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...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2021-07-01
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| Series: | Genome Medicine |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s13073-021-00924-9 |
| _version_ | 1831655792000892928 |
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| author | Julie M. Steinbrink Rachel A. Myers Kaiyuan Hua Melissa D. Johnson Jessica L. Seidelman Ephraim L. Tsalik Ricardo Henao Geoffrey S. Ginsburg Christopher W. Woods Barbara D. Alexander Micah T. McClain |
| author_facet | Julie M. Steinbrink Rachel A. Myers Kaiyuan Hua Melissa D. Johnson Jessica L. Seidelman Ephraim L. Tsalik Ricardo Henao Geoffrey S. Ginsburg Christopher W. Woods Barbara D. Alexander Micah T. McClain |
| author_sort | Julie M. Steinbrink |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-19T16:55:52Z |
| format | Article |
| id | doaj.art-6517eb40cff640dda7a2e51b7f418b6a |
| institution | Directory Open Access Journal |
| issn | 1756-994X |
| language | English |
| last_indexed | 2024-12-19T16:55:52Z |
| publishDate | 2021-07-01 |
| publisher | BMC |
| record_format | Article |
| series | Genome Medicine |
| spelling | doaj.art-6517eb40cff640dda7a2e51b7f418b6a2022-12-21T20:13:25ZengBMCGenome Medicine1756-994X2021-07-0113111310.1186/s13073-021-00924-9The host transcriptional response to Candidemia is dominated by neutrophil activation and heme biosynthesis and supports novel diagnostic approachesJulie M. Steinbrink0Rachel A. Myers1Kaiyuan Hua2Melissa D. Johnson3Jessica L. Seidelman4Ephraim L. Tsalik5Ricardo Henao6Geoffrey S. Ginsburg7Christopher W. Woods8Barbara D. Alexander9Micah T. McClain10Division of Infectious Diseases, Duke University Medical CenterCenter for Applied Genomics and Precision Medicine, Duke UniversityCenter for Applied Genomics and Precision Medicine, Duke UniversityDivision of Infectious Diseases, Duke University Medical CenterDivision of Infectious Diseases, Duke University Medical CenterDivision of Infectious Diseases, Duke University Medical CenterCenter for Applied Genomics and Precision Medicine, Duke UniversityCenter for Applied Genomics and Precision Medicine, Duke UniversityDivision of Infectious Diseases, Duke University Medical CenterDivision of Infectious Diseases, Duke University Medical CenterDivision of Infectious Diseases, Duke University Medical CenterAbstract 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.https://doi.org/10.1186/s13073-021-00924-9CandidemiaGene expressionBiomarkersHost responseFungal diagnostics |
| spellingShingle | Julie M. Steinbrink Rachel A. Myers Kaiyuan Hua Melissa D. Johnson Jessica L. Seidelman Ephraim L. Tsalik Ricardo Henao Geoffrey S. Ginsburg Christopher W. Woods Barbara D. Alexander Micah T. McClain The host transcriptional response to Candidemia is dominated by neutrophil activation and heme biosynthesis and supports novel diagnostic approaches Genome Medicine Candidemia Gene expression Biomarkers Host response Fungal diagnostics |
| title | The host transcriptional response to Candidemia is dominated by neutrophil activation and heme biosynthesis and supports novel diagnostic approaches |
| title_full | The host transcriptional response to Candidemia is dominated by neutrophil activation and heme biosynthesis and supports novel diagnostic approaches |
| title_fullStr | The host transcriptional response to Candidemia is dominated by neutrophil activation and heme biosynthesis and supports novel diagnostic approaches |
| title_full_unstemmed | The host transcriptional response to Candidemia is dominated by neutrophil activation and heme biosynthesis and supports novel diagnostic approaches |
| title_short | The host transcriptional response to Candidemia is dominated by neutrophil activation and heme biosynthesis and supports novel diagnostic approaches |
| title_sort | host transcriptional response to candidemia is dominated by neutrophil activation and heme biosynthesis and supports novel diagnostic approaches |
| topic | Candidemia Gene expression Biomarkers Host response Fungal diagnostics |
| url | https://doi.org/10.1186/s13073-021-00924-9 |
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