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 staphylococcal vaccine is designed to raise protective immunity in humans and to lower the morbidity and mortality caused by these infections.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
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Special Emphasis Panel (ZRG1-IDM-S (03))
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Huntley, Clayton C
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University of Chicago
Schools of Medicine
United States
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Winstel, Volker; Missiakas, Dominique; Schneewind, Olaf (2018) Staphylococcus aureus targets the purine salvage pathway to kill phagocytes. Proc Natl Acad Sci U S A 115:6846-6851
Yu, Wenqi; Missiakas, Dominique; Schneewind, Olaf (2018) Septal secretion of protein A in Staphylococcus aureus requires SecA and lipoteichoic acid synthesis. Elife 7:
Sun, Yan; Emolo, Carla; Holtfreter, Silva et al. (2018) Staphylococcal protein A contributes to persistent colonization of mice with Staphylococcus aureus. J Bacteriol :
Ohr, Ryan Jay; Anderson, Mark; Shi, Miaomiao et al. (2017) EssD, a Nuclease Effector of the Staphylococcus aureus ESS Pathway. J Bacteriol 199:
Anderson, Mark; Ohr, Ryan Jay; Aly, Khaled A et al. (2017) EssE Promotes Staphylococcus aureus ESS-Dependent Protein Secretion To Modify Host Immune Responses during Infection. J Bacteriol 199:
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; Schneewind, Olaf; Missiakas, Dominique (2016) Pathogenesis of Staphylococcus aureus Bloodstream Infections. Annu Rev Pathol 11:343-64
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
Nygaard, Tyler K; Kobayashi, Scott D; Freedman, Brett et al. (2016) Interaction of Staphylococci with Human B cells. PLoS One 11:e0164410
Missiakas, Dominique; Schneewind, Olaf (2016) Staphylococcus aureus vaccines: Deviating from the carol. J Exp Med 213:1645-53

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