Staphylococcus aureus is the leading cause of bloodstream, lower respiratory tract, skin and soft tissue infections in the United States and antibiotic resistant strains (MRSA) are isolated in more than half of all community and hospital infections. The search for protective immunity against invasive S. aureus disease has been a premier research goal since the discovery of this microbe. While several envelope components and secreted products have been investigated as vaccine antigens (surface proteins, capsular polysaccharide, exopolysaccharide, a-hemolysin, and leukocidins), no single antigen has facilitated the development of long-term protective immunity. Furthermore, investigations to date have not yielded a clear understanding of the features of the host immune response that are requisite for the generation of such protective immunity. This proposal is based on three fundamental discoveries. 1. S. aureus modulates immune responses during infection and prevents the development of protective immunity. The recent analysis of staphylococcal variants in the ess and agr pathways that are capable of generating protective immunity in live vaccination models now enables the characterization of protective antigens via genetic subtraction. 2. Levels of protective immunity against staphylococcal infection in animal models are increased when two or more antigens are combined. The reciprocal phenomenon is also true: genetic subtraction of more than one vaccine antigen (virulence factor) leads to a commensurate reduction of staphylococcal virulence. 3. For infectious processes in the lung, secretion of a-hemolysin is an essential virulence attribute of staphylococci, enabling the design of unique vaccine and immunotherapeutic strategies. Based on these discoveries, we propose a rational approach for vaccine testing, whereby the inclusion of individual subunits must be based on three criteria, (i) Genes specifying vaccine antigens must be present in relevant clinical isolates of S. aureus. (ii) Staphylococcal mutants lacking these genes must reveal a contribution of these components to the pathogenesis of S. aureus infections, (iii) Immunization with individual subunit components or a combination of subunits must generate immune responses that improve the outcome of S. aureus infections when tested with multiple animal models of disease.

Public Health Relevance

Methicillin-resistant S. aureus has become a significant public health threat, resulting in the death of an estimated 18,000 individuals per year in the US alone. The worldwide burden of morbidity and mortality from MRSA, while untabulated, is likely even more staggering. The ability of S. aureus to rapidly acquire both virulence potential traits and antimicrobial resistance positions this organism as a formidable emerging pathogen;novel strategies aimed at prevention and treatment of disease through vaccination are urgently needed, and form the focus of this proposal.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Specialized Center--Cooperative Agreements (U54)
Project #
Application #
Study Section
Special Emphasis Panel (ZAI1-DDS-M)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Chicago
United States
Zip Code
Hoang, Ky V; Rajaram, Murugesan V S; Curry, Heather Marie et al. (2018) Complement Receptor 3-Mediated Inhibition of Inflammasome Priming by Ras GTPase-Activating Protein During Francisella tularensis Phagocytosis by Human Mononuclear Phagocytes. Front Immunol 9:561
Mitchell, Anthony; Tam, Christina; Elli, Derek et al. (2017) Glutathionylation of Yersinia pestis LcrV and Its Effects on Plague Pathogenesis. MBio 8:
Chen, Grischa Y; McDougal, Courtney E; D'Antonio, Marc A et al. (2017) A Genetic Screen Reveals that Synthesis of 1,4-Dihydroxy-2-Naphthoate (DHNA), but Not Full-Length Menaquinone, Is Required for Listeria monocytogenes Cytosolic Survival. MBio 8:
Sloup, Rudolph E; Konal, Ashley E; Severin, Geoffrey B et al. (2017) Cyclic Di-GMP and VpsR Induce the Expression of Type II Secretion in Vibrio cholerae. J Bacteriol 199:
Kant, Sashi; Asthana, Shailendra; Missiakas, Dominique et al. (2017) A novel STK1-targeted small-molecule as an ""antibiotic resistance breaker"" against multidrug-resistant Staphylococcus aureus. Sci Rep 7:5067
Coulson, Garry B; Johnson, Benjamin K; Zheng, Huiqing et al. (2017) Targeting Mycobacterium tuberculosis Sensitivity to Thiol Stress at Acidic pH Kills the Bacterium and Potentiates Antibiotics. Cell Chem Biol 24:993-1004.e4
Hoang, Ky Van; Chen, Carolyn G; Koopman, Jacob et al. (2016) Identification of Genes Required for Secretion of the Francisella Oxidative Burst-Inhibiting Acid Phosphatase AcpA. Front Microbiol 7:605
Le, J; Dam, Q; Schweizer, M et al. (2016) Effects of vancomycin versus nafcillin in enhancing killing of methicillin-susceptible Staphylococcus aureus causing bacteremia by human cathelicidin LL-37. Eur J Clin Microbiol Infect Dis 35:1441-7
Hollands, Andrew; Corriden, Ross; Gysler, Gabriela et al. (2016) Natural Product Anacardic Acid from Cashew Nut Shells Stimulates Neutrophil Extracellular Trap Production and Bactericidal Activity. J Biol Chem 291:13964-73
Kuhn, Misty L; Alexander, Evan; Minasov, George et al. (2016) Structure of the Essential Mtb FadD32 Enzyme: A Promising Drug Target for Treating Tuberculosis. ACS Infect Dis 2:579-591

Showing the most recent 10 out of 516 publications