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.

Transcriptional Profiles Elucidate Differential Host Responses to Infection with Cryptococcus neoformans and Cryptococcus gattii

“…These data suggest that the observed gene expression changes are not isolated to the murine species. This degree of species overlap is similar to our previously published Candida data [ 29 , 55 ], where an overlap of less than 50% of the differentially expressed genes between mice and humans still allowed for highly accurate performance of the classifier in human hosts.…”

Prospective Validation of a Rapid Host Gene Expression Test to Discriminate Bacterial From Viral Respiratory Infection

“…The present study extended those findings, highlighting the opportunity to develop host gene expression–based diagnostic assessments for a variety of clinical applications. Signatures have been described for infectious disease applications (eg, sepsis, candidemia, Dengue, tuberculosis, and malaria) 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 and noncommunicable diseases (eg, rheumatic diseases, coronary artery disease, radiation exposure, and cancer). 48 , 49 , 50 , 51 , 52 , 53 As the path from signature discovery to test development and commercialization comes into focus, we expect the development and use of point-of-need host response–based diagnostic tools to expand.…”

Pathogen‐agnostic immune biomarkers that predict infection after solid organ transplantation

“…Fewer studies have examined host gene responses to fungal infections. A small study has defined transcriptomic responses to candidemia in human subjects, but this assay has yet to be evaluated prospectively 99 . Host expression profiling in mouse models has demonstrated discriminatory transcripts for Aspergillus colonization and infection, suggesting feasibility in humans as well 100,102 …”