Mortality Risk Profiling of Staphylococcus aureus Bacteremia by Multi-omic Serum Analysis Reveals Early Predictive and Pathogenic Signatures

Jacob M Wozniak; Robert H Mills; Joshua Olson; J R Caldera; Gregory D Sepich-Poore; Marvic Carrillo-Terrazas; Chih-Ming Tsai; Fernando Vargas; Rob Knight; Pieter C Dorrestein; George Y Liu; Victor Nizet; George Sakoulas; Warren Rose; David J Gonzalez

doi:10.1016/j.cell.2020.07.040

Mortality Risk Profiling of Staphylococcus aureus Bacteremia by Multi-omic Serum Analysis Reveals Early Predictive and Pathogenic Signatures

Cell. 2020 Sep 3;182(5):1311-1327.e14. doi: 10.1016/j.cell.2020.07.040.

Authors

Affiliations

¹ Department of Pharmacology, University of California, San Diego, La Jolla, CA 92093, USA; Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA 92093, USA; Collaborative to Halt Antibiotic-Resistant Microbes, University of California, San Diego, La Jolla, CA 92093, USA; Center for Microbiome Innovation, University of California, San Diego, La Jolla, CA 92093, USA.
² Department of Pharmacology, University of California, San Diego, La Jolla, CA 92093, USA; Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA 92093, USA; Collaborative to Halt Antibiotic-Resistant Microbes, University of California, San Diego, La Jolla, CA 92093, USA; Center for Microbiome Innovation, University of California, San Diego, La Jolla, CA 92093, USA; Department of Pediatrics, University of California, San Diego, La Jolla, CA 92093, USA; Department of Bioengineering, University of California, San Diego, La Jolla, CA 92093, USA; Department of Computer Science and Engineering, University of California, San Diego, La Jolla, CA 92093, USA.
³ Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA 92093, USA; Collaborative to Halt Antibiotic-Resistant Microbes, University of California, San Diego, La Jolla, CA 92093, USA; Department of Pediatrics, University of California, San Diego, La Jolla, CA 92093, USA.
⁴ Collaborative to Halt Antibiotic-Resistant Microbes, University of California, San Diego, La Jolla, CA 92093, USA; Department of Pediatrics, University of California, San Diego, La Jolla, CA 92093, USA; Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
⁵ Department of Bioengineering, University of California, San Diego, La Jolla, CA 92093, USA.
⁶ Collaborative to Halt Antibiotic-Resistant Microbes, University of California, San Diego, La Jolla, CA 92093, USA; Department of Pediatrics, University of California, San Diego, La Jolla, CA 92093, USA.
⁷ Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA 92093, USA; Division of Biological Sciences, University of California, San Diego, La Jolla, CA 92093, USA.
⁸ Collaborative to Halt Antibiotic-Resistant Microbes, University of California, San Diego, La Jolla, CA 92093, USA; Center for Microbiome Innovation, University of California, San Diego, La Jolla, CA 92093, USA; Department of Pediatrics, University of California, San Diego, La Jolla, CA 92093, USA; Department of Bioengineering, University of California, San Diego, La Jolla, CA 92093, USA; Department of Computer Science and Engineering, University of California, San Diego, La Jolla, CA 92093, USA.
⁹ Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA 92093, USA; Center for Microbiome Innovation, University of California, San Diego, La Jolla, CA 92093, USA.
¹⁰ School of Pharmacy, School of Medicine and Public Health University of Wisconsin-Madison, Madison, WI 53705, USA; Department of Medicine, School of Medicine and Public Health University of Wisconsin-Madison, Madison, WI 53705, USA.
¹¹ Department of Pharmacology, University of California, San Diego, La Jolla, CA 92093, USA; Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA 92093, USA; Collaborative to Halt Antibiotic-Resistant Microbes, University of California, San Diego, La Jolla, CA 92093, USA; Center for Microbiome Innovation, University of California, San Diego, La Jolla, CA 92093, USA. Electronic address: djgonzalez@ucsd.edu.

Abstract

Staphylococcus aureus bacteremia (SaB) causes significant disease in humans, carrying mortality rates of ∼25%. The ability to rapidly predict SaB patient responses and guide personalized treatment regimens could reduce mortality. Here, we present a resource of SaB prognostic biomarkers. Integrating proteomic and metabolomic techniques enabled the identification of >10,000 features from >200 serum samples collected upon clinical presentation. We interrogated the complexity of serum using multiple computational strategies, which provided a comprehensive view of the early host response to infection. Our biomarkers exceed the predictive capabilities of those previously reported, particularly when used in combination. Last, we validated the biological contribution of mortality-associated pathways using a murine model of SaB. Our findings represent a starting point for the development of a prognostic test for identifying high-risk patients at a time early enough to trigger intensive monitoring and interventions.

Keywords: Staphylococcus aureus; bacteremia; biomarkers; host-pathogen interaction; infectious disease; metabolomics; post-translational modifications; proteomics.

Publication types

Research Support, N.I.H., Extramural

MeSH terms

Animals
Bacteremia / blood*
Bacteremia / metabolism
Bacteremia / mortality*
Biomarkers / blood
Biomarkers / metabolism
Disease Models, Animal
Female
Humans
Male
Metabolomics / methods
Mice
Middle Aged
Prognosis
Proteomics / methods
Risk Factors
Staphylococcal Infections / blood*
Staphylococcal Infections / metabolism
Staphylococcal Infections / mortality*
Staphylococcus aureus / pathogenicity*

Substances

Biomarkers

Abstract

Publication types

MeSH terms

Substances

Grants and funding