{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T08:20:46Z","timestamp":1792138846601,"version":"4.4.0"},"reference-count":58,"publisher":"Public Library of Science (PLoS)","issue":"12","license":[{"start":{"date-parts":[[2024,12,12]],"date-time":"2024-12-12T00:00:00Z","timestamp":1733961600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000185","name":"Defense Advanced Research Projects Agency","doi-asserted-by":"publisher","award":["lN66001-07-C-0092"],"award-info":[{"award-number":["lN66001-07-C-0092"]}],"id":[{"id":"10.13039\/100000185","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:p>Immune responses during acute infection often contain canonical elements which are shared across the responses to an array of agents within a given pathogen class (i.e., respiratory viral infection). Identification of these shared, canonical elements across similar infections offers the potential for impacting development of novel diagnostics and therapeutics. In this way, analysis of host gene expression patterns (\u2018signatures\u2019) in white blood cells has been shown to be useful for determining the etiology of some acute viral and bacterial infections. In order to study conserved immune elements shared across the host response to related pathogens, we performed <jats:italic>in vitro<\/jats:italic> human PBMC challenges with common fungal pathogens (<jats:italic>Candida albicans<\/jats:italic>, <jats:italic>Cryptococcus neoformans<\/jats:italic> and <jats:italic>gattii<\/jats:italic>); four strains of influenza virus (Influenza A\/Puerto Rico\/08\/34 [H1N1, PR8], A\/Brisbane\/59\/2007 [H1N1], A\/Solomon Islands\/3\/2006 [H1N1], and A\/Wisconsin\/67\/2005 [H3N2]); and gram-negative (<jats:italic>Escherichia coli<\/jats:italic>) and gram-positive (<jats:italic>Streptococcus pneumoniae<\/jats:italic>) bacteria. Exposed human cells were then analyzed for differential gene expression utilizing Affymetrix microarrays. Analysis of pathogen exposure of PBMCs revealed strong, conserved gene expression patterns representing these canonical immune response elements to each broad pathogen class. A 41-gene multinomial signature was developed which correctly classified fungal, viral, or bacterial exposure with 94\u201398% accuracy. Furthermore, a 21-gene signature consisting of a subset of the discriminatory PBMC-derived genes was capable of accurately differentiating human patients with invasive candidiasis, acute viral infection, or bacterial infection (AUC 0.94, 0.83, and 0.96 respectively). These data reinforce the conserved nature of the genomic responses in human peripheral blood cells upon exposure to infectious agents and highlight the potential for <jats:italic>in vitro<\/jats:italic> models to augment our ability to develop novel diagnostic classifiers for acute infectious diseases, particularly devastating fungal infections.<\/jats:p>","DOI":"10.1371\/journal.pone.0311007","type":"journal-article","created":{"date-parts":[[2024,12,12]],"date-time":"2024-12-12T18:23:54Z","timestamp":1734027834000},"page":"e0311007","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":7,"title":["Pathogen class-specific transcriptional responses derived from PBMCs accurately discriminate between fungal, bacterial, and viral infections"],"prefix":"10.1371","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0771-3647","authenticated-orcid":true,"given":"Julie 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Fawcett","year":"2006","journal-title":"Pattern Recognition Letters"},{"issue":"4","key":"pone.0311007.ref027","doi-asserted-by":"crossref","first-page":"605","DOI":"10.1093\/cid\/ciab043","article-title":"Validation of a Host Gene Expression Test for Bacterial\/Viral Discrimination in Immunocompromised Hosts","volume":"73","author":"RE Mahle","year":"2021","journal-title":"Clin Infect Dis"},{"key":"pone.0311007.ref028","article-title":"Potential Cost-effectiveness of Early Identification of Hospital-acquired Infection in Critically Ill Patients","author":"EL Tsalik","year":"2015","journal-title":"Ann Am Thorac Soc"},{"issue":"11","key":"pone.0311007.ref029","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1186\/s13073-014-0111-5","article-title":"An integrated transcriptome and expressed variant analysis of sepsis survival and death","volume":"6","author":"EL Tsalik","year":"2014","journal-title":"Genome 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expression signatures predict invasive candidiasis","volume":"2","author":"AK Zaas","year":"2010","journal-title":"Science translational medicine"},{"issue":"10","key":"pone.0311007.ref037","doi-asserted-by":"crossref","first-page":"1014","DOI":"10.3390\/jof9101014","article-title":"Differential Transcriptional Responses of Human Granulocytes to Fungal Infection with Candida albicans and Aspergillus fumigatus","volume":"9","author":"TE Klassert","year":"2023","journal-title":"Journal of Fungi"},{"key":"pone.0311007.ref038","doi-asserted-by":"crossref","first-page":"76","DOI":"10.1016\/j.fgb.2014.11.006","article-title":"Immunity to Cryptococcus neoformans and C. gattii during cryptococcosis","volume":"78","author":"JF Gibson","year":"2015","journal-title":"Fungal genetics and biology: FG & B"},{"issue":"5","key":"pone.0311007.ref039","article-title":"Transcriptional Profiles Elucidate Differential Host Responses to Infection with Cryptococcus neoformans and Cryptococcus gattii","volume":"8","author":"ZE Holcomb","year":"2022","journal-title":"J Fungi (Basel)"},{"key":"pone.0311007.ref040","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.trsl.2020.02.005","article-title":"A transcriptional signature accurately identifies Aspergillus Infection across healthy and immunosuppressed states","volume":"219","author":"JM Steinbrink","year":"2020","journal-title":"Transl Res"},{"issue":"6","key":"pone.0311007.ref041","doi-asserted-by":"crossref","first-page":"1340","DOI":"10.1016\/j.cell.2019.01.041","article-title":"Human Anti-fungal Th17 Immunity and Pathology Rely on Cross-Reactivity against Candida albicans","volume":"176","author":"P Bacher","year":"2019","journal-title":"Cell"},{"issue":"5","key":"pone.0311007.ref042","doi-asserted-by":"crossref","first-page":"862","DOI":"10.1093\/infdis\/jiz206","article-title":"A Genome-Wide Functional Genomics Approach Identifies Susceptibility Pathways to Fungal Bloodstream Infection in Humans","volume":"220","author":"M Jaeger","year":"2019","journal-title":"J Infect Dis"},{"issue":"4","key":"pone.0311007.ref043","doi-asserted-by":"crossref","first-page":"e1008408","DOI":"10.1371\/journal.ppat.1008408","article-title":"Integrating GWAS with bulk and single-cell RNA-sequencing reveals a role for LY86 in the anti-Candida host response","volume":"16","author":"DH de Vries","year":"2020","journal-title":"PLoS Pathog"},{"issue":"13","key":"pone.0311007.ref044","doi-asserted-by":"crossref","first-page":"2802","DOI":"10.1016\/j.cell.2023.04.031","article-title":"C5a-licensed phagocytes drive sterilizing immunity during systemic fungal infection","volume":"186","author":"JV Desai","year":"2023","journal-title":"Cell"},{"issue":"5","key":"pone.0311007.ref045","doi-asserted-by":"crossref","first-page":"2066","DOI":"10.1182\/blood-2006-02-002477","article-title":"Gene expression patterns in blood leukocytes discriminate patients with acute infections","volume":"109","author":"O Ramilo","year":"2007","journal-title":"Blood"},{"issue":"2","key":"pone.0311007.ref046","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1093\/infdis\/jiv047","article-title":"Superiority of transcriptional profiling over procalcitonin for distinguishing bacterial from viral lower respiratory tract infections in hospitalized adults","volume":"212","author":"NM Suarez","year":"2015","journal-title":"J Infect Dis"},{"key":"pone.0311007.ref047","doi-asserted-by":"crossref","first-page":"382","DOI":"10.3389\/fcimb.2018.00382","article-title":"Molecular Distance to Health Transcriptional Score and Disease Severity in Children Hospitalized With Community-Acquired Pneumonia","volume":"8","author":"RG Wallihan","year":"2018","journal-title":"Front Cell Infect Microbiol"},{"key":"pone.0311007.ref048","article-title":"Differential evolution of peripheral cytokine levels in symptomatic and asymptomatic responses to experimental influenza virus challenge","author":"MT McClain","year":"2015","journal-title":"Clin Exp Immunol"},{"issue":"1","key":"pone.0311007.ref049","doi-asserted-by":"crossref","first-page":"e52198","DOI":"10.1371\/journal.pone.0052198","article-title":"A Host Transcriptional Signature for Presymptomatic Detection of Infection in Humans Exposed to Influenza H1N1 or H3N2","volume":"8","author":"CW Woods","year":"2013","journal-title":"PLoS One"},{"issue":"3","key":"pone.0311007.ref050","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1016\/j.chom.2009.07.006","article-title":"Gene expression signatures diagnose influenza and other symptomatic respiratory viral infections in humans","volume":"6","author":"AK Zaas","year":"2009","journal-title":"Cell Host Microbe"},{"issue":"9","key":"pone.0311007.ref051","doi-asserted-by":"crossref","first-page":"e22534","DOI":"10.1371\/journal.pone.0022534","article-title":"Clinical and virological factors associated with viremia in pandemic influenza A\/H1N1\/2009 virus 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Schlaberg","year":"2017","journal-title":"Arch Pathol Lab Med"},{"issue":"4","key":"pone.0311007.ref055","doi-asserted-by":"crossref","first-page":"1000","DOI":"10.1128\/JCM.03060-15","article-title":"Unbiased Detection of Respiratory Viruses by Use of RNA Sequencing-Based Metagenomics: a Systematic Comparison to a Commercial PCR Panel","volume":"54","author":"EH Graf","year":"2016","journal-title":"J Clin Microbiol"},{"issue":"7","key":"pone.0311007.ref056","doi-asserted-by":"crossref","first-page":"e27734","DOI":"10.1002\/pbc.27734","article-title":"Cell-free DNA next-generation sequencing successfully detects infectious pathogens in pediatric oncology and hematopoietic stem cell transplant patients at risk for invasive fungal disease","volume":"66","author":"AE Armstrong","year":"2019","journal-title":"Pediatr Blood Cancer"},{"issue":"11","key":"pone.0311007.ref057","doi-asserted-by":"crossref","first-page":"e893","DOI":"10.1093\/cid\/ciaa1527","article-title":"Diagnostic Tests Can 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