The host transcriptional response to Candidemia is dominated by neutrophil activation and heme biosynthesis and supports novel diagnostic approaches.

Abstract

Background

Candidemia is one of the most common nosocomial bloodstream infections in the United States, causing significant morbidity and mortality in hospitalized patients, but the breadth of the host response to Candida infections in human patients remains poorly defined.

Methods

In order to better define the host response to Candida infection at the transcriptional level, we performed RNA sequencing on serial peripheral blood samples from 48 hospitalized patients with blood cultures positive for Candida species and compared them to patients with other acute viral, bacterial, and non-infectious illnesses. Regularized multinomial regression was utilized to develop pathogen class-specific gene expression classifiers.

Results

Candidemia triggers a unique, robust, and conserved transcriptomic response in human hosts with 1641 genes differentially upregulated compared to healthy controls. Many of these genes corresponded to components of the immune response to fungal infection, heavily weighted toward neutrophil activation, heme biosynthesis, and T cell signaling. We developed pathogen class-specific classifiers from these unique signals capable of identifying and differentiating candidemia, viral, or bacterial infection across a variety of hosts with a high degree of accuracy (auROC 0.98 for candidemia, 0.99 for viral and bacterial infection). This classifier was validated on two separate human cohorts (auROC 0.88 for viral infection and 0.87 for bacterial infection in one cohort; auROC 0.97 in another cohort) and an in vitro model (auROC 0.94 for fungal infection, 0.96 for bacterial, and 0.90 for viral infection).

Conclusions

Transcriptional analysis of circulating leukocytes in patients with acute Candida infections defines novel aspects of the breadth of the human immune response during candidemia and suggests promising diagnostic approaches for simultaneously differentiating multiple types of clinical illnesses in at-risk, acutely ill patients.

Department

Description

Provenance

Citation

Published Version (Please cite this version)

10.1186/s13073-021-00924-9

Publication Info

Steinbrink, Julie M, Rachel A Myers, Kaiyuan Hua, Melissa D Johnson, Jessica L Seidelman, Ephraim L Tsalik, Ricardo Henao, Geoffrey S Ginsburg, et al. (2021). The host transcriptional response to Candidemia is dominated by neutrophil activation and heme biosynthesis and supports novel diagnostic approaches. Genome medicine, 13(1). p. 108. 10.1186/s13073-021-00924-9 Retrieved from https://hdl.handle.net/10161/26027.

This is constructed from limited available data and may be imprecise. To cite this article, please review & use the official citation provided by the journal.

Scholars@Duke

Steinbrink

Julie Steinbrink

Assistant Professor of Medicine

I am a transplant infectious diseases physician. My clinical care focuses on the management of infections in immunocompromised patients, including solid organ and bone marrow transplant recipients, as well as cancer patients. My research focuses on developing noninvasive biomarker diagnostics and severity prognostic tools for infectious diseases in immunocompromised patients.

Johnson

Melissa DePaoli Johnson

Professor in Medicine

Prognostic indicators for patients with Candida spp. bloodstream infections
Antifungal pharmacokinetics/pharmacodynamics
Immunogenetics among patients with candidiasis
Management of the HIV infected patient and antiretroviral pharmacotherapy
Antibacterial drug utilization, resistance, and appropriate prescribing
Antimicrobial Stewardship

Seidelman

Jessica Seidelman

Associate Professor of Medicine

Unless otherwise indicated, scholarly articles published by Duke faculty members are made available here with a CC-BY-NC (Creative Commons Attribution Non-Commercial) license, as enabled by the Duke Open Access Policy. If you wish to use the materials in ways not already permitted under CC-BY-NC, please consult the copyright owner. Other materials are made available here through the author’s grant of a non-exclusive license to make their work openly accessible.