Staphylococcus aureus bacteremia (SAB) is a common and life-threatening bloodstream infection that is often caused by methicillin-resistant strains (MRSA). Of urgent concern, up to 30% of SAB patients fail antibiotic treatment even when gold-standard anti-MRSA therapy (vancomycin [VAN] or daptomycin (DAP]) is used. These patients have persistent bacteremia, which frequently results in a dismal clinical outcome. Even though the MRSA isolates from these patients appear to be susceptible to VAN or DAP based upon in vitro CLSI breakpoints, these antibiotics fail to clear the bloodstream infection. Such in vivo antibiotic resistance is termed Antibiotic-Persistent MRSA Bacteremia, or APMB. At present, there are few therapeutic options for these life-threatening infections. There is a critical, unmet need to understand the unique intersection of host and pathogen factors driving APMB. Elucidating these factors holds promise to lead to new approaches to prospectively identify patients at risk for developing APMB, and novel strategies to prevent or treat this often devastating infection. Importantly, APMB represents a unique subset of antibiotic resistant infections that differ from biofilm-associated infections due to antibiotic-tolerant or recalcitrant / relapsing isolates. APMB isolates are genetically stable, but highly adaptive strains induced by in vivo antibiotic exposure. Thus, mechanisms of persistent infections (APMB) are distinct from antibiotic-tolerant infections. Based on our extensive preliminary data, we hypothesize that APMB results from a three-way interaction among the pathogen, host immune response and antibiotic. We further posit that conventional approaches to study this clinically important phenomenon may be insufficient to understand it. Therefore, we will: 1) analyze the interactions of wild-type and mutant APMB strains with host cells and constituents in vitro, ex vivo, and in discriminative animal models to resolve key genotypic & phenotypic determinants of the S. aureus persistome that drives APMB; 2) leverage our pioneering S. aureus Bacteremia Group (SABG) biorepository of human samples & matched clinical isolates, genomic & transcriptional analysis, and immunophenotyping to define host genetic and immune profiles of APMB during VAN or DAP treatment; and 3) use our powerful systems-based statistical and computational immunology approaches to integrate results of high-throughput genomics and transcriptomics data across studies to model the pathogen-host signatures unique to APMB. Therefore, we will resolve the pathogen and host factors that drive APMB to enable innovative approaches to predict, prevent and treat MRSA bloodstream infections that persist despite antibiotic treatment. These critically needed advances will derive from iterative refinement of studies that bring together proven strengths of an outstanding research team to apply an integrated, systems-based approach. The result will yield robust predictive algorithms for clinical evaluation for improved interventions against MRSA infections. Thus, through leading-edge methods and strategies that are optimized for synergy, our progressively focused studies in this U01 project are ideally responsive to the priorities of the NIH and this Systems Biology of Antibacterial Resistance RFA (RFA-AI-14-064).

Public Health Relevance

Systems Immunobiology of Antibiotic-Persistent MRSA Infection Staphylococcus aureus causes life-threatening bloodstream infections, many of which are caused by methicillin-resistant S. aureus (MRSA). Of urgent concern, up to 30% of these patients fail antibiotic treatment and have persistent growth of bacteria in their bloodstream, even when gold-standard anti-MRSA therapy (vancomycin or daptomycin) is used. This persistent bacteremia is associated with a dismal clinical outcome. Even though the MRSA isolates from these patients appear to be 'susceptible' to antibiotics by standard laboratory tests, the antibiotics fail to clear the bloodstream infection. At present there are few therapeuti options for this type of antibiotic resistance. Little is known about the S. aureus strains that cause persistent infections or the patient factors that contribute to them. There is a critical nee to define the unique interplay of bacterial, patient & antibiotic factors that cause persistent S. aureus infections. Based on our exciting findings thus far, we believe that persistent S. aureus infections result from a specific three-way interaction among the bacterium, the patient immune response and the antibiotic used to treat them. We will use state-of-the-art techniques to comprehensively analyze the genetics of persistent strains of S. aureus and study the interaction of S. aureus with the immune system and other components from patients and experimental models of infection. In turn, results from these studies will be analyzed using powerful biostatistical and computational systems that can detect unique patterns of results within large complex datasets. By understanding these factors and their interactions, new approaches to identify and treat high risk patients can be developed and applied to improve and save lives. This knowledge will enable new approaches to predict, prevent and treat MRSA bloodstream infections to benefit and save patient lives. These goals are ideally aligned with the priorities of the National Institutes of Health, Centers for Disease Control, and Infectious Disease Society of America.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project--Cooperative Agreements (U01)
Project #
1U01AI124319-01
Application #
9108773
Study Section
Special Emphasis Panel ()
Program Officer
Dugan, Vivien G
Project Start
2016-03-21
Project End
2021-02-28
Budget Start
2016-03-21
Budget End
2017-02-28
Support Year
1
Fiscal Year
2016
Total Cost
$1,999,922
Indirect Cost
$196,384
Name
La Biomed Research Institute/ Harbor UCLA Medical Center
Department
Type
DUNS #
069926962
City
Torrance
State
CA
Country
United States
Zip Code
90502
Dillen, Carly A; Pinsker, Bret L; Marusina, Alina I et al. (2018) Clonally expanded ?? T cells protect against Staphylococcus aureus skin reinfection. J Clin Invest 128:1026-1042
Yeaman, Michael R; B├╝ttner, Sabrina; Thevissen, Karin (2018) Regulated Cell Death as a Therapeutic Target for Novel Antifungal Peptides and Biologics. Oxid Med Cell Longev 2018:5473817
Roux, Antoine; Thomas, Kimberly A; Sage, Edouard et al. (2018) Donor-specific HLA antibody-mediated complement activation is a significant indicator of antibody-mediated rejection and poor long-term graft outcome during lung transplantation: a single center cohort study. Transpl Int 31:761-772
Li, Liang; Abdelhady, Wessam; Donegan, Niles P et al. (2018) Role of Purine Biosynthesis in Persistent Methicillin-Resistant Staphylococcus aureus Infection. J Infect Dis 218:1367-1377
Chan, Liana C; Rossetti, Maura; Miller, Lloyd S et al. (2018) Protective immunity in recurrent Staphylococcus aureus infection reflects localized immune signatures and macrophage-conferred memory. Proc Natl Acad Sci U S A 115:E11111-E11119
Jin, Yi-Ping; Valenzuela, Nicole M; Zhang, Xiaohai et al. (2018) HLA Class II-Triggered Signaling Cascades Cause Endothelial Cell Proliferation and Migration: Relevance to Antibody-Mediated Transplant Rejection. J Immunol 200:2372-2390
Zhang, Qiuheng; Hickey, Michelle; Drogalis-Kim, Diana et al. (2018) Understanding the Correlation Between DSA, Complement Activation, and Antibody-Mediated Rejection in Heart Transplant Recipients. Transplantation 102:e431-e438
Chan, Liana C; Chaili, Siyang; Filler, Scott G et al. (2017) Innate Immune Memory Contributes to Host Defense against Recurrent Skin and Skin Structure Infections Caused by Methicillin-Resistant Staphylococcus aureus. Infect Immun 85:
Cheng, Christine S; Behar, Marcelo S; Suryawanshi, Gajendra W et al. (2017) Iterative Modeling Reveals Evidence of Sequential Transcriptional Control Mechanisms. Cell Syst 4:330-343.e5
Li, Liang; Cheung, Ambrose; Bayer, Arnold S et al. (2016) The Global Regulon sarA Regulates ?-Lactam Antibiotic Resistance in Methicillin-Resistant Staphylococcus aureus In Vitro and in Endovascular Infections. J Infect Dis 214:1421-1429