DOI: 10.1002/ame2.70079
Molecular dynamics of the host response to Streptococcus pneumoniae pneumonia in baboons
Bryan D.Kraft1
Ashlee M.Valente2
Ephraim L.Tsalik3
Micah T.McClain3
Marshall Nichols2
Thomas W.Burke4
Ricardo Henao2
Erik J.Soderblom5
J.Will Thompson5
M.Arthur Moseley5
Lori L.Hudson2
Timothy Veldman2
Olga M.Better2
Mert Aydin2
Anna Mazur2
Karen E.Welty-Wolf6
Claude A.Piantadosi6
Geoffrey S.Ginsburg7
Christopher W.Woods3
1.Division of Pulmonary,Allergy,and Critical Care Medicine,Department of Medicine,Duke University School of Medicine,Durham,North Carolina,USA;Durham Veterans Affairs Health Care System,Durham,North Carolina,USA;Division of Pulmonary and Critical Care Medicine,Department of Medicine,Washington University School of Medicine,Saint Louis,Missouri,USA2.Center for Infectious Disease Diagnostics and Innovation,Duke University School of Medicine,Durham,North Carolina,USA3.Durham Veterans Affairs Health Care System,Durham,North Carolina,USA;Center for Infectious Disease Diagnostics and Innovation,Duke University School of Medicine,Durham,North Carolina,USA;Division of Infectious Diseases,Department of Medicine,Duke University School of Medicine,Durham,North Carolina,USA4.Center for Infectious Disease Diagnostics and Innovation,Duke University School of Medicine,Durham,North Carolina,USA;Division of Infectious Diseases,Department of Medicine,Duke University School of Medicine,Durham,North Carolina,USA5.Proteomics and Metabolomics Shared Resource,Duke University School of Medicine,Durham,North Carolina,USA6.Division of Pulmonary,Allergy,and Critical Care Medicine,Department of Medicine,Duke University School of Medicine,Durham,North Carolina,USA;Durham Veterans Affairs Health Care System,Durham,North Carolina,USA7.All of Us Research Program,National Institutes of Health,Bethesda,Maryland,USA
摘要：Background:Bacterial pneumonia remains a leading cause of morbidity and mortality worldwide despite the widespread availability of antibiotics.Novel pneumonia therapies and biomarkers are urgently needed to improve outcomes and advance personalized therapy.Using an established baboon model of S.pneumoniae pneumonia,we sought to characterize the temporal dynamics of pneumonia host responses to identify novel potential diagnostic and therapeutic molecular targets.
Methods:We performed whole blood transcriptomics,unbiased proteomics,and peripheral cytokine measurements serially in baboons inoculated with S.pneumoniae(n=23)or saline(n=10)and modeled the peripheral blood host response using principal components analysis and complex sparse logistic regression.Differentially expressed genes were analyzed for pathway analysis.
Results:Inoculated animals developed characteristic signs and symptoms of pneumonia.A 39-gene signature was derived that classified S.pneumoniae infection with high accuracy(auROC 0.9 and 0.99 at 24 and 48h post-inoculation,respectively).Similar performance was observed for 48-h biomarker signatures derived from peripheral blood plasma proteomic and cytokine measurements(both auROC＞0.9).The gene signature retained strong diagnostic performance(auROC=0.88)when transformed to human orthologs and applied to patients with acute respiratory illness(n=34)or healthy controls(n=20).Pathway analysis at 48 h identified down-regulation of mitophagy and glucocorticoid signaling in peripheral blood.
Conclusions:We report novel peripheral blood gene and protein expression signatures of S.pneumoniae pneumonia that could improve pneumonia diagnosis and found distinct pathways that may be amenable to modulation.Our findings illustrate how non-human primate models of bacterial pneumonia can successfully translate biomarker discoveries to patients.
机标关键词：moleculardynamicshostbaboonspneumoniaeresponsestreptococcus
论文发表日期：2025-10-30
在线出版日期：2025-12-16（本平台首次上网日期，不代表文献的发表时间）
页数：12( 1896-1907 )
英文信息