Related Experiment Video
Updated: Aug 6, 2026
A Reproducible Intensive Care Unit-Oriented Endotoxin Model in Rats
Published on: February 20, 2021
Activation of common antiviral pathways can potentiate inflammatory responses to septic shock
Lesley A Doughty1, Stacey Carlton, Benjamin Galen
1Department of Pediatrics and Surgery, Rhode Island Hospital, Providence, RI, USA.
Abstract:
Induction of the antiviral cytokine interferon alpha/beta (IFN-alpha/beta) is common in many viral infections. The impact of ongoing antiviral responses on subsequent bacterial infection is not well understood. In human disease, bacterial superinfection complicating a viral infection can result in significant morbidity and mortality. We injected mice with polyinosinic-polycytidylic (PIC) acid, a TLR3 ligand and known IFN-alpha/beta inducer as well as nuclear factor kappaB (NF-kappaB) activator to simulate very early antiviral pathways. We then challenged mice with an in vivo septic shock model characterized by slowly evolving bacterial infection to simulate bacterial superinfection early during a viral infection. Our data demonstrated robust induction of IFN-alpha in serum within 24 h of PIC injection with IFN-alpha/beta-dependent major histocompatibility antigen class II up-regulation on peritoneal macrophages. PIC pretreatment before septic shock resulted in augmented tumor necrosis factor alpha and interleukins 6 and 10 and heightened lethality compared with septic shock alone. Intact IFN-alpha/beta signaling was necessary for augmentation of the inflammatory response to in vivo septic shock and to both TLR2 and TLR4 agonists in vitro. To assess the NF-kappaB contribution to PIC-modulated inflammatory responses to septic shock, we treated with parthenolide, an NF-kappaB inhibitor before PIC and septic shock. Parthenolide did not inhibit IFN-alpha induction by PIC. Inhibition of NF-kappaB by parthenolide did reduce IFN-alpha-mediated potentiation of the cytokine response and lethality from septic shock. Our data demonstrate that pathways activated early during many viral infections can have a detrimental impact on the outcome of subsequent bacterial infection. These pathways may be critical to understanding the heightened morbidity and mortality from bacterial superinfection after viral infection in human disease.
Insights
Early viral responses, including interferon alpha/beta (IFN-alpha/beta) induction, can worsen subsequent bacterial infections. This interferon signaling amplifies inflammation and increases mortality in mice, highlighting a critical factor in human disease.
Area of Science:
- Immunology
- Infectious Diseases
- Molecular Biology
Background:
- Viral infections often trigger antiviral cytokine responses, such as interferon alpha/beta (IFN-alpha/beta) induction.
- The consequences of these innate antiviral pathways on subsequent bacterial superinfections are not fully understood.
- Bacterial superinfections following viral illnesses contribute significantly to morbidity and mortality in human disease.
Purpose of the Study:
- To investigate the impact of early antiviral responses on the outcome of subsequent bacterial infection.
- To elucidate the roles of interferon alpha/beta (IFN-alpha/beta) signaling and nuclear factor kappaB (NF-kappaB) activation in modulating inflammatory responses during bacterial superinfection.
Main Methods:
- Mice were pretreated with polyinosinic-polycytidylic (PIC) acid, a TLR3 ligand, to mimic early viral infection pathways.
- PIC-treated mice were subsequently challenged with an in vivo septic shock model to simulate bacterial superinfection.
- NF-kappaB inhibition was achieved using parthenolide to assess its contribution to PIC-mediated effects.
Main Results:
- PIC administration robustly induced IFN-alpha and upregulated MHC class II on macrophages, dependent on IFN-alpha/beta signaling.
- PIC pretreatment significantly augmented pro-inflammatory cytokines (TNF-alpha, IL-6, IL-10) and lethality in the septic shock model.
- IFN-alpha/beta signaling was essential for the potentiation of inflammatory responses to bacterial challenge, while NF-kappaB inhibition partially reduced this potentiation and lethality.
Conclusions:
- Early activation of antiviral pathways, particularly IFN-alpha/beta signaling, can exacerbate the inflammatory response and worsen outcomes of subsequent bacterial infections.
- These findings suggest that innate immune responses initiated during viral infections can have detrimental effects on the host's ability to combat secondary bacterial pathogens.
- Understanding these immunomodulatory effects is crucial for addressing the high morbidity and mortality associated with bacterial superinfections in clinical settings.
Related Concept Videos
01:25Acute Inflammation III: Local and Systemic Effects
01:29Immune Response Against Viral Pathogens
NK Cells
NK cells are a crucial part of our innate immune system, acting as the first line of defense against viral infections. These cells can recognize and kill infected cells without prior exposure to the virus, effectively slowing down the spread of infection. Additionally, NK cells produce proinflammatory...
01:30Inflammatory Response I: Vascular and Cellular
01:26Bacterial Meningitis II: Pathophysiology
01:30Inhibitors of Viral Protein Synthesis
01:28Inflammatory Response
Inflammation can be triggered by various stimuli, such as impact, abrasion, chemical irritation, infections, and extreme hot or cold temperatures. These can damage cells and connective tissue fibers,...