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Inherently Reduced Expression of ASC Restricts Caspase-1 Processing in Hepatocytes and Promotes Plasmodium Infection
Camila Marques-da-Silva1,2, Clyde Schmidt-Silva1,2, Rodrigo P Baptista2
1Department of Cellular Biology, University of Georgia, Athens, GA.
Abstract:
Inflammasome-mediated caspase-1 activation facilitates innate immune control of Plasmodium in the liver, thereby limiting the incidence and severity of clinical malaria. However, caspase-1 processing occurs incompletely in both mouse and human hepatocytes and precludes the generation of mature IL-1β or IL-18, unlike in other cells. Why this is so or how it impacts Plasmodium control in the liver has remained unknown. We show that an inherently reduced expression of the inflammasome adaptor molecule apoptosis-associated specklike protein containing CARD (ASC) is responsible for the incomplete proteolytic processing of caspase-1 in murine hepatocytes. Transgenically enhancing ASC expression in hepatocytes enabled complete caspase-1 processing, enhanced pyroptotic cell death, maturation of the proinflammatory cytokines IL-1β and IL-18 that was otherwise absent, and better overall control of Plasmodium infection in the liver of mice. This, however, impeded the protection offered by live attenuated antimalarial vaccination. Tempering ASC expression in mouse macrophages, on the other hand, resulted in incomplete processing of caspase-1. Our work shows how caspase-1 activation and function in host cells are fundamentally defined by ASC expression and offers a potential new pathway to create better disease and vaccination outcomes by modifying the latter.
Insights
Reduced apoptosis-associated specklike protein containing CARD (ASC) expression limits caspase-1 activation in liver cells, hindering malaria control. Increasing ASC enhances inflammasome activity and parasite clearance but impacts vaccine efficacy.
Area of Science:
- Immunology
- Infectious Diseases
- Cell Biology
Background:
- Inflammasome-mediated caspase-1 activation is crucial for innate immunity against Plasmodium, the parasite causing malaria.
- Hepatocyte caspase-1 processing is incomplete, preventing mature IL-1β/IL-18 production and limiting malaria control.
- The reasons for incomplete caspase-1 processing in hepatocytes and its impact on malaria remain unclear.
Purpose of the Study:
- To investigate the role of apoptosis-associated specklike protein containing CARD (ASC) in regulating caspase-1 activation within hepatocytes.
- To determine the impact of ASC expression levels on inflammasome activity, cytokine maturation, and Plasmodium liver-stage infection.
- To explore the consequences of modulating ASC expression on both disease control and vaccine-induced immunity.
Main Methods:
- Analysis of caspase-1 processing in murine hepatocytes with varying ASC expression levels.
- Genetic manipulation of ASC expression in hepatocytes and macrophages.
- Assessment of Plasmodium infection, pyroptosis, and cytokine maturation (IL-1β, IL-18) in vivo.
- Evaluation of live attenuated antimalarial vaccine efficacy in mice with altered hepatocyte ASC levels.
Main Results:
- Inherently low ASC expression in hepatocytes causes incomplete caspase-1 processing.
- Enhanced hepatocyte ASC expression leads to complete caspase-1 activation, pyroptosis, IL-1β/IL-18 maturation, and improved Plasmodium control.
- Increased ASC in hepatocytes diminishes the protective effect of live attenuated antimalarial vaccination.
- Reduced ASC expression in macrophages results in incomplete caspase-1 processing.
Conclusions:
- ASC expression levels fundamentally dictate caspase-1 activation and function in host cells.
- Modulating ASC expression offers a potential strategy for improving malaria control and vaccine outcomes.
- Understanding ASC-dependent inflammasome regulation in hepatocytes is key for developing novel therapeutic interventions.
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