Proteomic profiling of the local and systemic immune response to pediatric respiratory viral infections
ABSTRACT Viral lower respiratory tract infection (vLRTI) is a leading cause of hospitalization and death in children worldwide. Despite this, no studies have employed proteomics to characterize host immune responses to severe pediatric vLRTI in both the lower airway and systemic circulation. To addr...
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American Society for Microbiology
2025-01-01
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| Series: | mSystems |
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| Online Access: | https://journals.asm.org/doi/10.1128/msystems.01335-24 |
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| author | Emily Lydon Christina M. Osborne Brandie D. Wagner Lilliam Ambroggio J. Kirk Harris Ron Reeder Todd C. Carpenter Aline B. Maddux Matthew K. Leroue Nadir Yehya Joseph L. DeRisi Mark W. Hall Athena F. Zuppa Joseph Carcillo Kathleen Meert Anil Sapru Murray M. Pollack Patrick McQuillen Daniel A. Notterman Charles R. Langelier Peter M. Mourani |
| author_facet | Emily Lydon Christina M. Osborne Brandie D. Wagner Lilliam Ambroggio J. Kirk Harris Ron Reeder Todd C. Carpenter Aline B. Maddux Matthew K. Leroue Nadir Yehya Joseph L. DeRisi Mark W. Hall Athena F. Zuppa Joseph Carcillo Kathleen Meert Anil Sapru Murray M. Pollack Patrick McQuillen Daniel A. Notterman Charles R. Langelier Peter M. Mourani |
| author_sort | Emily Lydon |
| collection | DOAJ |
| description | ABSTRACT Viral lower respiratory tract infection (vLRTI) is a leading cause of hospitalization and death in children worldwide. Despite this, no studies have employed proteomics to characterize host immune responses to severe pediatric vLRTI in both the lower airway and systemic circulation. To address this gap, gain insights into vLRTI pathophysiology, and test a novel diagnostic approach, we assayed 1,305 proteins in tracheal aspirate (TA) and plasma from 62 critically ill children using SomaScan. We performed differential expression (DE) and pathway analyses comparing vLRTI (n = 40) to controls with non-infectious acute respiratory failure (n = 22), developed a diagnostic classifier using LASSO regression, and analyzed matched TA and plasma samples. We further investigated the impact of viral load and bacterial coinfection on the proteome. The TA signature of vLRTI was characterized by 200 DE proteins (Padj <0.05) with upregulation of interferons and T cell responses and downregulation of inflammation-modulating proteins including FABP and MIP-5. A nine-protein TA classifier achieved an area under the receiver operator curve (AUC) of 0.96 (95% CI: 0.90–1.00) for identifying vLRTI. In plasma, the host response to vLRTI was more muted with 56 DE proteins. Correlation between TA and plasma was limited, although ISG15 was elevated in both compartments. In bacterial coinfection, we observed increases in the TNF-stimulated protein TSG-6, as well as CRP, and interferon-related proteins. Viral load correlated positively with interferon signaling and negatively with neutrophil-activation pathways. Taken together, our study provides fresh insights into the lower airway and systemic proteome of severe pediatric vLRTI and identifies novel protein biomarkers with diagnostic potential.IMPORTANCEWe describe the first proteomic profiling of the lower airway and blood in critically ill children with severe viral lower respiratory tract infection (vLRTI). From tracheal aspirate (TA), we defined a proteomic signature of vLRTI characterized by increased expression of interferon signaling proteins and decreased expression of proteins involved in immune modulation including FABP and MIP-5. Using machine learning, we developed a parsimonious diagnostic classifier that distinguished vLRTI from non-infectious respiratory failure with high accuracy. Comparative analysis of paired TA and plasma specimens demonstrated limited concordance, although the interferon-stimulated protein ISG15 was significantly upregulated with vLRTI in both compartments. We further identified TSG-6 and CRP as airway biomarkers of bacterial-viral coinfection, and viral load analyses demonstrated a positive correlation with interferon-related protein expression and a negative correlation with the expression of neutrophil activation proteins. Taken together, our study provides new insights into the lower airway and systemic proteome of severe pediatric vLRTI. |
| format | Article |
| id | doaj-art-cee365fb36c94a1f847b84c25db1232b |
| institution | Kabale University |
| issn | 2379-5077 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | American Society for Microbiology |
| record_format | Article |
| series | mSystems |
| spelling | doaj-art-cee365fb36c94a1f847b84c25db1232b2025-01-21T14:00:28ZengAmerican Society for MicrobiologymSystems2379-50772025-01-0110110.1128/msystems.01335-24Proteomic profiling of the local and systemic immune response to pediatric respiratory viral infectionsEmily Lydon0Christina M. Osborne1Brandie D. Wagner2Lilliam Ambroggio3J. Kirk Harris4Ron Reeder5Todd C. Carpenter6Aline B. Maddux7Matthew K. Leroue8Nadir Yehya9Joseph L. DeRisi10Mark W. Hall11Athena F. Zuppa12Joseph Carcillo13Kathleen Meert14Anil Sapru15Murray M. Pollack16Patrick McQuillen17Daniel A. Notterman18Charles R. Langelier19Peter M. Mourani20Department of Medicine, University of California San Francisco, San Francisco, California, USADepartment of Anesthesiology and Critical Care Medicine, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USADepartment of Biostatistics and Informatics, University of Colorado, Colorado School of Public Health, Aurora, Colorado, USASections of Emergency Medicine and Hospital Medicine, Children’s Hospital Colorado, Aurora, Colorado, USADepartment of Pediatrics, University of Colorado School of Medicine and Children’s Hospital Colorado, Aurora, Colorado, USADepartment of Pediatrics, University of Utah, Salt Lake City, Utah, USADepartment of Pediatrics, University of Colorado School of Medicine and Children’s Hospital Colorado, Aurora, Colorado, USADepartment of Pediatrics, University of Colorado School of Medicine and Children’s Hospital Colorado, Aurora, Colorado, USADepartment of Pediatrics, University of Colorado School of Medicine and Children’s Hospital Colorado, Aurora, Colorado, USADepartment of Anesthesiology and Critical Care Medicine, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USAChan Zuckerberg Biohub, San Francisco, California, USADepartment of Pediatrics, Nationwide Children’s Hospital, Columbus, Ohio, USADepartment of Anesthesiology and Critical Care Medicine, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USADepartments of Pediatrics and Critical Care Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USADepartment of Pediatrics, Children’s Hospital of Michigan, Central Michigan University, Detroit, Michigan, USADepartment of Pediatrics, University of California Los Angeles, Los Angeles, California, USADepartment of Pediatrics,, Children’s National Medical Center and George Washington School of Medicine and Health Sciences, Washington, DC, USADepartment of Pediatrics, University of California San Francisco, San Francisco, California, USADepartment of Molecular Biology, Princeton University, Princeton, New Jersey, USADepartment of Medicine, University of California San Francisco, San Francisco, California, USADepartment of Pediatrics, Critical Care, University of Arkansas for Medical Sciences and Arkansas Children’s Hospital, Little Rock, Arkansas, USAABSTRACT Viral lower respiratory tract infection (vLRTI) is a leading cause of hospitalization and death in children worldwide. Despite this, no studies have employed proteomics to characterize host immune responses to severe pediatric vLRTI in both the lower airway and systemic circulation. To address this gap, gain insights into vLRTI pathophysiology, and test a novel diagnostic approach, we assayed 1,305 proteins in tracheal aspirate (TA) and plasma from 62 critically ill children using SomaScan. We performed differential expression (DE) and pathway analyses comparing vLRTI (n = 40) to controls with non-infectious acute respiratory failure (n = 22), developed a diagnostic classifier using LASSO regression, and analyzed matched TA and plasma samples. We further investigated the impact of viral load and bacterial coinfection on the proteome. The TA signature of vLRTI was characterized by 200 DE proteins (Padj <0.05) with upregulation of interferons and T cell responses and downregulation of inflammation-modulating proteins including FABP and MIP-5. A nine-protein TA classifier achieved an area under the receiver operator curve (AUC) of 0.96 (95% CI: 0.90–1.00) for identifying vLRTI. In plasma, the host response to vLRTI was more muted with 56 DE proteins. Correlation between TA and plasma was limited, although ISG15 was elevated in both compartments. In bacterial coinfection, we observed increases in the TNF-stimulated protein TSG-6, as well as CRP, and interferon-related proteins. Viral load correlated positively with interferon signaling and negatively with neutrophil-activation pathways. Taken together, our study provides fresh insights into the lower airway and systemic proteome of severe pediatric vLRTI and identifies novel protein biomarkers with diagnostic potential.IMPORTANCEWe describe the first proteomic profiling of the lower airway and blood in critically ill children with severe viral lower respiratory tract infection (vLRTI). From tracheal aspirate (TA), we defined a proteomic signature of vLRTI characterized by increased expression of interferon signaling proteins and decreased expression of proteins involved in immune modulation including FABP and MIP-5. Using machine learning, we developed a parsimonious diagnostic classifier that distinguished vLRTI from non-infectious respiratory failure with high accuracy. Comparative analysis of paired TA and plasma specimens demonstrated limited concordance, although the interferon-stimulated protein ISG15 was significantly upregulated with vLRTI in both compartments. We further identified TSG-6 and CRP as airway biomarkers of bacterial-viral coinfection, and viral load analyses demonstrated a positive correlation with interferon-related protein expression and a negative correlation with the expression of neutrophil activation proteins. Taken together, our study provides new insights into the lower airway and systemic proteome of severe pediatric vLRTI.https://journals.asm.org/doi/10.1128/msystems.01335-24proteomicsLRTIpneumoniahost responseco-infectionviral pneumonia |
| spellingShingle | Emily Lydon Christina M. Osborne Brandie D. Wagner Lilliam Ambroggio J. Kirk Harris Ron Reeder Todd C. Carpenter Aline B. Maddux Matthew K. Leroue Nadir Yehya Joseph L. DeRisi Mark W. Hall Athena F. Zuppa Joseph Carcillo Kathleen Meert Anil Sapru Murray M. Pollack Patrick McQuillen Daniel A. Notterman Charles R. Langelier Peter M. Mourani Proteomic profiling of the local and systemic immune response to pediatric respiratory viral infections mSystems proteomics LRTI pneumonia host response co-infection viral pneumonia |
| title | Proteomic profiling of the local and systemic immune response to pediatric respiratory viral infections |
| title_full | Proteomic profiling of the local and systemic immune response to pediatric respiratory viral infections |
| title_fullStr | Proteomic profiling of the local and systemic immune response to pediatric respiratory viral infections |
| title_full_unstemmed | Proteomic profiling of the local and systemic immune response to pediatric respiratory viral infections |
| title_short | Proteomic profiling of the local and systemic immune response to pediatric respiratory viral infections |
| title_sort | proteomic profiling of the local and systemic immune response to pediatric respiratory viral infections |
| topic | proteomics LRTI pneumonia host response co-infection viral pneumonia |
| url | https://journals.asm.org/doi/10.1128/msystems.01335-24 |
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