ArticleCommunications biology2026
Macrophage-derived MBL restrains coronavirus-induced pulmonary inflammation by modulating metabolic regulator PKM2-mediated NLRP3 activation.
Article in Communications biology, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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13 authors.
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Abstract
The precise mechanisms governing innate immune response to coronaviruses remain elusive. Our study reveals that mannose-binding lectin (MBL), a key pattern recognition molecule, exhibits significant upregulation in PBMCs from COVID-19 patients, with expression levels positively correlating with clinical severity. Through intranasal coronavirus MHV-A59 challenge in MBL-deficient mice, we demonstrate that macrophage-derived MBL attenuates viral pneumonia by limiting NLRP3 inflammasome hyperactivation. Mechanistically, MBL directly binds pyruvate kinase M2 (PKM2), an interaction significantly enhanced upon viral stimulation. Crucially, MBL competitively inhibits O-GlcNAcylation at PKM2 Thr405/Ser406 residues, thereby disrupting PKM2 tetramer-to-dimer transition and its subsequent nuclear translocation. The MBL-mediated metabolic reprogramming effectively dampens NLRP3 inflammasome activation, with wild-type mice exhibiting markedly reduced caspase-1 cleavage and IL-1β maturation relative to MBL-deficient mice following MHV-A59 infection. Genetic ablation of NLRP3 abolished the differential susceptibility between wild-type and MBL-deficient animals, confirming NLRP3 as the critical downstream effector. Pharmacological inhibition of either PKM2 or NLRP3 restored cytokine homeostasis in virus-infected MBL-deficient mice. These findings establish a previously unrecognized regulatory pathway in which macrophage-specific MBL fine-tunes antiviral immunity through the PKM2-NLRP3 axis. Our work provides crucial insights into the sophisticated interplay between innate immunity and cellular metabolism, laying the groundwork for developing host-directed therapies against coronaviruses.
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