How Inflammasomes Shape the Ability of Astrocytes to Control Infection

The team infected primary mouse astrocytes with SARS-CoV-2 and Zika virus: both viruses could invade, replicate, and induce caspase-1 activation, but only SARS-CoV-2 triggered the canonical NLRP3 inflammasome (ASC specks, IL-1β secretion), dependent on viral N and S proteins.；Clearance of SARS-CoV-2 depends on NLRP3/caspase-1; loss of these raises viral load, and exogenous IL-1β can rescue it; gasdermin loss has no effect (no LDH release, no pyroptosis), suggesting IL-1β inhibits replication via the IL-1 receptor.；Zika virus does not elicit a canonical inflammasome in astrocytes (no IL-1β, no LDH), yet caspase-1 loss still raises viral load; the mechanism is caspase-1 regulation of glycolysis—knockout cells show elevated lactate secretion, extracellular acidification rate (ECAR), and hexokinase expression, and inhibition of hexokinase with 2-DG reduces viral load.；Metabolic analyses show caspase-1 acts via an mTOR–hexokinase–pyruvate axis: both rapamycin and mitochondrial pyruvate carrier (MPC) inhibition reduce Zika load, and exogenous pyruvate boosts replication only in wild-type, not caspase-1-deficient, cells.；NLRC4 loss does not affect control of SARS-CoV-2 in astrocytes; the team concludes that inflammasomes enhance astrocyte-intrinsic antiviral capacity via two effector mechanisms—canonical (IL-1β) and non-canonical (metabolic reprogramming) (pathways and clinical significance remain to be verified).

• The team infected primary mouse astrocytes with SARS-CoV-2 and Zika virus: both viruses could invade, replicate, and induce caspase-1 activation, but only SARS-CoV-2 triggered the canonical NLRP3 inflammasome (ASC specks, IL-1β secretion), dependent on viral N and S proteins.
• Clearance of SARS-CoV-2 depends on NLRP3/caspase-1; loss of these raises viral load, and exogenous IL-1β can rescue it; gasdermin loss has no effect (no LDH release, no pyroptosis), suggesting IL-1β inhibits replication via the IL-1 receptor.
• Zika virus does not elicit a canonical inflammasome in astrocytes (no IL-1β, no LDH), yet caspase-1 loss still raises viral load; the mechanism is caspase-1 regulation of glycolysis—knockout cells show elevated lactate secretion, extracellular acidification rate (ECAR), and hexokinase expression, and inhibition of hexokinase with 2-DG reduces viral load.
• Metabolic analyses show caspase-1 acts via an mTOR–hexokinase–pyruvate axis: both rapamycin and mitochondrial pyruvate carrier (MPC) inhibition reduce Zika load, and exogenous pyruvate boosts replication only in wild-type, not caspase-1-deficient, cells.
• NLRC4 loss does not affect control of SARS-CoV-2 in astrocytes; the team concludes that inflammasomes enhance astrocyte-intrinsic antiviral capacity via two effector mechanisms—canonical (IL-1β) and non-canonical (metabolic reprogramming) (pathways and clinical significance remain to be verified).