CV19: CALMING THE CYTOKINE STORM WITH PROTEASOME-TARGETING IMMUNOMODULATORS

Cytokine storm or macrophage activation syndrome (MAS; (1)) leads to secondary haemophagocytic lymphohistiocytosis (sHLH) and a deadly sepsis-like multi-organ failure in severe viral infections (2.3). including COVID-19 (4.5). Currently there are no established safe and effective therapies against MAS (5.6). It is accepted that an improper interplay between pro- inflammatory (M1) and anti-inflammatory (M2) macrophages (7) is. in part. responsible for MAS. M1s are activated early during infection and secrete the ???storm??? of cytokines leading to hyper inflammation (8). Then. excessive hemophagocytic actions of M2s terminally damage organs (7???9) instead of mitigating the inflammation. We found that a group of novel agents: allosteric regulators of proteasome activity specifically restrict viability and inter-cellular interactions of M2-polarized macrophages. Such anti-M2 actions may limit MAS and bring a balance to innate response. Proteasome. a novel target for anti-viral drugs. is a hub of intracellular protein catabolism regulating multiple pathways including the immune response (10). Allosteric regulation of the proteasome benefits from the high specificity. low toxicity. and negligible side effects. To the contrary. corticosteroids destroy the overall COVID-19 patients??? immune response with no proven efficacy (11) whereas ruxolitinib (12.13). now in clinical trials. may have limited use due to its strong immunosuppressive side effects. We propose that a targeted anti-M2 immunomodulatory intervention via the proteasome pathway will provide a safe and productive relief to sHLH in MAS.