Dataset Information

A transcriptional signature accurately identifies Aspergillus Infection across healthy and immunosuppressed states.

ABSTRACT: Invasive aspergillosis (IA) is a major cause of critical illness in immunocompromised (IC) patients. However, current fungal tests are limited. Disease-specific gene expression patterns in circulating host cells show promise as novel diagnostics, however it is unknown whether such a 'signature' exists for IA and the effect of iatrogenic immunosuppression on any such biomarkers. Male BALB/c mice were separated into 6 experimental groups based on Aspergillus fumigatus inhalational exposure and IC status (no immunosuppression, cyclophosphamide, and corticosteroids). Mice were sacrificed 4 days postinfection. Whole blood was assayed for transcriptomic responses in peripheral white blood cells via microarray. An elastic net regularized logistic regression was employed to develop classifiers of IA based on gene expression. Aspergillus infection triggers a powerful response in non-IC hosts with 2718 genes differentially expressed between IA and controls. We generated a 146-gene classifier able to discriminate between non-IC infected and uninfected mice with an AUC of 1. However, immunosuppressive medications exhibited a confounding effect on this transcriptomic classifier. After controlling for the genomic effects of immunosuppression, we were able to generate a 187-gene classifier with an AUC of 0.92 in the absence of immunosuppression, 1 with cyclophosphamide, and 0.9 with steroids. The host transcriptomic response to IA is robust and conserved. Pharmacologic perturbation of the host immune response has powerful effects on classifier performance and must be considered when developing such novel diagnostics. When appropriately designed, host-derived peripheral blood transcriptomic responses demonstrate the ability to accurately diagnose Aspergillus infection, even in the presence of immunosuppression.

SUBMITTER: Steinbrink JM

PROVIDER: S-EPMC7170547 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Similar Datasets

Project description:Background: Acute respiratory infections (ARIs) are the leading indication for antibacterial prescriptions despite a viral etiology in the majority of cases. The lack of available diagnostics to discriminate viral and bacterial etiologies contributes to this discordance. Recent efforts have focused on the host response as a source for novel diagnostic targets although none have explored the ability of host-derived microRNAs (miRNA) to discriminate between these etiologies. Methods: In this study, we compared host-derived miRNAs and mRNAs from human H3N2 influenza challenge subjects to those from patients with Streptococcus pneumoniae pneumonia. Sparse logistic regression models were used to generate miRNA signatures diagnostic of ARI etiologies. Generalized linear modeling of mRNAs to identify differentially expressed (DE) genes allowed analysis of potential miRNA:mRNA relationships. High likelihood miRNA:mRNA interactions were examined using binding target prediction and negative correlation to further explore potential changes in pathway regulation in response to infection. Results: The resultant miRNA signatures were highly accurate in discriminating ARI etiologies. Mean accuracy was 100% [88.8-100; 95% Confidence Interval (CI)] in discriminating the healthy state from S. pneumoniae pneumonia and 91.3% (72.0-98.9; 95% CI) in discriminating S. pneumoniae pneumonia from influenza infection. Subsequent differential mRNA gene expression analysis revealed alterations in regulatory networks consistent with known biology including immune cell activation and host response to viral infection. Negative correlation network analysis of miRNA:mRNA interactions revealed connections to pathways with known immunobiology such as interferon regulation and MAP kinase signaling. Conclusion: We have developed novel human host-response miRNA signatures for bacterial and viral ARI etiologies. miRNA host response signatures reveal accurate discrimination between S. pneumoniae pneumonia and influenza etiologies for ARI and integrated analyses of the host-pathogen interface are consistent with expected biology. These results highlight the differential miRNA host response to bacterial and viral etiologies of ARI, offering new opportunities to distinguish these entities.

Dataset Information

A transcriptional signature accurately identifies Aspergillus Infection across healthy and immunosuppressed states.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets