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Passive immunization against tumor necrosis factor-alpha impairs host defense during pneumococcal pneumonia in mice
T van der Poll1, C V Keogh, W A Buurman
1Cornell University Medical College, Department of Surgery, New York, New York 10021, USA.
Abstract:
Streptococcus pneumoniae is the most frequent cause of community-acquired pneumonia. We sought to determine the role of tumor necrosis factor-alpha (TNF) in the pathogenesis of pneumococcal pneumonia. Induction of pneumonia in C57B1/6 mice by intranasal inoculation with 10(6) colony-forming units (cfu) S. pneumoniae resulted in a sustained increase in TNF activity in lung homogenates reaching a plateau between 12 and 72 h (72 h: 185.49 +/- 54.41 ng/g), while plasma TNF activity remained low or undetectable. Treatment with a neutralizing anti-TNF monoclonal antibody 2 h before inoculation strongly reduced lung TNF activity, but only modestly diminished lung interleukin (IL)-1beta levels, and did not significantly influence lung IL-6, IL-10, and interferon-gamma concentrations. Anti-TNF-treated mice had fourfold more S. pneumoniae cfu isolated from lungs than control mice 40 h after inoculation (p < 0.05), although lung myeloperoxidase activities were similar in both treatment groups. Anti-TNF-treated mice died significantly earlier from pneumococcal pneumonia than control mice (p < 0.05). Endogenously produced TNF is important for host defense during pneumococcal pneumonia.
Insights
Tumor necrosis factor-alpha (TNF) plays a crucial role in fighting pneumococcal pneumonia. Blocking TNF in mice worsened the infection and led to earlier deaths, highlighting its importance in host defense.
Area of Science:
- Immunology
- Infectious Diseases
- Pulmonary Medicine
Background:
- Streptococcus pneumoniae is a leading cause of community-acquired pneumonia.
- The precise role of tumor necrosis factor-alpha (TNF) in pneumococcal pneumonia pathogenesis requires further elucidation.
Purpose of the Study:
- To investigate the role of TNF in the host's defense mechanisms against Streptococcus pneumoniae infection.
- To assess the impact of TNF neutralization on disease progression and outcomes in a murine model of pneumococcal pneumonia.
Main Methods:
- Induction of pneumococcal pneumonia in C57BL/6 mice via intranasal inoculation.
- Measurement of TNF and cytokine levels (IL-1beta, IL-6, IL-10, IFN-gamma) in lung homogenates and plasma.
- Administration of a neutralizing anti-TNF monoclonal antibody prior to infection.
- Quantification of bacterial load (cfu) and myeloperoxidase activity in lung tissues.
- Survival analysis of treated versus control mice.
Main Results:
- Intranasal S. pneumoniae inoculation led to sustained increases in lung TNF activity, with minimal plasma TNF.
- Anti-TNF antibody treatment significantly reduced lung TNF activity but only modestly affected IL-1beta levels and did not alter other measured cytokines.
- Mice treated with anti-TNF showed a fourfold increase in bacterial load and significantly earlier mortality compared to control mice.
- Lung myeloperoxidase activity was comparable between anti-TNF-treated and control groups, suggesting TNF's role is not solely mediated by neutrophil infiltration.
Conclusions:
- Endogenously produced TNF is essential for effective host defense during Streptococcus pneumoniae pneumonia.
- Neutralization of TNF impairs bacterial clearance and exacerbates disease severity, leading to increased mortality.
- These findings underscore the critical role of TNF in combating pneumococcal infections and suggest potential therapeutic implications.