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Updated: Aug 29, 2026
Use of Animal Model of Sepsis to Evaluate Novel Herbal Therapies
Published on: April 11, 2012
Treatment of experimental sepsis-induced immunoparalysis with TNF
Bernd Echtenacher1, Renate Urbaschek, Karin Weigl
1Institute for Pathology/Tumor Immunology, University of Regensburg, Regensburg, Germany.
Abstract:
Following a severe septic abdominal infection induced by sublethal cecal ligation and puncture (CLP) in mice, a phase of depressed immune reactivity occurred two days after CLP characterized by a reduced capacity to produce TNF. To determine whether this reduced TNF production causes immunoparalysis as determined by increased susceptibility to bacterial infection and whether therapeutic TNF substitution can be beneficial during this phase, a super-infection with Salmonella enterica Serovar typhimurium or Listeria monocytogenes was induced two days after sublethal CLP. After CLP a state of true immunoparalysis developed during which Salmonella or Listeria super-infection led to increased lethality paralleled by increased bacterial numbers in spleens and livers. Injection of recombinant human TNF before or at the time of super-infection conferred protection to Salmonella but not to Listeria. In the latter case, the infection mortality was even enhanced. Thus, super-infection during the state of sepsis-induced immunoparalysis leads to increased lethality. TNF substitution during this state of immunoparalysis can be beneficial or deleterious, depending on the location of TNF activity in the animal, timing of TNF administration, or the type of super-infection. These results demonstrate that impaired TNF production capacity can account for some aspects of immunoparalysis, however, diagnostic parameters are required for a safe TNF substitution therapy.
Insights
Sepsis can cause immunoparalysis, increasing susceptibility to secondary infections. Therapeutic tumor necrosis factor (TNF) substitution during this phase may improve outcomes for some infections but can worsen others, highlighting the need for careful diagnostics.
Area of Science:
- Immunology
- Infectious Diseases
- Sepsis Pathophysiology
Background:
- Severe sepsis, induced by cecal ligation and puncture (CLP) in mice, leads to a period of suppressed immune function.
- This immune suppression, occurring two days post-CLP, is characterized by a reduced capacity to produce tumor necrosis factor (TNF).
Purpose of the Study:
- To investigate if reduced TNF production causes immunoparalysis and increased susceptibility to secondary bacterial infections.
- To determine the efficacy of therapeutic TNF substitution during this immunoparalytic phase.
Main Methods:
- Mice underwent sublethal CLP to induce sepsis and subsequent immunoparalysis.
- Super-infection with Salmonella enterica or Listeria monocytogenes was performed two days after CLP.
- Recombinant human TNF was administered before or during super-infection.
Main Results:
- CLP-induced immunoparalysis increased lethality following Salmonella or Listeria super-infection, with higher bacterial loads in spleen and liver.
- TNF administration protected against Salmonella but exacerbated mortality in Listeria infections.
- The effects of TNF substitution were dependent on administration timing, location, and the type of super-infecting pathogen.
Conclusions:
- Impaired TNF production contributes to sepsis-induced immunoparalysis and heightened susceptibility to secondary infections.
- TNF substitution therapy during sepsis-induced immunoparalysis can be beneficial or detrimental, necessitating precise diagnostic parameters for safe application.
- The findings underscore the complex role of TNF in sepsis and secondary infections, emphasizing the need for tailored therapeutic strategies.
