immune surveillance by blocking the development of protective antibody responses. S. aureus variants that display mutant protein A (SpA/KKAA) are unable to bind Ig Fc-gamma and Fab. These variants allow infected mice to generate protective antibodies and trigger opsonophagocytic killing (OPK) of S. aureus. Protective immunity can be achieved by both active immunization with SpA/KKAA vaccine and by passive transfer of SpA-neutralizing antibodies [SpA/KKAA mouse monoclonal antibodies (mAbs)]. To advance SpA/KKAA-mAbs for clinical development, we generated humanized IgG1, for example SpA/KKAA-huAb 3F6 from SpA/KKAA -mAb 3F6 VH template. huAb-3F6 and mAb-3F6 promote OPK and protection against S. aureus in a host specific manner, suggesting that protective immune responses involve the effector functions of specific FcR receptors on myeloid cells. By characterizing mouse and human FcR receptors responsible for antibody mediated protection, we propose to unravel the molecular and cellular bases of protective immunity against S. aureus. SpA/KKAA -mAbs neutralize both SpA and Sbi, a secreted protein of S. aureus whose Ig binding attributes trigger futile consumption of complement. The contributions of SpA/KKAA and Sbi/KKAA towards the establishment of natural and vaccine induced protective immune responses in mice and guinea pigs will be studied. The guinea pig model offers B cell as well as IgG and IgM antibody repertoires with close resemblance to humans. Generated data will enable rational clinical development of vaccines and immune therapeutics against S. aureus.

Public Health Relevance

MRSA, antibiotic-resistant S. aureus, is the most frequent cause of infectious disease mortality in the United States, however vaccines or antibody therapies for MRSA infections are not available. This need is addressed in a proposal that will reveal the molecular basis for protective immunity against S. aureus and provide MRSA vaccines as well as immune therapeutics for clinical development.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
2R01AI052474-11A1
Application #
8694656
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Zou, Lanling
Project Start
Project End
Budget Start
Budget End
Support Year
11
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Chicago
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
City
Chicago
State
IL
Country
United States
Zip Code
60637
Schneewind, Olaf; Missiakas, Dominique (2014) Genetic manipulation of Staphylococcus aureus. Curr Protoc Microbiol 32:Unit 9C.3.
Becker, Samuel; Frankel, Matthew B; Schneewind, Olaf et al. (2014) Release of protein A from the cell wall of Staphylococcus aureus. Proc Natl Acad Sci U S A 111:1574-9
Rauch, Sabine; Gough, Portia; Kim, Hwan Keun et al. (2014) Vaccine protection of leukopenic mice against Staphylococcus aureus bloodstream infection. Infect Immun 82:4889-98
Kim, Hwan Keun; Missiakas, Dominique; Schneewind, Olaf (2014) Mouse models for infectious diseases caused by Staphylococcus aureus. J Immunol Methods 410:88-99
Cheng, Alice G; Missiakas, Dominique; Schneewind, Olaf (2014) The giant protein Ebh is a determinant of Staphylococcus aureus cell size and complement resistance. J Bacteriol 196:971-81
Thomer, Lena; Becker, Samuel; Emolo, Carla et al. (2014) N-acetylglucosaminylation of serine-aspartate repeat proteins promotes Staphylococcus aureus bloodstream infection. J Biol Chem 289:3478-86
Schneewind, Olaf; Missiakas, Dominique (2014) Sec-secretion and sortase-mediated anchoring of proteins in Gram-positive bacteria. Biochim Biophys Acta 1843:1687-97
Chen, Chen; Krishnan, Vengadesan; Macon, Kevin et al. (2013) Secreted proteases control autolysin-mediated biofilm growth of Staphylococcus aureus. J Biol Chem 288:29440-52
Thammavongsa, Vilasack; Missiakas, Dominique M; Schneewind, Olaf (2013) Staphylococcus aureus degrades neutrophil extracellular traps to promote immune cell death. Science 342:863-6
Kim, Hwan Keun; Thammavongsa, Vilasack; Schneewind, Olaf et al. (2012) Recurrent infections and immune evasion strategies of Staphylococcus aureus. Curr Opin Microbiol 15:92-9

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