SARS-CoV-2 variant-dependent inflammasome activation

Teyssou, Elisa; Marot, Stéphane; Gothland, Adélie; Malet, Isabelle; Zafilaza, Karen; Leducq, Valentin; Cocherie, Théophile; Todesco, Eve; Soulié, Cathia; Marcelin, Anne Geneviève; Cálvez, Vincent

doi:10.1016/j.jinf.2023.04.005

Cited by 2 publications

(1 citation statement)

References 8 publications

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“…In contrast to the blunting of IFN-I/III pathways, SARS-CoV-2 viral factors trigger a pro-inflammatory program through the activation of inflammasomes 19,20,22,58 , particularly the NLRP3 inflammasome 58,59 . The unbridled activation of this pathway may underlie the multi-organ immunopathology caused by the most pathogenic variants of this virus, leading to severe disease and death 60,61 , a mechanism shared with other highly pathogenic viruses 62 . SARS-CoV-2 structural (S, N, E), non-structural (nsp1, nsp6, nsp13) and accessory (ORF3a, ORF8) proteins have been shown to affect the activation state of the NLRP3 inflammasome to various degrees and through diverse mechanisms 63 .…”

Section: Discussionmentioning

confidence: 99%

Induction of the inflammasome by the SARS-CoV-2 accessory protein ORF9b, abrogated by small-molecule ORF9b homodimerization inhibitors

Zodda,

Pons,

DeMoya-Valenzuela

et al. 2024

Preprint

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Viral accessory proteins play critical roles in viral escape form host innate immune responses and in viral inflammatory pathogenesis. Here we show that the SARS-CoV-2 accessory protein, ORF9b, but not other SARS-CoV-2 accessory proteins (ORF3a, ORF3b, ORF6, ORF7, ORF8, ORF9c, ORF10), strongly activates inflammasome-dependent caspase-1 in A549 lung carcinoma cells and THP-1 monocyte-macrophage cells. Exposure to lipopolysaccharide (LPS) and ATP additively enhanced the activation of caspase-1 by ORF9b, suggesting that ORF9b and LPS follow parallel pathways in the activation of the inflammasome and caspase-1. Following rationalin silicoapproaches, we have designed small molecules capable of inhibiting the homodimerization of ORF9b, which experimentally inhibited ORF9b-ORF9b homotypic interactions, caused mitochondrial eviction of ORF9b, inhibited ORF9b-induced activation of caspase-1 in A549 and THP-1 cells, cytokine release in THP-1 cells, and restored type I interferon (IFN-I) signaling suppressed by ORF9b in both cell models. These small molecules are first-in-class compounds targeting a viral accessory protein critical for viral-induced exacerbated inflammation and escape from innate immune responses, with the potential of mitigating the severe immunopathogenic damage induced by highly pathogenic coronaviruses and restoring antiviral innate immune responses curtailed by viral infection.

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