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Updated: Feb 12, 2026
Development and Assessment of Intracellular Infection Models for Staphylococcus aureus
Published on: January 17, 2025
The inflammasome potentiates influenza/Staphylococcus aureus superinfection in mice
Keven M Robinson1, Krishnaveni Ramanan1, Michelle E Clay2
1Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
Abstract:
Secondary bacterial respiratory infections are commonly associated with both acute and chronic lung injury. Influenza complicated by bacterial pneumonia is an effective model to study host defense during pulmonary superinfection due to its clinical relevance. Multiprotein inflammasomes are responsible for IL-1β production in response to infection and drive tissue inflammation. In this study, we examined the role of the inflammasome during viral/bacterial superinfection. We demonstrate that ASC-/- mice are protected from bacterial superinfection and produce sufficient quantities of IL-1β through an apoptosis-associated speck-like protein containing CARD (ASC) inflammasome-independent mechanism. Despite the production of IL-1β by ASC-/- mice in response to bacterial superinfection, these mice display decreased lung inflammation. A neutrophil elastase inhibitor blocked ASC inflammasome-independent production of IL-1β and the IL-1 receptor antagonist, anakinra, confirmed that IL-1 remains crucial to the clearance of bacteria during superinfection. Delayed inhibition of NLRP3 during influenza infection by MCC950 decreases bacterial burden during superinfection and leads to decreased inflammatory cytokine production. Collectively, our results demonstrate that ASC augments the clearance of bacteria, but can also contribute to inflammation and mortality. ASC should be considered as a therapeutic target to decrease morbidity and mortality during bacterial superinfection.
Insights
The inflammasome protein ASC aids bacterial clearance but also causes lung inflammation and death during superinfections. Inhibiting ASC may reduce illness and fatalities in these critical conditions.
Area of Science:
- Immunology
- Pulmonary Medicine
- Microbiology
Background:
- Secondary bacterial respiratory infections frequently complicate acute and chronic lung injuries.
- Influenza and bacterial pneumonia serve as a clinically relevant model for studying host defense during pulmonary superinfections.
- Multiprotein inflammasomes orchestrate IL-1β production and drive inflammation in response to infection.
Purpose of the Study:
- To investigate the inflammasome's role in viral/bacterial superinfection.
- To evaluate the impact of ASC inflammasome on host defense and inflammation during superinfection.
Main Methods:
- Utilized ASC knockout (ASC-/-) mice to assess inflammasome-independent mechanisms.
- Employed a neutrophil elastase inhibitor and anakinra (IL-1 receptor antagonist) to probe IL-1β pathways.
- Administered MCC950 to inhibit NLRP3 inflammasome during influenza infection.
Main Results:
- ASC-/- mice showed protection against bacterial superinfection with reduced lung inflammation.
- IL-1β production was observed via an ASC inflammasome-independent pathway in knockout mice.
- Neutrophil elastase inhibition blocked this ASC-independent IL-1β production, while anakinra confirmed IL-1's necessity for bacterial clearance.
- Delayed NLRP3 inhibition reduced bacterial load and inflammatory cytokines during superinfection.
Conclusions:
- ASC enhances bacterial clearance but also contributes to inflammation and mortality during superinfections.
- Targeting ASC presents a potential therapeutic strategy to mitigate morbidity and mortality associated with bacterial superinfections.
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