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A Reproducible Intensive Care Unit-Oriented Endotoxin Model in Rats
Published on: February 20, 2021
Systemic cytokine response in moribund mice of streptococcal toxic shock syndrome model
Mitsumasa Saito1, Hideko Kajiwara, Ken-ichiro Iida
1Molecular Structure & Function Program, Research Institute, The Hospital for Sick Children, 555 University Ave., Toronto, Ontario, Canada.
Abstract:
Streptococcus pyogenes causes severe invasive disease in humans, including streptococcal toxic shock syndrome (STSS). We previously reported a mouse model that is similar to human STSS. When mice were infected intramuscularly with 10(7) CFU of S. pyogenes, all of them survived acute phase of infection. After 20 or more days of infection, a number of them died suddenly accompanied by S. pyogenes bacteremia. We call this phenomenon "delayed death". We analyzed the serum cytokine levels of mice with delayed death, and compared them with those of mice who died in the acute phase of intravenous S. pyogenes infection. The serum levels of TNF-α and IFN-γ in mice of delayed death were more than 100 times higher than those in acute death mice. IL-10 and IL-12, which were not detected in acute death, were also significantly higher in mice of delayed death. IL-6 and MCP-1 (CCL-2) were elevated in both groups of mice. It was noteworthy that not only pro-inflammatory cytokines but also anti-inflammatory cytokines were elevated in delayed death. We also found that intravenous TNF-α injection accelerated delayed death, suggesting that an increase of serum TNF-α induced S. pyogenes bacteremia in our mouse model.
Insights
Streptococcus pyogenes infection can cause delayed death in mice, characterized by high levels of both pro-inflammatory and anti-inflammatory cytokines. Elevated TNF-α may accelerate this process, offering insights into severe streptococcal disease.
Area of Science:
- Microbiology
- Immunology
- Pathogenesis
Background:
- Streptococcus pyogenes is a significant human pathogen causing invasive diseases like streptococcal toxic shock syndrome (STSS).
- A previously established mouse model mimics human STSS, exhibiting delayed mortality after intramuscular infection.
Purpose of the Study:
- To investigate the cytokine profiles associated with delayed death in a Streptococcus pyogenes mouse model.
- To compare these profiles with those observed in acute death from S. pyogenes infection.
Main Methods:
- Intramuscular infection of mice with S. pyogenes (10^7 CFU).
- Monitoring survival and onset of delayed death (after 20 days).
- Serum cytokine analysis (TNF-α, IFN-γ, IL-10, IL-12, IL-6, MCP-1) in delayed death and acute death groups.
- Intravenous TNF-α injection to assess its effect on delayed death.
Main Results:
- Delayed death mice exhibited significantly higher serum levels of TNF-α and IFN-γ (>100x) compared to acute death mice.
- Anti-inflammatory cytokines IL-10 and IL-12 were elevated in delayed death but not detected in acute death.
- Both pro-inflammatory (IL-6, MCP-1) and anti-inflammatory cytokines were elevated in delayed death.
- Intravenous TNF-α administration accelerated the onset of delayed death.
Conclusions:
- Delayed death in this S. pyogenes model is associated with a complex cytokine storm involving both pro- and anti-inflammatory mediators.
- Elevated serum TNF-α appears to play a crucial role in accelerating S. pyogenes bacteremia and subsequent delayed mortality.
