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Beneficial Effects of CpG-Oligodeoxynucleotide Treatment on Trauma and Secondary Lung Infection
Lorenz Wanke-Jellinek1, Joshua W Keegan2, James W Dolan2
1Department of Surgery, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115; Department of Trauma Surgery, Technical University of Munich, 81675 Munich, Germany;
Abstract:
Although Streptococcus pneumoniae is usually found as a commensal in healthy individuals, it can act as a pathogen in trauma patients, causing such complications as early-onset pneumonia and sepsis. We discovered that treating mice with an A-class CpG-oligodeoxynucleotide (ODN) at 2 h after traumatic injury significantly improved mouse survival following early-onset secondary lung infection with S. pneumoniae. This study used mass cytometry (cytometry by time-of-flight) and Luminex technologies to characterize the cellular immune response to secondary S. pneumoniae lung infection at 1 and 3 d postinfection. We found increased expression of CD14, CD64, and PD-L1 on F4-80(+) and F4-80(+)CD11c(+) macrophages, CD11c(+) dendritic cells, and CD14(+)CD172a(+) cells after burn-injury and infection, supporting previous reports of innate immune cell activation in sepsis. CpG-ODN treatment at 2 h after burn-injury reversed these effects; improved pathogen clearance; and led to an increased expression of CD25, CD27, MHCII, and IL-17 on or in TCRγδ cells at 1 d postinfection. At 3 d postinfection, CpG-ODN treatment increased the expression of PD-L1 on innate cell subsets. Furthermore, we analyzed cytokine levels in lung-washout samples of TCRγδ cell-depleted (TCRγδ(-)) mice to demonstrate that the effects of CpG-ODN on cytokine expression after burn-injury and S. pneumoniae infection rely on functional TCRγδ cells. In summary, we demonstrate that cytometry by time-of-flight provides an effective strategy to systematically identify specific cellular phenotypic responses to trauma and bacterial pneumonia and to discover changes in immune system phenotypes associated with beneficial immunotherapy.
Insights
CpG-oligodeoxynucleotide (ODN) treatment improved survival in mice with secondary Streptococcus pneumoniae lung infections after trauma. This immunotherapy modulated innate and adaptive immune cell responses, highlighting the role of T cell receptor gamma delta (TCRγδ) cells.
Area of Science:
- Immunology
- Microbiology
- Trauma Research
Background:
- * Streptococcus pneumoniae is a commensal but can cause severe infections like pneumonia and sepsis in trauma patients.
- * Innate immune cell activation is a known response to sepsis following traumatic injury.
- * Early-onset secondary lung infections pose a significant threat to trauma patient survival.
Purpose of the Study:
- * To investigate the efficacy of A-class CpG-oligodeoxynucleotide (ODN) immunotherapy in improving survival after secondary S. pneumoniae lung infection in a mouse model of burn injury.
- * To characterize the cellular immune response to infection and the impact of CpG-ODN treatment using mass cytometry and Luminex technologies.
- * To elucidate the role of T cell receptor gamma delta (TCRγδ) cells in the immune response and immunotherapy effectiveness.
Main Methods:
- * Establishment of a mouse model of burn injury followed by secondary S. pneumoniae lung infection.
- * Administration of A-class CpG-ODN at 2 hours post-injury.
- * Analysis of cellular immune responses using mass cytometry (cytometry by time-of-flight) and Luminex at 1 and 3 days post-infection.
- * Assessment of cytokine levels in lung-washout samples from TCRγδ cell-depleted mice.
Main Results:
- * CpG-ODN treatment significantly improved mouse survival.
- * CpG-ODN reversed the upregulation of CD14, CD64, and PD-L1 on innate immune cells observed post-injury and infection.
- * CpG-ODN treatment led to increased expression of CD25, CD27, MHCII, and IL-17 on TCRγδ cells and enhanced pathogen clearance.
- * The beneficial effects of CpG-ODN on cytokine expression were dependent on functional TCRγδ cells.
Conclusions:
- * A-class CpG-ODN immunotherapy is a promising strategy for improving outcomes in trauma patients with secondary S. pneumoniae lung infections.
- * Cytometry by time-of-flight is effective for identifying cellular responses to trauma and infection and for discovering beneficial immunotherapy-induced immune phenotypes.
- * Functional TCRγδ cells are critical mediators of the CpG-ODN immunotherapy's effects in this trauma-infection model.
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