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A Mouse Model to Assess Innate Immune Response to Staphylococcus aureus Infection
Published on: February 28, 2019
Enhancement of neutrophil function by interleukin-18 therapy protects burn-injured mice from methicillin-resistant
Manabu Kinoshita1, Hiromi Miyazaki, Satoshi Ono
1Department of Microbiology, National Defense Medical College, Namiki 3-2, Tokorozawa 359-8513, Japan.
Abstract:
Methicillin-resistant Staphylococcus aureus (MRSA) infection is a grave concern in burn-injured patients. We investigated the efficacy of interleukin-18 (IL-18) treatment in postburn MRSA infection. Alternate-day injections of IL-18 into burn-injured C57BL/6 mice significantly increased their survival after MRSA infection and after methicillin-sensitive S. aureus infection. Although IL-18 treatment of burn-injured mice augmented natural IgM production before MRSA infection and gamma interferon (IFN-γ) production after MRSA infection, neither IgM nor IFN-γ significantly contributed to the improvement in mouse survival. IL-18 treatment increased/restored the serum tumor necrosis factor (TNF), IL-17, IL-23, granulocyte colony-stimulating factor (G-CSF), and macrophage inflammatory protein (MIP-2) levels, as well as the neutrophil count, after MRSA infection of burn-injured mice; it also improved impaired neutrophil functions, phagocytic activity, production of reactive oxygen species, and MRSA-killing activity. However, IL-18 treatment was ineffective against MRSA infection in both burn- and sham-injured neutropenic mice. Enhancement of neutrophil functions by IL-18 was also observed in vitro. Furthermore, when neutrophils from IL-18-treated burn-injured mice were adoptively transferred into nontreated burn-injured mice 2 days after MRSA challenge, survival of the recipient mice increased. NOD-SCID mice that have functionally intact neutrophils and macrophages (but not T, B, or NK cells) were substantially resistant to MRSA infection. IL-18 treatment increased the survival of NOD-SCID mice after burn injury and MRSA infection. An adoptive transfer of neutrophils using NOD-SCID mice also showed a beneficial effect of IL-18-activated neutrophils, similar to that seen in C57BL/6 mice. Thus, although neutrophil functions were impaired in burn-injured mice, IL-18 therapy markedly activated neutrophil functions, thereby increasing survival from postburn MRSA infection.
Insights
Interleukin-18 (IL-18) therapy boosts survival in burn-injured mice with Methicillin-resistant Staphylococcus aureus (MRSA) infection by enhancing neutrophil function. This treatment shows promise for combating post-burn MRSA infections.
Area of Science:
- Immunology
- Infectious Diseases
- Wound Healing
Background:
- Methicillin-resistant Staphylococcus aureus (MRSA) poses a significant threat to burn-injured patients.
- Burn injury often impairs the immune system, increasing susceptibility to infections like MRSA.
- Effective therapeutic strategies are needed to combat post-burn MRSA infections.
Purpose of the Study:
- To investigate the efficacy of interleukin-18 (IL-18) treatment in a murine model of post-burn MRSA infection.
- To elucidate the mechanisms by which IL-18 influences the immune response and survival in this context.
Main Methods:
- Burn-injured C57BL/6 mice were treated with alternate-day injections of IL-18.
- Survival rates, immune mediator levels (TNF, IL-17, IL-23, G-CSF, MIP-2), and neutrophil counts and functions were assessed.
- Experiments included neutropenic mice and adoptive transfer of neutrophils to confirm the role of neutrophils.
Main Results:
- IL-18 treatment significantly increased survival in burn-injured mice infected with MRSA or methicillin-sensitive S. aureus.
- IL-18 enhanced neutrophil count, serum cytokine levels, and improved neutrophil phagocytic and killing activities.
- The therapeutic effect of IL-18 was dependent on functional neutrophils, as demonstrated in neutropenic and adoptive transfer models.
Conclusions:
- IL-18 therapy effectively improves survival from post-burn MRSA infection by activating neutrophil functions.
- Neutrophil activation by IL-18 is a key mechanism underlying its protective effects in burn-injured hosts.
- IL-18 represents a potential therapeutic agent for managing severe bacterial infections in burn patients.
