Staphylococcus aureus is the leading cause of bloodstream, lower respiratory tract, skin and soft tissue infections in the United States. Demonstrating the broad tissue range and virulence properties of the pathogen, S. aureus also causes osteomyelitis, septic arthritis, and a spectrum of toxin-mediated entities including staphylococcal toxic shock syndrome, enterotoxin-induced gastrointestinal disease, and life-threatening desquamation caused by a family of epidermolytic toxins. Recent estimates suggest that S. aureus contributes to half a million infections per year in the United States alone, resulting in over 10,000 deaths. The annual economic burden of S. aureus infection reached $14.5 billion in 2003. To date, there is no commercially available vaccine to prevent S. aureus infection, and novel antimicrobial agents that successfully target this organism have been few. In the context of widespread disease that has been met with a paucity of highly effective, durable anti-infective strategies, it is imperative that we obtain a more detailed understanding of the molecular mechanisms of S. aureus pathogenesis. S. aureus alpha-hemolysin (Hla) is a pore-forming cytotoxin encoded in the genome and expressed by almost all S. aureus strains. Hla contributes to the pathogenesis of pneumonia, primary and recurrent skin infection, and sepsis through its interaction with ADAM10, the toxin's eukaryotic receptor. Hla is a premier target of ongoing clinical vaccine and passive immunization studies. The primary goal of this proposal is to develop a comprehensive knowledge of how the Hla-ADAM10 complex injures a diverse array of cells and modulates tissue repair within the context of specific host tissue microenvironments, thereby enhancing our knowledge of disease progression host susceptibility. This knowledge will enable the rational translation of novel anti-toxin therapies to impact human disease. This proposal is based on four fundamental discoveries: 1) Through the use of cell-type specific ADAM10 knockout mice, we have isolated the effects of Hla on individual cells within specific tissues in well-defined disease states. 2) The actions of Hla are not merely a product of toxic pore-formation, but depend on toxin-mediated activation of ADAM10 and pathologic cleavage of native ADAM10 substrates. 3) We have demonstrated that the physiologic and pathologic manifestations of infection are a composite of Hla action on discrete cell populations, integrated in the tissue over time. 4) We have demonstrated that an anti-Hla antibody response is associated with protection against recurrent S. aureus infection in children. Through studies that reveal the precise mechanism by which the Hla-ADAM10 complex results in host cell and tissue injury, coupled with focused analysis of human susceptibility to Hla-mediated disease, we anticipate that these studies will enable refinement of clinical trials targeting Hla, and inform the approach to disease prevention and therapeutic intervention. Simultaneously, these studies will contribute more broadly to our understanding of bacterial pore forming cytotoxins.

Public Health Relevance

Staphylococcus aureus is an aggressive human pathogen, contributing to an estimated 500,000 infections that claim the life of more than 10,000 individuals per year in the US alone. Drug resistant S. aureus strains are now widespread, mandating the development of novel strategies to prevent and treat infection. The design of such strategies necessitates that we obtain a clear understanding of the mechanisms by which S. aureus injures its host and the unique features of host susceptibility to infection, together forming the focus of this proposal.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI097434-10
Application #
10087841
Study Section
Host Interactions with Bacterial Pathogens Study Section (HIBP)
Program Officer
Huntley, Clayton C
Project Start
2011-12-01
Project End
2021-12-31
Budget Start
2021-01-01
Budget End
2021-12-31
Support Year
10
Fiscal Year
2021
Total Cost
Indirect Cost
Name
Washington University
Department
Pediatrics
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Lee, Brandon; Bubeck Wardenburg, Juliane (2018) A common approach to toxin specificity. Nat Microbiol 3:644-645
Hernandez, Sonia L; Nelson, Mildred; Sampedro, Georgia R et al. (2018) Staphylococcus aureus alpha toxin activates Notch in vascular cells. Angiogenesis :
Surewaard, Bas G J; Thanabalasuriar, Ajitha; Zeng, Zhutian et al. (2018) ?-Toxin Induces Platelet Aggregation and Liver Injury during Staphylococcus aureus Sepsis. Cell Host Microbe 24:271-284.e3
Doctor, Allan; Zimmerman, Jerry; Agus, Michael et al. (2017) Pediatric Multiple Organ Dysfunction Syndrome: Promising Therapies. Pediatr Crit Care Med 18:S67-S82
Sampedro, Georgia R; Bubeck Wardenburg, Juliane (2017) Staphylococcus aureus in the Intensive Care Unit: Are These Golden Grapes Ripe for a New Approach? J Infect Dis 215:S64-S70
Seilie, E Sachiko; Bubeck Wardenburg, Juliane (2017) Staphylococcus aureus pore-forming toxins: The interface of pathogen and host complexity. Semin Cell Dev Biol 72:101-116
Yu, Karl O A; Randolph, Adrienne G; Agan, Anna A et al. (2016) Staphylococcus aureus ?-Toxin Response Distinguishes Respiratory Virus-Methicillin-Resistant S. aureus Coinfection in Children. J Infect Dis 214:1638-1646
Powers, Michael E; Becker, Russell E N; Sailer, Anne et al. (2015) Synergistic Action of Staphylococcus aureus ?-Toxin on Platelets and Myeloid Lineage Cells Contributes to Lethal Sepsis. Cell Host Microbe 17:775-87
Becker, Russell E N; Bubeck Wardenburg, Juliane (2015) Staphylococcus aureus and the skin: a longstanding and complex interaction. Skinmed 13:111-9; quiz 120
Powers, Michael E; Bubeck Wardenburg, Juliane (2015) Host autophagy combating S. aureus: ?-toxin will be tolerated. Cell Host Microbe 17:419-20

Showing the most recent 10 out of 17 publications