A CDC/APIC sponsored study revealed in June 2007 a pressing health crisis for the United States: Staphylococcus aureus is the leading cause of bloodstream, lower respiratory tract, skin and soft tissue infections. The broad spectrum of clinically important staphylococcal diseases includes also endocarditis, septic arthritis, toxic shock syndrome, scalded skin syndrome and food poisoning. S. aureus strains exhibiting multiple antibiotic resistances, methicillin-resistant S. aureus (MRSA), are isolated in up to 60% of community and 80% of hospital infections. 4.6 % of individuals admitted into American hospitals suffer staphylococcal infections, claiming an aggregate mortality of about 100,000 lives this year. Vancomycin and other glycopeptide inhibitors of cell wall synthesis are considered last-resort-therapies for MRSA, however strains with intermediate (VISA) or full resistance (VRSA) to vancomycin have caused infections for which antimicrobial treatment is no longer effective. The search for protective immunity against invasive S. aureus disease has been a goal since the discovery of this microbe. Whole-cell live or killed vaccines, however, failed to generate protective immune responses in humans and, because of safety concerns, are no longer considered for staphylococcal vaccine development. Research conducted under NIAID AI52747 studied the molecular biology of heme-iron scavenging in staphylococci and identified the molecular properties of iron-regulated surface determinants (IsdA-I). Other work sought to develop a broadly protective subunit vaccine by studying surface proteins conserved among different S. aureus strains as antigens in a murine model of abscess formation. Immunization with surface proteins, including the heme-transport proteins IsdA and IsdB, generated significant protective immunity that correlated with the induction of specific antibodies. When assembled into a combined vaccine, the surface protein vaccine afforded high levels of protection against invasive disease or lethal challenge with human clinical S. aureus isolates. This proposal aims to understand the molecular basis of staphylococcal vaccines from surface proteins and to appreciate the function of surface proteins and other secreted polypeptides in animal models of infection. Specifically, the role of heme scavenging in immunity against staphylococcal disease, the molecular biology of staphylococcal immune suppression by SasH, and the contribution of hlb-converting phages towards staphylococcal immune evasion will be investigated.

Public Health Relevance

Staphylococcus aureus is the leading cause of bloodstream, lower respiratory tract, skin and soft tissue infections in the United States with annual morbidity of about 3 million and annual mortality approaching 100,000 Americans lives. Our research into the development of a staphhylococcal vaccine is designed to raise protective immunity in humans and to lower the morbidity and mortality caused by these infections.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI052474-09
Application #
8197089
Study Section
Special Emphasis Panel (ZRG1-IDM-S (03))
Program Officer
Huntley, Clayton C
Project Start
2002-06-01
Project End
2013-11-30
Budget Start
2011-12-01
Budget End
2012-11-30
Support Year
9
Fiscal Year
2012
Total Cost
$376,970
Indirect Cost
$131,945
Name
University of Chicago
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
005421136
City
Chicago
State
IL
Country
United States
Zip Code
60637
Chan, Yvonne G Y; Frankel, Matthew B; Missiakas, Dominique et al. (2016) SagB Glucosaminidase Is a Determinant of Staphylococcus aureus Glycan Chain Length, Antibiotic Susceptibility, and Protein Secretion. J Bacteriol 198:1123-36
Missiakas, Dominique; Schneewind, Olaf (2016) Staphylococcus aureus vaccines: Deviating from the carol. J Exp Med 213:1645-53
Kim, Hwan Keun; Falugi, Fabiana; Missiakas, Dominique M et al. (2016) Peptidoglycan-linked protein A promotes T cell-dependent antibody expansion during Staphylococcus aureus infection. Proc Natl Acad Sci U S A 113:5718-23
Thomer, Lena; Emolo, Carla; Thammavongsa, Vilasack et al. (2016) Antibodies against a secreted product of Staphylococcus aureus trigger phagocytic killing. J Exp Med 213:293-301
Thomer, Lena; Schneewind, Olaf; Missiakas, Dominique (2016) Pathogenesis of Staphylococcus aureus Bloodstream Infections. Annu Rev Pathol 11:343-64
Thammavongsa, Vilasack; Kim, Hwan Keun; Missiakas, Dominique et al. (2015) Staphylococcal manipulation of host immune responses. Nat Rev Microbiol 13:529-43
Thammavongsa, Vilasack; Rauch, Sabine; Kim, Hwan Keun et al. (2015) Protein A-neutralizing monoclonal antibody protects neonatal mice against Staphylococcus aureus. Vaccine 33:523-6
Kim, Hwan Keun; Falugi, Fabiana; Thomer, Lena et al. (2015) Protein A suppresses immune responses during Staphylococcus aureus bloodstream infection in guinea pigs. MBio 6:
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
Schneewind, Olaf; Missiakas, Dominique (2014) Sec-secretion and sortase-mediated anchoring of proteins in Gram-positive bacteria. Biochim Biophys Acta 1843:1687-97

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