Impaired Lymphocyte Responses in Pediatric Sepsis Vary by Pathogen Type and are Associated with Features of Immunometabolic Dysregulation
Year: 2022
Type: article
Study design: Observational Study
Abstract: BACKGROUND: Sepsis is the leading cause of death in hospitalized children worldwide. Despite its hypothesized immune-mediated mechanism, targeted immunotherapy for sepsis is not available for clinical use. OBJECTIVE: To determine the association between longitudinal cytometric, proteomic, bioenergetic, and metabolomic markers of immunometabolic dysregulation and pathogen type in pediatric sepsis. METHODS: Serial peripheral blood mononuclear cell (PBMC) samples were obtained from 14 sepsis patients (34 total samples) and 7 control patients for this observational study. Flow cytometry was used to define immunophenotype, including T cell subset frequency and activation state, and assess intracellular cytokine production. Global immune dysfunction was assessed by tumor necrosis factor-α (TNF-α) production capacity and monocyte human leukocyte antigen DR (HLA-DR) expression. Mitochondrial function was assessed by bulk respirometry. Plasma cytokine levels were determined via Luminex assay. Metabolites were measured by liquid chromatography-mass spectrometry. Results were compared by timepoint and pathogen type. RESULTS: Sepsis patients were older (15.9 years vs. 10.4 years, P = 0.02) and had higher illness severity by PRISM-III (12.0 vs. 2.0, P < 0.001) compared to controls; demographics were otherwise similar, though control patients were predominately male. Compared to controls, sepsis patients at timepoint 1 demonstrated lower monocyte HLA-DR expression (75% vs. 92%, P = 0.02), loss of peripheral of non-naïve CD4+ T cells (62.4% vs. 77.6%, P = 0.04), and reduced PBMC mitochondrial spare residual capacity (SRC; 4.0 pmol/s/106 cells vs. 8.4 pmol/s/106 cells, P = 0.01). At sepsis onset, immunoparalysis (defined as TNF-α production capacity < 200 pg/mL) was present in 39% of sepsis patients and not identified among controls. Metabolomic findings in sepsis patients were most pronounced at sepsis onset and included elevated uridine and 2-dehydrogluconate and depleted citrulline. Loss of peripheral non-naïve CD4+ T cells was associated with immune dysfunction and reduced cytokine production despite increased T cell activation. CD4+ T cell differentiation and corresponding pro- and anti-inflammatory cytokines varied by pathogen. CONCLUSION: Pediatric sepsis patients exhibit a complex, dynamic physiologic state characterized by impaired T cell function and immunometabolic dysregulation which varies by pathogen type.
Source: Shock
Language: English
Subfield: Epidemiology
Field: Medicine
Domain: Health Sciences
Open Access status: green
Funders: U.S. Department of Defense, Burroughs Wellcome Fund, American Academy of Allergy Asthma and Immunology, Thrasher Research Fund, Children's Hospital of Philadelphia, University of Pennsylvania, Parker Institute for Cancer Immunotherapy, National Institutes of Health, Perelman School of Medicine, University of Pennsylvania, National Institute of Mental Health, National Institute of General Medical Sciences, National Institute of Allergy and Infectious Diseases, National Institute of Neurological Disorders and Stroke, Eunice Kennedy Shriver National Institute of Child Health and Human Development
Awards: Testing the role of BATF as a pioneer transcription factor in effector T cells, G1194463175, G1433873921, Mitochondrial Dysfunction in Pediatric Sepsis, G2262409748, G23045533, G2379706858, G2838882005, G3979633579, G4119534169, A MITOCHONDRIAL-INTERNEURONAL HYPOTHESIS OF AUTISM, G5034783206, COVID-19 SARS-COV-2 PROPAGATION AND PATHOLOGY AND MITOCHONDRIAL GENETICS, G5850682332, Effect of Mitochondrial Quality Control on Systemic Inflammation and Organ Dysfunction in Pediatric Sepsis, G6486204101, Engineering T cells to Provide Durable Control of HIV-1 Replication, G6583938578, Mitochondrial Inborn Errors in Metabolism, Mouse models for mitochondrial disorders caused by mutations in mtDNA, Temporal control of differentiation and epigenetics of Exhausted CD8 T cells by Tox, POWERING UP MITOCHONDRIAL FUNCTIONS TO TREAT MITOCHONDRIAL DISEASE, G8390724461, G9000178764, G9000299776, G9000341336, Durable Alteration of the Human Immune system after Infection or Immunotherapy, Synergies among inhibitory receptors in tolerance and disease, Obesity dysregulates immune and metabolic status in asthma and alters infection susceptibility.
OpenAlex ID: W4283656067